Pharmaceutics

13 pages, 1924 KB

Open AccessEditor’s ChoiceArticle

Synthesis of Gelatin Methacryloyl Analogs and Their Use in the Fabrication of pH-Responsive Microspheres

by Karolina Valente, Geneviève N. Boice, Cameron Polglase, Roman G. Belli, Elaina Bourque, Afzal Suleman and Alexandre Brolo

Pharmaceutics 2024, 16(8), 1016; https://doi.org/10.3390/pharmaceutics16081016 - 31 Jul 2024

Cited by 6 | Viewed by 3594

Abstract

pH-responsive hydrogels have numerous applications in tissue engineering, drug delivery systems, and diagnostics. Gelatin methacryloyl (GelMA) is a biocompatible, semi-synthetic polymer prepared from gelatin. When combined with aqueous solvents, GelMA forms hydrogels that have extensive applications in biomedical engineering. GelMA can be produced [...] Read more.

pH-responsive hydrogels have numerous applications in tissue engineering, drug delivery systems, and diagnostics. Gelatin methacryloyl (GelMA) is a biocompatible, semi-synthetic polymer prepared from gelatin. When combined with aqueous solvents, GelMA forms hydrogels that have extensive applications in biomedical engineering. GelMA can be produced with different degrees of methacryloyl substitution; however, the synthesis of this polymer has not been tuned towards producing selectively modified materials for single-component pH-responsive hydrogels. In this work, we have explored two different synthetic routes targeting different gelatin functional groups (amine, hydroxyl, and/or carboxyl) to produce two GelMA analogs: gelatin A methacryloyl glycerylester (polymer A) and gelatin B methacrylamide (polymer B). Polymers A and B were used to fabricate pH-responsive hydrogel microspheres in a flow-focusing microfluidic device. At neutral pH, polymer A and B microspheres displayed an average diameter of ~40 µm. At pH 6, microspheres from polymer A showed a swelling ratio of 159.1 ± 11.5%, while at pH 10, a 288.6 ± 11.6% swelling ratio was recorded for polymer B particles. Full article

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19 pages, 8754 KB

Open AccessEditor’s ChoiceArticle

Unraveling Novel Strategies in Mesothelioma Treatments Using a Newly Synthetized Platinum(IV) Compound

by Cristina Favaron, Ludovica Gaiaschi, Claudio Casali, Fabrizio De Luca, Federica Gola, Margherita Cavallo, Valeria Ramundo, Elisabetta Aldieri, Gloria Milanesi, Silvia Damiana Visonà, Mauro Ravera and Maria Grazia Bottone

Pharmaceutics 2024, 16(8), 1015; https://doi.org/10.3390/pharmaceutics16081015 - 31 Jul 2024

Cited by 2 | Viewed by 2052

Abstract

Malignant mesothelioma is a rare tumor associated with asbestos exposure. Mesothelioma carcinogenesis is related to enhanced reactive oxygen species (ROS) production and iron overload. Despite the recent advances in biomedical sciences, to date the only available treatments include surgery in a small fraction [...] Read more.

Malignant mesothelioma is a rare tumor associated with asbestos exposure. Mesothelioma carcinogenesis is related to enhanced reactive oxygen species (ROS) production and iron overload. Despite the recent advances in biomedical sciences, to date the only available treatments include surgery in a small fraction of patients and platinum-based chemotherapy in combination with pemetrexed. In this view, the purpose of this study was to evaluate the therapeutic potential of the newly synthetized platinum prodrug Pt(IV)Ac-POA compared to cisplatin (CDDP) on human biphasic mesothelioma cell line MSTO-211H using different complementary techniques, such as flow-cytometry, transmission electron microscopy (TEM), and immunocytochemistry. Healthy mesothelial cell lines Met-5A were also employed to assess the cytotoxicity of the above-mentioned compounds. Our in vitro results showed that Pt(IV)Ac-POA significantly interfere with iron metabolisms and more importantly is able to trigger cell death, through different pathways, including ferroptosis, necroptosis, and apoptosis, in neoplastic cells. On the other hand, CDDP triggers mainly apoptotic and necrotic cell death. In conclusion, Pt(IV)Ac-POA may represent a new promising pharmacological agent in the treatment of malignant mesothelioma. Full article

(This article belongs to the Special Issue The State-of-the-art in Improving the Antitumor Efficacy of Platinum Drugs)

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15 pages, 5014 KB

Open AccessEditor’s ChoiceArticle

A Stereolithography-Based Modified Spin-Casting Method for Faster Laboratory-Scale Production of Dexamethasone-Containing Dissolving Microneedle Arrays

by Martin Cseh, Gábor Katona, Szilvia Berkó, Mária Budai-Szűcs and Ildikó Csóka

Pharmaceutics 2024, 16(8), 1005; https://doi.org/10.3390/pharmaceutics16081005 - 29 Jul 2024

Viewed by 1798

Abstract

Microneedle arrays (MNAs) consist of a few dozens of submillimeter needles, which tend to penetrate through the stratum corneum layer of the skin and deliver hardly penetrating drugs to the systemic circulation. The application of this smart dosage form shows several advantages, such [...] Read more.

Microneedle arrays (MNAs) consist of a few dozens of submillimeter needles, which tend to penetrate through the stratum corneum layer of the skin and deliver hardly penetrating drugs to the systemic circulation. The application of this smart dosage form shows several advantages, such as simple use and negligible pain caused by needle punctures compared to conventional subcutaneous injections. Dissolving MNAs (DMNAs) represent a promising form of cutaneous drug delivery due to their high drug content, biocompatibility, and ease of use. Although different technologies are suitable to produce microneedle arrays (e.g., micromilling, chemical etching, laser ablation etc.), many of these are expensive or hardly accessible. Following the exponential growth of the 3D-printing industry in the last decade, high-resolution desktop printers became accessible for researchers to easily and cost-effectively design and produce microstructures, including MNAs. In this work, a low force stereolithography (LFS) 3D-printer was used to develop the dimensionally correct MNA masters for the spin-casting method. The present study aimed to develop and characterize drug-loaded DMNAs using a two-level, full factorial design for three factors focusing on the optimization of DMNA production and adequate drug content. For the preparation of DMNAs, carboxymethylcellulose and trehalose were used in certain amounts as matrices for dexamethasone sodium phosphate (DEX). Investigation of the produced DexDMNAs included mechanical analysis via texture analyzer and optical microscopy, determination of drug content and distribution with HPLC and Raman microscopy, dissolution studies via HPLC, and ex vivo qualitative permeation studies by Raman mapping. It can be concluded that a DEX-containing, mechanically stable, biodegradable DexDMNA system was successfully developed in two dosage strengths, of which both efficiently delivered the drug to the lower layers (dermis) of human skin. Moreover, the ex vivo skin penetration results support that the application of DMNAs for cutaneous drug delivery can be more effective than that of a conventional dermal gel. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of 3D Printing)

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20 pages, 7014 KB

Open AccessEditor’s ChoiceArticle

Amorphous Polymer–Phospholipid Solid Dispersions for the Co-Delivery of Curcumin and Piperine Prepared via Hot-Melt Extrusion

by Kamil Wdowiak, Andrzej Miklaszewski and Judyta Cielecka-Piontek

Pharmaceutics 2024, 16(8), 999; https://doi.org/10.3390/pharmaceutics16080999 - 28 Jul 2024

Cited by 8 | Viewed by 3432

Abstract

Curcumin and piperine are plant compounds known for their health-promoting properties, but their use in the prevention or treatment of various diseases is limited by their poor solubility. To overcome this drawback, the curcumin–piperine amorphous polymer–phospholipid dispersions were prepared by hot melt extrusion [...] Read more.

Curcumin and piperine are plant compounds known for their health-promoting properties, but their use in the prevention or treatment of various diseases is limited by their poor solubility. To overcome this drawback, the curcumin–piperine amorphous polymer–phospholipid dispersions were prepared by hot melt extrusion technology. X-ray powder diffraction indicated the formation of amorphous systems. Differential scanning calorimetry confirmed amorphization and provided information on the good miscibility of the active compound–polymer–phospholipid dispersions. Owing to Fourier-transform infrared spectroscopy, the intermolecular interactions in systems were investigated. In the biopharmaceutical properties assessment, the improvement in solubility as well as the maintenance of the supersaturation state were confirmed. Moreover, PAMPA models simulating the gastrointestinal tract and blood-brain barrier showed enhanced permeability of active compounds presented in dispersions compared to the crystalline form of individual compounds. The presented paper suggests that polymer–phospholipid dispersions advantageously impact the bioaccessibility of poorly soluble active compounds. Full article

(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery)

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12 pages, 2398 KB

Open AccessEditor’s ChoiceArticle

Mesoporous Silica-Based Membranes in Transdermal Drug Delivery: The Role of Drug Loss in the Skin

by Frank Baumann, Theresa Paul, Susann Ossmann, Dirk Enke and Achim Aigner

Pharmaceutics 2024, 16(8), 995; https://doi.org/10.3390/pharmaceutics16080995 - 26 Jul 2024

Cited by 3 | Viewed by 1613

Abstract

Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance [...] Read more.

Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance due to their non-invasive means of application and others. Mesoporous silica membranes are of particular interest in this regard, due to their chemical stability and their tunable porous system, with adjustable pore sizes, pore volumes and surface chemistries. While this allows for fine-tuning and, thus, the development of optimized TDDSs with high loading capacities and the desired release profile of a given drug, its systemic availability also relies on skin penetration. In this paper, using a TDDS based on mesoporous silica membranes in Franz cell experiments on porcine skin, we demonstrate surprisingly substantial drug loss during skin penetration. Drug passage through porcine skin was found to be dependent on the age and pre-treatment of the skin. pH and temperature were major determinants of drug recovery rates as well, indicating drug loss in the skin by enzymatic metabolization. Regarding the TDDS, higher loading obtained by SO₃H surface modification of the mesoporous silica membranes reduced drug loss. Still, high loss rates in the skin were determined for different drugs, including anastrozole, xylazine and imiquimod. We conclude that, beyond the fine-tuned drug release profiles from the mesoporous silica membrane TDDS, remarkably high drug loss in the skin is a major issue for achieving desired skin penetration and, thus, the systemic availability of drugs. This also poses critical requirements for defining an optimal TDDS based on mesoporous silica membranes. Full article

(This article belongs to the Special Issue Mesoporous Silica-Based Materials in Drug Delivery and Controlled Release)

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21 pages, 3365 KB

Open AccessEditor’s ChoiceArticle

Development of Proniosome Gel Formulation for CHIKV Infection

by Ayça Altay Benetti, Ma Thinzar Thwin, Ahmad Suhaimi, Ryan Sia Tze Liang, Lisa Fong-Poh Ng, Fok-Moon Lum and Camillo Benetti

Pharmaceutics 2024, 16(8), 994; https://doi.org/10.3390/pharmaceutics16080994 - 26 Jul 2024

Cited by 4 | Viewed by 2100

Abstract

Given the increasing aging population and the rising prevalence of musculoskeletal diseases due to obesity and injury, urgent research is needed to formulate new treatment alternatives, as current options remain inadequate. Viruses can exacerbate arthritis and worsen symptoms in patients with pre-existing osteoarthritis. [...] Read more.

Given the increasing aging population and the rising prevalence of musculoskeletal diseases due to obesity and injury, urgent research is needed to formulate new treatment alternatives, as current options remain inadequate. Viruses can exacerbate arthritis and worsen symptoms in patients with pre-existing osteoarthritis. Over the past decade, the chikungunya virus (CHIKV) has emerged as a significant public health concern, especially in Asia and South America. Exploring natural products, such as berberine, has shown promise due to its anticatabolic, antioxidative, and anti-inflammatory effects. However, berberine’s low stability and bioavailability limit its efficacy. We hypothesized that encapsulating berberine into a proniosome gel, known for its ease of preparation and stability, could enhance its bioavailability and efficacy when applied topically, potentially treating CHIKV infection. Our investigation focused on how varying berberine loads and selected excipients in the proniosome gel influenced its physical properties, stability, and skin permeability. We also examined the biological half-life of berberine in plasma upon topical administration in mice to assess the potential for controlled and sustained drug release. Additionally, we analyzed the antioxidant stress activity and cell viability of HaCaT keratinocytes and developed a lipopolysaccharide-stimulated cell culture model to evaluate anti-inflammatory effects using pro-inflammatory cytokines. Overall, the research aims to transform the treatment landscape for arthritis by leveraging berberine’s therapeutic potential. Full article

(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Biotechnological Drugs: Innovations in Preparation and Delivery Strategies)

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29 pages, 8084 KB

Open AccessEditor’s ChoiceArticle

Local, Sustained, and Targeted Co-Delivery of MEK Inhibitor and Doxorubicin Inhibits Tumor Progression in E-Cadherin-Positive Breast Cancer

by Paul M. Kuhn, Gabriella C. Russo, Ashleigh J. Crawford, Aditya Venkatraman, Nanlan Yang, Bartholomew A. Starich, Zachary Schneiderman, Pei-Hsun Wu, Thi Vo, Denis Wirtz and Efrosini Kokkoli

Pharmaceutics 2024, 16(8), 981; https://doi.org/10.3390/pharmaceutics16080981 - 25 Jul 2024

Cited by 2 | Viewed by 2690

Abstract

Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically [...] Read more.

Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically delivered nanoparticles, which require frequent, high-dose injections. Here, we present a different approach, employing a thermosensitive, biodegradable hydrogel with functionalized liposomes for local, sustained release of MEK inhibitor PD0325901 and doxorubicin. The poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) triblock co-polymer gels at physiological temperature and has an optimal degradation time in vivo. Liposomes were functionalized with PR_b, a biomimetic peptide targeting the α₅β₁ integrin receptor, which is overexpressed in E-cadherin-positive triple negative breast cancer (TNBC). In various TNBC models, the hydrogel-liposome system delivered via local injection reduced tumor progression and improved animal survival without toxic side effects. Our work presents the first demonstration of local, sustained delivery of MEK inhibitors to E-cadherin-positive tumors alongside traditional chemotherapeutics, offering a safe and promising therapeutic strategy. Full article

(This article belongs to the Special Issue Recent Advances in Hydrogels for Biomedical Applications)

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18 pages, 3072 KB

Open AccessEditor’s ChoiceArticle

Hyaluronic Acid-Based Nanoparticles Loaded with Rutin as Vasculo-Protective Tools against Anthracycline-Induced Endothelial Damages

by Carla Serri, Vincenzo Quagliariello, Iriczalli Cruz-Maya, Vincenzo Guarino, Nicola Maurea, Paolo Giunchedi, Giovanna Rassu and Elisabetta Gavini

Pharmaceutics 2024, 16(8), 985; https://doi.org/10.3390/pharmaceutics16080985 - 25 Jul 2024

Cited by 4 | Viewed by 1912

Abstract

Anthracycline-based therapies exert endothelial damages through peroxidation and the production of proinflammatory cytokines, resulting in a high risk of cardiovascular complications in cancer patients. Hyaluronic acid-based hybrid nanoparticles (LicpHA) are effective pharmacological tools that can target endothelial cells and deliver drugs or nutraceuticals. [...] Read more.

Anthracycline-based therapies exert endothelial damages through peroxidation and the production of proinflammatory cytokines, resulting in a high risk of cardiovascular complications in cancer patients. Hyaluronic acid-based hybrid nanoparticles (LicpHA) are effective pharmacological tools that can target endothelial cells and deliver drugs or nutraceuticals. This study aimed to prepared and characterized a novel LicpHA loaded with Rutin (LicpHA Rutin), a flavonoid with high antioxidant and anti-inflammatory properties, to protect endothelial cells against epirubicin-mediated endothelial damages. LicpHA Rutin was prepared using phosphatidylcholine, cholesterol, poloxamers, and hyaluronic acid by a modified nanoprecipitation technique. The chemical-physical characterization of the nanoparticles was carried out (size, zeta potential, morphology, stability, thermal analysis, and encapsulation efficiency). Cytotoxicity studies were performed in human endothelial cells exposed to epirubicin alone or in combination with Free-Rutin or LicpHA Rutin. Anti-inflammatory studies were performed through the intracellular quantification of NLRP-3, MyD-88, IL-1β, IL-6, IL17-α, TNF-α, IL-10, and IL-4 using selective ELISA methods. Morphological studies via TEM and image analysis highlighted a heterogeneous population of LicpHA particles with non-spherical shapes (circularity equal to 0.78 ± 0.14), and the particle size was slightly affected by Rutin entrapment (the mean diameter varied from 179 ± 4 nm to 209 ± 4 nm). Thermal analysis and zeta potential analyses confirmed the influence of Rutin on the chemical-physical properties of LicpHA Rutin, mainly indicated by the decrease in the surface negative charge (from −35 ± 1 mV to −30 ± 0.5 mV). Cellular studies demonstrated that LicpHA Rutin significantly reduced cell death and inflammation when compared to epirubicin alone. The levels of intracellular NLRP3, Myd-88, and proinflammatory cytokines were significantly lower in epirubicin + LicpHA Rutin-exposed cells when compared to epirubicin groups (p < 0.001). Hyaluronic acid-based nanoparticles loaded with Rutin exerts significant vasculo-protective properties during exposure to anthracyclines. The overall picture of this study pushes towards preclinical and clinical studies in models of anthracycline-induced vascular damages. Full article

(This article belongs to the Special Issue Advances in Nanotechnology-Based Drug Delivery Systems)

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19 pages, 4993 KB

Open AccessEditor’s ChoiceArticle

Nanosized Complexes of the Proteolytic Enzyme Serratiopeptidase with Cationic Block Copolymer Micelles Enhance the Proliferation and Migration of Human Cells

by Katya Kamenova, Anna Prancheva, Lyubomira Radeva, Krassimira Yoncheva, Maya M. Zaharieva, Hristo M. Najdenski and Petar D. Petrov

Pharmaceutics 2024, 16(8), 988; https://doi.org/10.3390/pharmaceutics16080988 - 25 Jul 2024

Cited by 5 | Viewed by 1644

Abstract

In this study, we describe the preparation of the cationic block copolymer nanocarriers of the proteolytic enzyme serratiopeptidase (SER). Firstly, an amphiphilic poly(2-(dimethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA₉-b-PCL₃₅-b-PDMAEMA₉) triblock copolymer was synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Then, [...] Read more.

In this study, we describe the preparation of the cationic block copolymer nanocarriers of the proteolytic enzyme serratiopeptidase (SER). Firstly, an amphiphilic poly(2-(dimethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA₉-b-PCL₃₅-b-PDMAEMA₉) triblock copolymer was synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Then, cationic micellar nanocarriers consisting of a PCL hydrophobic core and a PDMAEMA hydrophilic shell were formed by the solvent evaporation method. SER was loaded into the polymeric micelles by electrostatic interaction between the positively charged micellar shell and the negatively charged enzyme molecules. The particle size, zeta potential, and colloid stability of complexes as a function of SER concentration were investigated by dynamic and electrophoretic light scattering. It was found that SER retained its proteolytic activity after immobilization in polymeric carriers. Moreover, the complexes have a concentration-dependent enhancing effect on the proliferation and migration of human keratinocyte HaCaT and gingival fibroblast HGF cells. Full article

(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery, 2nd Edition)

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17 pages, 3181 KB

Open AccessEditor’s ChoiceArticle

Inulin Amphiphilic Copolymer-Based Drug Delivery: Unraveling the Structural Features of Graft Constructs

by Carla Sardo, Giulia Auriemma, Carmela Mazzacano, Claudia Conte, Virgilio Piccolo, Tania Ciaglia, Marta Denel-Bobrowska, Agnieszka B. Olejniczak, Donatella Fiore, Maria Chiara Proto, Patrizia Gazzerro and Rita Patrizia Aquino

Pharmaceutics 2024, 16(8), 971; https://doi.org/10.3390/pharmaceutics16080971 - 23 Jul 2024

Cited by 3 | Viewed by 1860

Abstract

In this study, the structural attributes of nanoparticles obtained by a renewable and non-immunogenic “inulinated” analog of the “pegylated” PLA (PEG-PLA) were examined, together with the potential of these novel nanocarriers in delivering poorly water-soluble drugs. Characterization of INU-PLA assemblies, encompassing critical aggregation [...] Read more.

In this study, the structural attributes of nanoparticles obtained by a renewable and non-immunogenic “inulinated” analog of the “pegylated” PLA (PEG-PLA) were examined, together with the potential of these novel nanocarriers in delivering poorly water-soluble drugs. Characterization of INU-PLA assemblies, encompassing critical aggregation concentration (CAC), NMR, DLS, LDE, and SEM analyses, was conducted to elucidate the core/shell architecture of the carriers and in vitro cyto- and hemo-compatibility were assayed. The entrapment and in vitro delivery of sorafenib tosylate (ST) were also studied. INU-PLA copolymers exhibit distinctive features: (1) Crew-cut aggregates are formed with coronas of 2–4 nm; (2) a threshold surface density of 1 INU/nm² triggers a configuration change; (3) INU surface density influences PLA core dynamics, with hydrophilic segment stretching affecting PLA distribution towards the interface. INU-PLA₂NPs demonstrated an outstanding loading of ST and excellent biological profile, with effective internalization and ST delivery to HepG2 cells, yielding a comparable IC₅₀. Full article

(This article belongs to the Special Issue Supernatural: Delivery of Natural and Biotechnological Actives)

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23 pages, 8493 KB

Open AccessEditor’s ChoiceArticle

Chitosan-Tricarbocyanine-Based Nanogels Were Able to Cross the Blood–Brain Barrier Showing Its Potential as a Targeted Site Delivery Agent

by Emilio Rivera López, Cecilia Samaniego López, Carla C. Spagnuolo, Bruno G. Berardino, Agustina Alaimo and Oscar E. Pérez

Pharmaceutics 2024, 16(7), 964; https://doi.org/10.3390/pharmaceutics16070964 - 21 Jul 2024

Cited by 9 | Viewed by 2413

Abstract

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood–brain barrier (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through the effective engineering of nanogels. The primary objective [...] Read more.

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood–brain barrier (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through the effective engineering of nanogels. The primary objective of the present report was to develop and characterize a biocompatible natural chitosan (CS)-based NG that can be tracked thanks to the tricarbocyanine (CNN) fluorescent probe addition on the biopolymer backbone. FTIR shed light on the chemical groups involved in the CS and CNN interactions and between CNN-CS and tripolyphosphate, the cross-linking agent. Both in vitro and in vivo experiments were carried out to determine if CS-NGs can be utilized as therapeutic delivery vehicles directed towards the brain. An ionic gelation method was chosen to generate cationic CNN-CS-NG. DLS and TEM confirmed that these entities’ sizes fell into the nanoscale. CNN-CS-NG was found to be non-cytotoxic, as determined in the SH-SY5Y neuroblastoma cell line through biocompatibility assays. After cellular internalization, the occurrence of an endo-lysosomal escape (a crucial event for an efficient drug delivery) of CNN-CS-NG was detected. Furthermore, CNN-CS-NG administered intraperitoneally to female CF-1 mice were detected in different brain regions after 2 h of administration, using fluorescence microscopy. To conclude, the obtained findings in the present report can be useful in the field of neuro-nanomedicine when designing drug vehicles with the purpose of delivering drugs to the CNS. Full article

(This article belongs to the Special Issue Recent Progress in Microencapsulation and Nanoencapsulation for Pharmaceutical Applications)

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22 pages, 2852 KB

Open AccessEditor’s ChoiceArticle

Upgrading Mitochondria-Targeting Peptide-Based Nanocomplexes for Zebrafish In Vivo Compatibility Assays

by Rúben Faria, Eric Vivès, Prisca Boisguérin, Simon Descamps, Ângela Sousa and Diana Costa

Pharmaceutics 2024, 16(7), 961; https://doi.org/10.3390/pharmaceutics16070961 - 20 Jul 2024

Cited by 4 | Viewed by 2286

Abstract

The lack of effective delivery systems has slowed the development of mitochondrial gene therapy. Delivery systems based on cell-penetrating peptides (CPPs) like the WRAP (tryptophan and arginine-rich peptide) family conjugated with a mitochondrial targeting sequence (MTS) have emerged as adequate carriers to mediate [...] Read more.

The lack of effective delivery systems has slowed the development of mitochondrial gene therapy. Delivery systems based on cell-penetrating peptides (CPPs) like the WRAP (tryptophan and arginine-rich peptide) family conjugated with a mitochondrial targeting sequence (MTS) have emerged as adequate carriers to mediate gene expression into the mitochondria. In this work, we performed the PEGylation of WRAP/pDNA nanocomplexes and compared them with previously analyzed nanocomplexes such as (KH)₉/pDNA and CpMTP/pDNA. All nanocomplexes exhibited nearly homogeneous sizes between 100 and 350 nm in different environments. The developed complexes were biocompatible and hemocompatible to both human astrocytes and lung smooth muscle cells, ensuring in vivo safety. The nanocomplexes displayed mitochondria targeting ability, as through transfection they preferentially accumulate into the mitochondria of astrocytes and muscle cells to the detriment of cytosol and lysosomes. Moreover, the transfection of these cells with MTS–CPP/pDNA complexes produced significant levels of mitochondrial protein ND1, highlighting their efficient role as gene delivery carriers toward mitochondria. The positive obtained data pave the way for in vivo research. Using confocal microscopy, the cellular internalization capacity of these nanocomplexes in the zebrafish embryo model was assessed. The peptide-based nanocomplexes were easily internalized into zebrafish embryos, do not cause harmful or toxic effects, and do not affect zebrafish’s normal development and growth. These promising results indicate that MTS–CPP complexes are stable nanosystems capable of internalizing in vivo models and do not present associated toxicity. This work, even at an early stage, offers good prospects for continued in vivo zebrafish research to evaluate the performance of nanocomplexes for mitochondrial gene therapy. Full article

(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Advances and Future Trends in Drug Delivery)

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37 pages, 40998 KB

Open AccessEditor’s ChoiceArticle

Development and Evaluation of Docetaxel-Loaded Nanostructured Lipid Carriers for Skin Cancer Therapy

by Florentina-Iuliana Cocoș, Valentina Anuța, Lăcrămioara Popa, Mihaela Violeta Ghica, Mihaela-Alexandra Nica, Mirela Mihăilă, Radu Claudiu Fierăscu, Bogdan Trică, Cristian Andi Nicolae and Cristina-Elena Dinu-Pîrvu

Pharmaceutics 2024, 16(7), 960; https://doi.org/10.3390/pharmaceutics16070960 - 19 Jul 2024

Cited by 9 | Viewed by 3329

Abstract

This study focuses on the design, characterization, and optimization of nanostructured lipid carriers (NLCs) loaded with docetaxel for the treatment of skin cancer. Employing a systematic formulation development process guided by Design of Experiments (DoE) principles, key parameters such as particle size, polydispersity [...] Read more.

This study focuses on the design, characterization, and optimization of nanostructured lipid carriers (NLCs) loaded with docetaxel for the treatment of skin cancer. Employing a systematic formulation development process guided by Design of Experiments (DoE) principles, key parameters such as particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency were optimized to ensure the stability and drug-loading efficacy of the NLCs. Combined XRD and cryo-TEM analysis were employed for NLC nanostructure evaluation, confirming the formation of well-defined nanostructures. In vitro kinetics studies demonstrated controlled and sustained docetaxel release over 48 h, emphasizing the potential for prolonged therapeutic effects. Cytotoxicity assays on human umbilical vein endothelial cells (HUVEC) and SK-MEL-24 melanoma cell line revealed enhanced efficacy against cancer cells, with significant selective cytotoxicity and minimal impact on normal cells. This multidimensional approach, encompassing formulation optimization and comprehensive characterization, positions the docetaxel-loaded NLCs as promising candidates for advanced skin cancer therapy. The findings underscore the potential translational impact of these nanocarriers, paving the way for future preclinical investigations and clinical applications in skin cancer treatment. Full article

(This article belongs to the Special Issue Nano-Based Drug Delivery System: Recent Developments and Future Prospects)

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25 pages, 3975 KB

Open AccessEditor’s ChoiceArticle

Exploring a New Generation of Pyrimidine and Pyridine Derivatives as Anti-Influenza Agents Targeting the Polymerase PA–PB1 Subunits Interaction

by Ilaria Giacchello, Annarita Cianciusi, Chiara Bertagnin, Anna Bonomini, Valeria Francesconi, Mattia Mori, Anna Carbone, Francesca Musumeci, Arianna Loregian and Silvia Schenone

Pharmaceutics 2024, 16(7), 954; https://doi.org/10.3390/pharmaceutics16070954 - 18 Jul 2024

Cited by 2 | Viewed by 2299

Abstract

The limited range of available flu treatments due to virus mutations and drug resistance have prompted the search for new therapies. RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex of three subunits, i.e., polymerase acidic protein (PA) and polymerase basic proteins 1 and [...] Read more.

The limited range of available flu treatments due to virus mutations and drug resistance have prompted the search for new therapies. RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex of three subunits, i.e., polymerase acidic protein (PA) and polymerase basic proteins 1 and 2 (PB1 and PB2). It is widely recognized as one of the most promising anti-flu targets because of its critical role in influenza infection and high amino acid conservation. In particular, the disruption of RdRp complex assembly through protein–protein interaction (PPI) inhibition has emerged as a valuable strategy for discovering a new therapy. Our group previously identified the 3-cyano-4,6-diphenyl-pyridine core as a privileged scaffold for developing PA–PB1 PPI inhibitors. Encouraged by these findings, we synthesized a small library of pyridine and pyrimidine derivatives decorated with a thio-N-(m-tolyl)acetamide side chain (compounds 2a–n) or several amino acid groups (compounds 3a–n) at the C2 position. Interestingly, derivative 2d, characterized by a pyrimidine core and a phenyl and 4-chloro phenyl ring at the C4 and C6 positions, respectively, showed an IC₅₀ value of 90.1 μM in PA–PB1 ELISA, an EC₅₀ value of 2.8 μM in PRA, and a favorable cytotoxic profile, emerging as a significant breakthrough in the pursuit of new PPI inhibitors. A molecular modeling study was also completed as part of this project, allowing us to clarify the biological profile of these compounds. Full article

(This article belongs to the Section Drug Targeting and Design)

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21 pages, 1156 KB

Open AccessEditor’s ChoiceReview

Low-Density Lipoprotein Receptor-Related Protein 1 as a Potential Therapeutic Target in Alzheimer’s Disease

by Sabrina Petralla, Maria Panayotova, Elisa Franchina, Gert Fricker and Elena Puris

Pharmaceutics 2024, 16(7), 948; https://doi.org/10.3390/pharmaceutics16070948 - 17 Jul 2024

Cited by 27 | Viewed by 7566

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between the production and Aβ clearance in the brain and across the blood–brain barrier (BBB). In this respect, low-density lipoprotein receptor-related protein 1 (LRP1) plays a significant role by mediating both brain Aβ production and clearance. Due to its important role in AD pathogenesis, LRP1 is considered an attractive drug target for AD therapies. In the present review, we summarize the current knowledge about the role of LRP1 in AD pathogenesis as well as recent findings on changes in LRP1 expression and function in AD. Finally, we discuss the advances in utilizing LRP1 as a drug target for AD treatments as well as future perspectives on LRP1 research. Full article

(This article belongs to the Special Issue New Discoveries in Drug Targets and Delivery for Alzheimer’s Disease)

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22 pages, 7760 KB

Open AccessEditor’s ChoiceReview

Chemodynamic Therapy of Glioblastoma Multiforme and Perspectives

by Zia Ullah, Yasir Abbas, Jingsi Gu, Sai Ko Soe, Shubham Roy, Tingting Peng and Bing Guo

Pharmaceutics 2024, 16(7), 942; https://doi.org/10.3390/pharmaceutics16070942 - 15 Jul 2024

Cited by 4 | Viewed by 3298

Abstract

Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood–brain barrier (BBB) to [...] Read more.

Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood–brain barrier (BBB) to reach the GBM is another endless marathon. In this review, the physiology of the BBB has been elaborated to understand the mechanism of crossing these potential barriers to treat GBM. Moreover, the designing of Fenton-based nanomaterials has been discussed for the production of reactive oxygen species in the tumor area to eradicate the cancer cells. For effective tumor targeting, biological nanomaterials that can cross the BBB via neurovascular transport channels have also been explored. To overcome the neurotoxicity caused by inorganic nanomaterials, the use of smart nanoagents having both enhanced biocompatibility and effective tumor targeting ability to enhance the efficiency of CDT are systematically summarized. Finally, the advancements in intelligent Fenton-based nanosystems for a multimodal therapeutic approach in addition to CDT are demonstrated. Hopefully, this systematic review will provide a better understanding of Fenton-based CDT and insight into GBM treatment. Full article

(This article belongs to the Special Issue Recent Advances in NIR-II Fluorescence Imaging-Based Cancer Treatment)

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20 pages, 2207 KB

Open AccessEditor’s ChoiceArticle

Pharmacokinetics and Enterohepatic Circulation of 2-(Quinoline-8-carboxamido)benzoic Acid (2-QBA) in Mice

by Ji-Hyeon Jeon, So-Yeon Jeon, Yeon-Ju Baek, Chan-E Park, Min-Koo Choi, Young Taek Han and Im-Sook Song

Pharmaceutics 2024, 16(7), 934; https://doi.org/10.3390/pharmaceutics16070934 - 12 Jul 2024

Cited by 2 | Viewed by 2128

Abstract

The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson’s disease. We developed an analytical method for 2-QBA using a liquid chromatography–tandem mass spectrometry [...] Read more.

The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson’s disease. We developed an analytical method for 2-QBA using a liquid chromatography–tandem mass spectrometry (LC-MS/MS) in mouse plasma, in which a protein precipitation method for the sample preparation of 2-QBA in mouse plasma was used due to its simplicity and good extraction recovery rates (80.49–97.56%). The linearity of the calibration standard sample, inter- and intraday precision and accuracy, and stability of three quality control samples were suitable based on the assessment criteria and the lower limit of quantification (LLOQ) of the 2-QBA was 1 ng/mL. A pharmacokinetic study of 2-QBA was performed in mice divided into oral (2.0, 5.0, and 15 mg/kg) and intravenous (0.5 and 1.0 mg/kg) administration groups. The absolute oral bioavailability (BA) range of 2-QBA was calculated as 68.3–83.7%. Secondary peaks were observed at approximately 4–8 h after the oral administration of 2-QBA at all doses. The elimination half-life of the orally administered 2-QBA was significantly longer than that of the intravenous 2-QBA. In addition, glucuronide metabolites of 2-QBA were identified. They were transformed into 2-QBA using the β-glucuronidase treatment. Furthermore, the 2-QBA was readily absorbed from the jejunum to lower ileum. Taken together, the secondary peaks could be explained by the enterohepatic circulation of 2-QBA. In conclusion, the reabsorption of orally administered 2-QBA could contribute to the high oral BA of 2-QBA and could be beneficial for the efficacy of 2-QBA. Moreover, the simple and validated analytical method for 2-QBA using LC-MS/MS was applied to the pharmacokinetic study and BA assessments of 2-QBA in mice and would be helpful for subsequent pharmacokinetic studies, as well as for evaluations of the toxicokinetics and pharmacokinetic–pharmacodynamic correlation of 2-QBA to assess its potential as a drug. Full article

(This article belongs to the Special Issue Bioanalysis and Metabolomics, 2nd Edition)

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20 pages, 4385 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Photodynamic Therapy: Metal-Based Nanoparticles as Tools to Improve Cancer Therapy

by Stefania Mariano, Elisabetta Carata, Lucio Calcagnile and Elisa Panzarini

Pharmaceutics 2024, 16(7), 932; https://doi.org/10.3390/pharmaceutics16070932 - 12 Jul 2024

Cited by 20 | Viewed by 4088

Abstract

Cancer remains a significant global health challenge, with traditional therapies like surgery, chemotherapy, and radiation often accompanied by systemic toxicity and damage to healthy tissues. Despite progress in treatment, these approaches have limitations such as non-specific targeting, systemic toxicity, and resistance development in [...] Read more.

Cancer remains a significant global health challenge, with traditional therapies like surgery, chemotherapy, and radiation often accompanied by systemic toxicity and damage to healthy tissues. Despite progress in treatment, these approaches have limitations such as non-specific targeting, systemic toxicity, and resistance development in cancer cells. In recent years, nanotechnology has emerged as a revolutionary frontier in cancer therapy, offering potential solutions to these challenges. Nanoparticles, due to their unique physical and chemical properties, can carry therapeutic payloads, navigate biological barriers, and selectively target cancer cells. Metal-based nanoparticles, in particular, offer unique properties suitable for various therapeutic applications. Recent advancements have focused on the integration of metal-based nanoparticles to enhance the efficacy and precision of photodynamic therapy. Integrating nanotechnology into cancer therapy represents a paradigm shift, enabling the development of strategies with enhanced specificity and reduced off-target effects. This review aims to provide a comprehensive understanding of the pivotal role of metal-based nanoparticles in photodynamic therapy. We explore the mechanisms, biocompatibility, and applications of metal-based nanoparticles in photodynamic therapy, highlighting the challenges and the limitations in their use, as well as the combining of metal-based nanoparticles/photodynamic therapy with other strategies as a synergistic therapeutic approach for cancer treatment. Full article

(This article belongs to the Special Issue Metal-Based Nanoparticles for Pharmaceutical Applications)

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19 pages, 8763 KB

Open AccessEditor’s ChoiceArticle

pH-Triggered Hydrogel Nanoparticles for Efficient Anticancer Drug Delivery and Bioimaging Applications

by Keristina Wagdi K. Amin, Ágota Deák, Miklós Csanády, Jr., Nikoletta Szemerédi, Diána Szabó, Árpád Turcsányi, Ditta Ungor, Gabriella Spengler, László Rovó and László Janovák

Pharmaceutics 2024, 16(7), 931; https://doi.org/10.3390/pharmaceutics16070931 - 11 Jul 2024

Cited by 5 | Viewed by 2258

Abstract

In this work, we developed multifunctional hydrogel nanoparticles (NPs) that can encapsulate anticancer drugs and imaging contrast agents as well. Mitomycin C (MMC) and rhodamine B (RB) were selected as models for anticancer drugs and imaging contrasting agents, respectively. Both MMC and RB [...] Read more.

In this work, we developed multifunctional hydrogel nanoparticles (NPs) that can encapsulate anticancer drugs and imaging contrast agents as well. Mitomycin C (MMC) and rhodamine B (RB) were selected as models for anticancer drugs and imaging contrasting agents, respectively. Both MMC and RB were linked to the succinated polyvinyl alcohol polymer (PVA-SA). The selected labeled hydrogel NPs ((0.5% RB)-PVA-SA NPs and (1.5% RB)-PVA-SA NPs) improved the RB quantum yield from 29.8% to a minimum of 42.7%. Moreover, they showed higher emission stability compared to free RB when they were repeatedly excited at 554 nm for 2 h. Furthermore, the dye polymeric interactions significantly increased the RB fluorescence lifetime by approximately twofold. All these optical properties pave the way for our labeled hydrogel NPs to be used in imaging-guided therapy. For the labeled MMC-loaded NPs, the MMC-binding efficiency was found to be exceedingly high in all synthesized samples: a minimum of 92% was achieved. In addition, the obtained pH-dependent drug release profiles as well as the cytotoxicity evaluation demonstrated the high potential of releasing MMC under acidic cancerous conditions. Moreover, the in vitro cellular uptake experiment confirmed the accumulation of MMC NPs throughout the cytoplasm. Full article

(This article belongs to the Special Issue Recent Advances in Hydrogels for Biomedical Applications)

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21 pages, 4774 KB

Open AccessEditor’s ChoiceArticle

Inhibition of Enzyme and Bacteria Activities in Diabetic Ulcer-like Scenarios via WAAPV-Loaded Electrospun Fibers

by Ana R. M. Ribeiro, Catarina S. Miranda, Ana Francisca G. Silva, Filipa D. P. Mendes, Beatriz M. Silva, Bruna A. S. Oliveira, Eduardo D. Paiva, Sónia P. Gonçalves, Sílvia M. M. A. Pereira-Lima, Susana P. G. Costa and Helena P. Felgueiras

Pharmaceutics 2024, 16(7), 911; https://doi.org/10.3390/pharmaceutics16070911 - 8 Jul 2024

Cited by 2 | Viewed by 2170

Abstract

In diabetic ulcers, an increased secretion of human neutrophil elastase (HNE) and bacterial infections play crucial roles in hindering healing. Considering that, the present study proposed the development of multi-action polycaprolactone (PCL)/polyethylene glycol (PEG) electrospun fibers incorporating elastase-targeting peptides, AAPV and WAAPV, via [...] Read more.

In diabetic ulcers, an increased secretion of human neutrophil elastase (HNE) and bacterial infections play crucial roles in hindering healing. Considering that, the present study proposed the development of multi-action polycaprolactone (PCL)/polyethylene glycol (PEG) electrospun fibers incorporating elastase-targeting peptides, AAPV and WAAPV, via blending. Characterization confirmed WAAPV’s efficacy in regulating proteolytic enzymes by inhibiting HNE. The engineered fibers, particularly those containing PEG, exhibited optimal wettability but an accelerated degradation that was mitigated with the peptide’s inclusion, thus promoting a sustained peptide release over 24 h. Peptide loading was verified indirectly through thermal stability and hydration capacity studies (hydrophobic bonding between PCL and WAAPV and hydrophilic affinities between PCL/PEG and AAPV) and determined at ≈51.1 µg/cm² and ≈46.0 µg/cm² for AAPV and ≈48.5 µg/cm² and ≈51.3 µg/cm² for WAAPV, respectively, for PCL and PCL/PEG. Both AAPV and WAAPV effectively inhibited HNE, with PEG potentially enhancing this effect by interacting with the peptides and generating detectable peptide–PEG complexes (≈10% inhibition with PCL + peptide fibers after 6 h of incubation, and ≈20% with PCL/PEG + peptide fibers after 4 h incubation). Peptide-loaded fibers demonstrated antibacterial efficacy against Staphylococcus aureus (up to ≈78% inhibition) and Escherichia coli (up to ≈66% inhibition), with peak effectiveness observed after 4 and 2 h of incubation, respectively. This study provides initial insights into the WAAPV’s potential for inhibiting HNE and bacteria activities, showing promise for applications in diabetic ulcer management. Full article

(This article belongs to the Special Issue Fiber-Based Scaffolds as Drug Carriers: Recent Advances)

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16 pages, 1828 KB

Open AccessEditor’s ChoiceArticle

Design of Thermosensitive Niosomes by Eutectic Mixture of Natural Fatty Acids

by Elisabetta Mazzotta, Martina Romeo, Zakaria Hafidi, Lourdes Perez, Ida Daniela Perrotta and Rita Muzzalupo

Pharmaceutics 2024, 16(7), 909; https://doi.org/10.3390/pharmaceutics16070909 - 7 Jul 2024

Cited by 5 | Viewed by 1928

Abstract

In the current study, a smart release system responsive to temperature was developed to improve the efficiency of tetracycline (TC) in antibacterial therapy. The nanovesicles designed consist of a non-ionic surfactant, SPAN60, cholesterol and a phase change material (PCM) as a thermoresponsive gating [...] Read more.

In the current study, a smart release system responsive to temperature was developed to improve the efficiency of tetracycline (TC) in antibacterial therapy. The nanovesicles designed consist of a non-ionic surfactant, SPAN60, cholesterol and a phase change material (PCM) as a thermoresponsive gating material. Niosomes were prepared using an increasing amount of PCM and characterized in terms of size, zeta potential, colloidal stability and thermoresponsive properties. The vesicles that developed were homogenous in size, had good biocompatibility and stability for up to 3 months and demonstrated thermoresponsive behavior. A low drug leakage was observed at 37 °C, while a rapid release occurred at 42 °C, due to the faster diffusion rate of the drug trough the melted PCM. This controllable drug release capacity allows us to avoid premature drug release, minimizing unwanted and toxic effects and ensuring a long retention time in the nanodevice so that it reaches the infected sites. In addition, TC-loaded niosomes were screened to investigate their antibacterial activity against various Gram-positive and Gram-negative bacteria by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. An interesting temperature-dependent antibacterial activity was observed against some bacterial strains: the niosomes activity against S. epidermis, for example, was improved by the temperature increase, as suggested by a reduction in MIC values from 112.81 to 14.10 μM observed at 37 and 42 °C, respectively. Taken together, the thermoresponsive platform developed allows us to use lower antibiotic amounts while ensuring therapeutic efficacy and, so, will advance the development of a novel antibacterial agent in clinical practice. Full article

(This article belongs to the Special Issue Novel Technological Approaches for Targeted Drug Delivery Systems)

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13 pages, 784 KB

Open AccessEditor’s ChoiceReview

New and Emerging Treatments for Generalized Pustular Psoriasis: Focus on IL-36 Receptor Inhibitors

by João Vilaça, Orhan Yilmaz and Tiago Torres

Pharmaceutics 2024, 16(7), 908; https://doi.org/10.3390/pharmaceutics16070908 - 6 Jul 2024

Cited by 6 | Viewed by 5443

Abstract

Generalized Pustular Psoriasis (GPP) is a rare and severe subtype of psoriasis that significantly impacts patients’ quality of life. Until recently, no specific treatment modalities were available, and treatment for GPP followed the guidelines for the treatment of plaque psoriasis, consisting of conventional [...] Read more.

Generalized Pustular Psoriasis (GPP) is a rare and severe subtype of psoriasis that significantly impacts patients’ quality of life. Until recently, no specific treatment modalities were available, and treatment for GPP followed the guidelines for the treatment of plaque psoriasis, consisting of conventional treatments, such as retinoids, methotrexate, and even biologics, which although effective in some cases, may be associated with significant side effects, necessitating more effective and safe options. The pathophysiology of Generalized Pustular Psoriasis is complex and not fully understood, but there is some overlap with the pathogenesis of Plaque Psoriasis. In GPP, the innate immune system seems to play a more significant role, with the interleukin (IL)-36 pathway being fundamentally involved. Spesolimab and imsidolimab, two recently developed therapeutic agents, target the IL-36 inflammatory pathway by binding to the IL-36 receptor (IL-36R). Both biologics have already been evaluated in phase 1 and 2 clinical trials and have shown promising results in terms of safety and efficacy. IL-36 receptor inhibitors demonstrated great efficacy and good safety profile in the management of patients with GPP, demonstrating their potential to emerge as a leading treatment option. This review aims to explore and summarize the current scientific literature on the most recently developed treatments for GPP. Full article

(This article belongs to the Special Issue New and Emerging Targeted Topical and Systemic Drugs for Immunemediated Cutaneous Diseases)

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15 pages, 2278 KB

Open AccessEditor’s ChoiceArticle

Enhanced Cytotoxicity against a Pancreatic Cancer Cell Line Combining Radiation and Gold Nanoparticles

by Alexandra Martins, Brigida C. Ferreira, Maria Manuela Gaspar, Sandra Vieira, Joana Lopes, Ana S. Viana, António Paulo, Filipa Mendes, Maria Paula Cabral Campello, Rui Martins and Catarina Pinto Reis

Pharmaceutics 2024, 16(7), 900; https://doi.org/10.3390/pharmaceutics16070900 - 5 Jul 2024

Cited by 6 | Viewed by 2595

Abstract

The present work consisted of an exploratory study aiming to evaluate in vitro the potential of AuNPs during Radiation Therapy (RT) in human pancreatic adenocarcinoma cells. AuNPs coated with hyaluronic and oleic acids (HAOA-AuNPs) or with bombesin peptides (BBN-AuNPs) were used. AuNPs were [...] Read more.

The present work consisted of an exploratory study aiming to evaluate in vitro the potential of AuNPs during Radiation Therapy (RT) in human pancreatic adenocarcinoma cells. AuNPs coated with hyaluronic and oleic acids (HAOA-AuNPs) or with bombesin peptides (BBN-AuNPs) were used. AuNPs were characterized by Atomic Force Microscopy (AFM) and Dynamic Light Scattering. BxPC-3 tumor cells were irradiated with a 6 MV X-rays beam, in the absence or presence of AuNPs. AFM showed that HAOA-AuNPs and BBN-AuNPs are spherical with a mean size of 83 ± 20 nm and 49 ± 12 nm, respectively. For RT alone, a reduction in cell viability of up to 33 ± 12% was obtained compared to the control (p ≤ 0.0001). HAOA-AuNPs alone at 200 and 400 μM showed a reduction in cell viability of 20 ± 4% and 35 ± 4%, respectively, while for BBN-AuNPs, at 50 and 200 μM, a reduction in cell viability of 25 ± 3% and 37 ± 3% was obtained, respectively, compared to the control (p < 0.0001). At 72 h post-irradiation, a decrease in cell viability of 26 ± 3% and 22 ± 2% between RT + HAOA-AuNPs at 400 μM and RT + BBN-AuNPs at 50 μM, compared to RT alone, was obtained (p < 0.004). The combination of RT with AuNPs led to a significant decrease in cell viability compared to the control, or RT alone, thus representing an improved effect. Full article

(This article belongs to the Special Issue Novel Micro/Nanomaterials Based Drug Delivery Systems for Theranostic Applications)

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19 pages, 4663 KB

Open AccessEditor’s ChoiceArticle

Enrofloxacin Pharmaceutical Formulations through the Polymer-Free Electrospinning of β-Cyclodextrin–oligolactide Derivatives

by Diana-Andreea Blaj, Cătălina Anișoara Peptu, Maricel Danu, Valeria Harabagiu, Cristian Peptu, Alexandra Bujor, Lăcrămioara Ochiuz and Cristina Gabriela Tuchiluș

Pharmaceutics 2024, 16(7), 903; https://doi.org/10.3390/pharmaceutics16070903 - 5 Jul 2024

Cited by 7 | Viewed by 1824

Abstract

Enrofloxacin (ENR), a member of the fluoroquinolone class of antibiotics, is widely used in veterinary medicine to treat bacterial infections. Like many antibiotics, ENR has limited water solubility and low bioavailability. To address these challenges, drug formulations using solid dispersions, nanosuspensions, surfactants, cocrystal/salt [...] Read more.

Enrofloxacin (ENR), a member of the fluoroquinolone class of antibiotics, is widely used in veterinary medicine to treat bacterial infections. Like many antibiotics, ENR has limited water solubility and low bioavailability. To address these challenges, drug formulations using solid dispersions, nanosuspensions, surfactants, cocrystal/salt formation, and inclusion complexes with cyclodextrins may be employed. The approach described herein proposes the development of ENR formulations by co-electrospinning ENR with custom-prepared cyclodextrin–oligolactide (CDLA) derivatives. This method benefits from the high solubility of these derivatives, enabling polymer-free electrospinning. The electrospinning parameters were optimized to incorporate significant amounts of ENR into the CDLA nanofibrous webs, reaching up to 15.6% by weight. The obtained formulations were characterized by FTIR and NMR spectroscopy methods and evaluated for their antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. This study indicates that the presence of CDLA derivative does not inhibit the antibacterial activity of ENR, recommending these formulations for further development. Full article

(This article belongs to the Special Issue Advances in Polymeric Drug Delivery Systems, 2nd Edition)

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21 pages, 2422 KB

Open AccessEditor’s ChoiceReview

The Role of Different Types of Cannabinoids in Periodontal Disease: An Integrative Review

by Jaiane Carmelia Monteiro Viana, Gabriela Ellen da Silva Gomes, Francisca Jennifer Duarte Oliveira, Lidya Nara Marques de Araújo, Guilherme Teles, Carlos Fernando Mourão and Bruno César de Vasconcelos Gurgel

Pharmaceutics 2024, 16(7), 893; https://doi.org/10.3390/pharmaceutics16070893 - 4 Jul 2024

Cited by 8 | Viewed by 4333

Abstract

This integrative review addresses the potential of the Endocannabinoid System (ES) and cannabinoids in the pathogenesis and treatment of periodontal disease (PD). Cannabinoid receptors are expressed in healthy and inflamed periodontal tissues, indicating a potential regulatory role for SEC in oral homeostasis. Healthy [...] Read more.

This integrative review addresses the potential of the Endocannabinoid System (ES) and cannabinoids in the pathogenesis and treatment of periodontal disease (PD). Cannabinoid receptors are expressed in healthy and inflamed periodontal tissues, indicating a potential regulatory role for SEC in oral homeostasis. Healthy periodontal cells express more CB1 receptors, while inflamed sites show increased CB2 receptors. This suggests a dynamic involvement of the SEC in the inflammatory response associated with PD. Cannabinoids such as cannabidiol (CBD) and cannabinoid receptor agonists such as HU-308, anandamide (AEA), and methanamide (Meta-AEA) have demonstrated promising therapeutic potential in studies. CBD has been associated with the control of bone resorption, antibacterial activity, and increased production of gingival fibroblasts, indicating effects in mitigating the progression of PD. HU-308 demonstrated preventive effects against alveolar bone loss, and anti-inflammatory, osteoprotective, and pro-homeostatic properties in animal models of periodontitis. AEA and Meta-AEA have anti-inflammatory effects by reducing pro-inflammatory mediators such as IL-1, IL-6, and TNF-α. The activation of cannabinoid receptors attenuates inflammatory processes, inhibits alveolar bone loss, exerts antibacterial effects, and promotes tissue repair. However, clinical trials are especially needed to validate these results and explore the therapeutic potential of cannabinoids in the treatment of PD in humans. Full article

(This article belongs to the Special Issue New Perspectives for the Administration of Cannabis for Medical Use: From Traditional to Advanced Formulations. What Next?)

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33 pages, 2541 KB

Open AccessEditor’s ChoiceReview

The Evolving Paradigm of Antibody–Drug Conjugates Targeting the ErbB/HER Family of Receptor Tyrosine Kinases

by Peyton High, Cara Guernsey, Shraddha Subramanian, Joan Jacob and Kendra S. Carmon

Pharmaceutics 2024, 16(7), 890; https://doi.org/10.3390/pharmaceutics16070890 - 2 Jul 2024

Cited by 6 | Viewed by 9650

Abstract

Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody–drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with [...] Read more.

Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody–drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with 13 presently approved by the FDA. Importantly, ADCs represent a promising therapeutic option with the potential to overcome traditional HER-targeted therapy resistance by delivering highly potent cytotoxins specifically to HER-overexpressing cancer cells and exerting both mAb- and payload-mediated antitumor efficacy. The clinical utility of HER-targeted ADCs is exemplified by the immense success of HER2-targeted ADCs including trastuzumab emtansine and trastuzumab deruxtecan. Still, strategies to improve upon existing HER2-targeted ADCs as well as the development of ADCs against other HER family members, particularly EGFR and HER3, are of great interest. To date, no HER4-targeting ADCs have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, and HER3-targeting monospecific ADCs as well as novel clinical and pre-clinical bispecific ADCs (bsADCs) directed against this receptor family. We close by discussing nascent trends in the development of HER-targeting ADCs, including novel ADC payloads and HER ligand-targeted ADCs. Full article

(This article belongs to the Special Issue Next-Generation Antibody-Drug Conjugates (ADCs))

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17 pages, 4849 KB

Open AccessEditor’s ChoiceArticle

Solid Lipid Nanoparticles Loaded with Dexamethasone Palmitate for Pulmonary Inflammation Treatment by Nebulization Approach

by Hsin-Hung Chen, Chen-Hsiang Sang, Chang-Wei Chou, Yi-Ting Lin, Yi-Shou Chang and Hsin-Cheng Chiu

Pharmaceutics 2024, 16(7), 878; https://doi.org/10.3390/pharmaceutics16070878 - 29 Jun 2024

Cited by 9 | Viewed by 3324

Abstract

Pneumonia stands as the leading infectious cause of childhood mortality annually, underscoring its significant impact on pediatric health. Although dexamethasone (DXMS) is effective for treating pulmonary inflammation, its therapeutic potential is compromised by systemic side effects and suboptimal carrier systems. To address this [...] Read more.

Pneumonia stands as the leading infectious cause of childhood mortality annually, underscoring its significant impact on pediatric health. Although dexamethasone (DXMS) is effective for treating pulmonary inflammation, its therapeutic potential is compromised by systemic side effects and suboptimal carrier systems. To address this issue, the current study introduces solid lipid nanoparticles encapsulating hydrophobic dexamethasone palmitate (DXMS-Pal-SLNs) as an anti-inflammatory nanoplatform to treat pneumonia. The specialized nanoparticle formulation is characterized by high drug loading efficiency, low drug leakage and excellent colloidal stability in particular during nebulization and is proficiently designed to target alveolar macrophages in deep lung regions via local delivery with the nebulization administration. In vitro analyses revealed substantial reductions in the secretions of tumor necrosis factor-α and interleukin-6 from alveolar macrophages, highlighting the potential efficacy of DXMS-Pal-SLNs in alleviating pneumonia-related inflammation. Similarly, in vivo experiments showed a significant reduction in the levels of these cytokines in the lungs of mice experiencing lipopolysaccharide-induced pulmonary inflammation after the administration of DXMS-Pal-SLNs via nebulization. Furthermore, the study demonstrated that DXMS-Pal-SLNs effectively control acute infections without causing pulmonary infiltration or excessive recruitment of immunocytes in lung tissues. These findings highlight the potential of nebulized DXMS-Pal-SLNs as a promising therapeutic strategy for mitigating pneumonia-related inflammations. Full article

(This article belongs to the Special Issue Lipid-Based Nanoparticulate Drug Delivery Systems: Preparation, Biomedical Applications, and Evaluation)

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17 pages, 5659 KB

Open AccessEditor’s ChoiceArticle

Antimicrobial Peptide Screening for Designing Custom Bactericidal Hydrogels

by Matthias Recktenwald, Muskanjot Kaur, Mohammed M. Benmassaoud, Aryanna Copling, Tulika Khanna, Michael Curry, Dennise Cortes, Gilbert Fleischer, Valerie J. Carabetta and Sebastián L. Vega

Pharmaceutics 2024, 16(7), 860; https://doi.org/10.3390/pharmaceutics16070860 - 27 Jun 2024

Cited by 4 | Viewed by 3078

Abstract

Staphylococcus aureus (S. aureus) is an opportunistic pathogen that lives on surfaces and skin and can cause serious infections inside the body. Antimicrobial peptides (AMPs) are part of the innate immune system and can eliminate pathogens, including bacteria and viruses, and [...] Read more.

Staphylococcus aureus (S. aureus) is an opportunistic pathogen that lives on surfaces and skin and can cause serious infections inside the body. Antimicrobial peptides (AMPs) are part of the innate immune system and can eliminate pathogens, including bacteria and viruses, and are a promising alternative to antibiotics. Although studies have reported that AMP-functionalized hydrogels can prevent bacterial adhesion and biofilm formation, AMP dosing and the combined effects of multiple AMPs are not well understood. Here, three AMPs with different antibacterial properties were synthesized and the soluble minimum inhibitory concentrations (MICs) of each AMP against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) were determined. Hydrogels with immobilized AMPs at their MIC (DD₁₃-RIP 27.5 µM; indolicidin 43.8 µM; P10 120 µM) were effective in preventing MRSA adhesion and biofilm formation. Checkerboard AMP screens identified synergy between indolicidin (3.1 µM) and P10 (12.5 µM) based on soluble fractional inhibitory concentration indices (FICIs) against MRSA, and hydrogels formed with these AMPs at half of their synergistic concentrations (total peptide concentration, 7.8 µM) were highly efficacious in killing MRSA. Mammalian cells cultured atop these hydrogels were highly viable, demonstrating that these AMP hydrogels are biocompatible and selectively eradicate bacteria, based on soluble checkerboard-screening data. Full article

(This article belongs to the Special Issue Recent Advances in the Prevention and Eradication Strategies for Combating Biofilm-Related Infections)

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23 pages, 4798 KB

Open AccessEditor’s ChoiceArticle

Imiquimod-Loaded Nanosystem for Treatment Human Papillomavirus-Induced Lesions

by Izamara Maocha, Beatriz Rosado, Jéssica Lopes-Nunes, Melanie Lopes, Joana Rolo, Bruno Pires, Eugénia Gallardo, Ana Palmeira-de-Oliveira, José Martinez-de-Oliveira, Rita Palmeira de Oliveira, Rui Medeiros and Carla Cruz

Pharmaceutics 2024, 16(7), 864; https://doi.org/10.3390/pharmaceutics16070864 - 27 Jun 2024

Cited by 6 | Viewed by 3196

Abstract

Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via [...] Read more.

Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via Toll-like receptors 7/8 when formulated in carriers, like nanogels, for topical use. An effective alternative to conventional therapies is the nanoparticle drug delivery system. We studied lipidic nanoparticles with IQ (Lipo IQ) and functionalized them with a DNA aptamer, AT11 (Lipo IQ AT11), to improve the selectivity for cervical cancer cells combined with the efficacy of essential oils. The formulations showed that the physicochemical properties are adequate for vaginal drug delivery and have antimicrobial activity at higher concentrations (with MIC₅₀ starting from 0.625%). The final formulations exhibited cytotoxicity in cancer cells, enhanced by essential oils without affecting healthy cells, resulting in less than 10% cell viability in HeLa cells and over 60% in NHDF cells. Essential oils potentiate Lipo IQ’s effectiveness, while AT11 increases the selectivity for cervical cancer cells. As suggested by the results of the permeation assay, the formulations were internalized by the cancer cells. Overall, the obtained results suggested that the synergistic effect of the essential oils and the nanosystem potentiate the cytotoxic effect of Lipo IQ and that Lipo IQ AT11 promotes selectivity towards cancer cells. Full article

(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Aptamers as Novel Therapeutics)

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29 pages, 1354 KB

Open AccessEditor’s ChoiceReview

Gene Therapy with Chitosan Nanoparticles: Modern Formulation Strategies for Enhancing Cancer Cell Transfection

by Varvara Antoniou, Elena A. Mourelatou, Eleftheria Galatou, Konstantinos Avgoustakis and Sophia Hatziantoniou

Pharmaceutics 2024, 16(7), 868; https://doi.org/10.3390/pharmaceutics16070868 - 27 Jun 2024

Cited by 19 | Viewed by 3679

Abstract

Gene therapy involves the introduction of exogenous genetic material into host tissues to modify gene expression or cellular properties for therapeutic purposes. Initially developed to address genetic disorders, gene therapy has expanded to encompass a wide range of conditions, notably cancer. Effective delivery [...] Read more.

Gene therapy involves the introduction of exogenous genetic material into host tissues to modify gene expression or cellular properties for therapeutic purposes. Initially developed to address genetic disorders, gene therapy has expanded to encompass a wide range of conditions, notably cancer. Effective delivery of nucleic acids into target cells relies on carriers, with non-viral systems gaining prominence due to their enhanced safety profile compared to viral vectors. Chitosan, a biopolymer, is frequently utilized to fabricate nanoparticles for various biomedical applications, particularly nucleic acid delivery, with recent emphasis on targeting cancer cells. Chitosan’s positively charged amino groups enable the formation of stable nanocomplexes with nucleic acids and facilitate interaction with cell membranes, thereby promoting cellular uptake. Despite these advantages, chitosan-based nanoparticles face challenges such as poor solubility at physiological pH, non-specificity for cancer cells, and inefficient endosomal escape, limiting their transfection efficiency. To address these limitations, researchers have focused on enhancing the functionality of chitosan nanoparticles. Strategies include improving stability, enhancing targeting specificity, increasing cellular uptake efficiency, and promoting endosomal escape. This review critically evaluates recent formulation approaches within these categories, aiming to provide insights into advancing chitosan-based gene delivery systems for improved efficacy, particularly in cancer therapy. Full article

(This article belongs to the Special Issue Cancer Gene Therapy with Non-Viral Nanocarriers, 2nd Edition)

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10 pages, 2992 KB

Open AccessEditor’s ChoiceArticle

Histological Assessment of Respiratory Tract and Liver of BALB/c Mice Nebulized with Tocilizumab

by Paloma Jimena de Andres, Sergio Ferreiro, Angela Flores, Almudena Garcia and Cesar Henriquez-Camacho

Pharmaceutics 2024, 16(7), 862; https://doi.org/10.3390/pharmaceutics16070862 - 27 Jun 2024

Cited by 1 | Viewed by 2020

Abstract

Pulmonary drug delivery offers a minimally invasive and efficient method for treating lung conditions, leveraging the lungs’ extensive surface area and blood flow for rapid drug absorption. Nebulized therapies aim to deliver drugs directly to the lung tissue. This study investigates the histological [...] Read more.

Pulmonary drug delivery offers a minimally invasive and efficient method for treating lung conditions, leveraging the lungs’ extensive surface area and blood flow for rapid drug absorption. Nebulized therapies aim to deliver drugs directly to the lung tissue. This study investigates the histological impact of nebulized tocilizumab—a monoclonal antibody targeting IL-6, traditionally administered intravenously for rheumatoid arthritis and severe COVID-19—on a murine model. Thirty BALB/c mice were nebulized with tocilizumab (10 mg, 5 mg, and 2.5 mg) and six controls were nebulized with saline solution. They were euthanized 48 h later, and their organs (lungs, nasal mucosa, and liver) were analyzed by a microscopic histological evaluation. The results indicate that all the mice survived the 48 h post-nebulization period without systemic compromise. The macroscopic examination showed no abnormalities, and the histopathological analysis revealed greater lung vascular changes in the control group than in the nebulized animals, which is attributable to the euthanasia with carbon dioxide. Additionally, increased alveolar macrophages were observed in the nebulized groups compared to controls. No significant histological changes were observed in the liver, indicating the safety of nebulized tocilizumab. In conclusion, these findings suggest the potential of nebulized tocilizumab for treating pulmonary inflammation, warranting further research to establish its efficacy and safety in clinical settings. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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20 pages, 2426 KB

Open AccessEditor’s ChoiceArticle

Evaluation of Polyvinyl Alcohol as Binder during Continuous Twin Screw Wet Granulation

by Phaedra Denduyver, Gudrun Birk, Alessandra Ambruosi, Chris Vervaet and Valérie Vanhoorne

Pharmaceutics 2024, 16(7), 854; https://doi.org/10.3390/pharmaceutics16070854 - 25 Jun 2024

Cited by 3 | Viewed by 4627

Abstract

Binder selection is a crucial step in continuous twin-screw wet granulation (TSWG), as the material experiences a much shorter residence time (2–40 s) in the granulator barrel compared to batch-wise granulation processes. Polyvinyl alcohol (PVA) 4-88 was identified as an effective binder during [...] Read more.

Binder selection is a crucial step in continuous twin-screw wet granulation (TSWG), as the material experiences a much shorter residence time (2–40 s) in the granulator barrel compared to batch-wise granulation processes. Polyvinyl alcohol (PVA) 4-88 was identified as an effective binder during TSWG, but the potential of other PVA grades—differing in polymerization and hydrolysis degree—has not yet been studied. Therefore, the aim of the current study was to evaluate the potential of different PVA grades as a binder during TSWG. The breakage and drying behavior during the fluidized bed drying of drug-loaded granules containing the PVA grades was also studied. Three PVA grades (4-88, 18-88, and 40-88) were characterized and their attributes were compared to previously investigated binders by Vandevivere et al. through principal component analysis. Three binder clusters could be distinguished according to their attributes, whereby each cluster contained a PVA grade and a previously investigated binder. PVA 4-88 was the most effective binder of the PVA grades for both a good water-soluble and water-insoluble formulation. This could be attributed to its high total surface energy, low viscosity, good wettability of hydrophilic and hydrophobic surfaces, and good wettability by water of the binder. Compared to the previously investigated binders, all PVA grades were more effective in the water-insoluble formulation, as they yielded strong granules (friability below 30%) at lower L/S-ratios. This was linked to the high dispersive surface energy of the high-energy sites on the surface of PVA grades and their low surface tension. During fluidized bed drying, PVA grades proved suitable binders, as the acetaminophen (APAP) granules were dried within a short time due to the low L/S-ratio, at which high-quality granules could be produced. In addition, no attrition occurred, and strong tablets were obtained. Based on this study, PVA could be the preferred binder during twin screw granulation due to its high binder effectiveness at a low L/S-ratio, allowing efficient downstream processing. However, process robustness must be controlled by the included excipients, as PVA grades are operating in a narrow L/S-ratio range. Full article

(This article belongs to the Special Issue Impact of Raw Material Properties on Solid Dosage Form Processes)

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31 pages, 7459 KB

Open AccessEditor’s ChoiceArticle

Polymeric Microneedles Enhance Transdermal Delivery of Therapeutics

by Hiep X. Nguyen, Thomas Kipping and Ajay K. Banga

Pharmaceutics 2024, 16(7), 845; https://doi.org/10.3390/pharmaceutics16070845 - 22 Jun 2024

Cited by 11 | Viewed by 5860

Abstract

This research presents the efficacy of polymeric microneedles in improving the transdermal permeation of methotrexate across human skin. These microneedles were fabricated from PLGA Expansorb^® 50-2A and 50-8A and subjected to comprehensive characterization via scanning electron microscopy, Fourier-transform infrared spectroscopy, and mechanical [...] Read more.

This research presents the efficacy of polymeric microneedles in improving the transdermal permeation of methotrexate across human skin. These microneedles were fabricated from PLGA Expansorb^® 50-2A and 50-8A and subjected to comprehensive characterization via scanning electron microscopy, Fourier-transform infrared spectroscopy, and mechanical analysis. We developed and assessed a methotrexate hydrogel for physicochemical and rheological properties. Dye binding, histological examinations, and assessments of skin integrity demonstrated the effective microporation of the skin by PLGA microneedles. We measured the dimensions of microchannels in the skin using scanning electron microscopy, pore uniformity analysis, and confocal microscopy. The skin permeation and disposition of methotrexate were researched in vitro. PLGA 50-8A microneedles appeared significantly longer, sharper, and more mechanically uniform than PLGA 50-2A needles. PLGA 50-8A needles generated substantially more microchannels, as well as deeper, larger, and more uniform channels in the skin than PLGA 50-2A needles. Microneedle insertion substantially reduced skin electrical resistance, accompanied by an elevation in transepidermal water loss values. PLGA 50-8A microneedle treatment provided a significantly higher cumulative delivery, flux, diffusion coefficient, permeability coefficient, and predicted steady-state plasma concentration; however, there was a shorter lag time than for PLGA 50-2A needles, base-treated, and untreated groups (p < 0.05). Conclusively, skin microporation using polymeric microneedles significantly improved the transdermal delivery of methotrexate. Full article

(This article belongs to the Special Issue Microarray Patches for Transdermal Drug Delivery)

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21 pages, 3630 KB

Open AccessEditor’s ChoiceArticle

Investigation of the Electrokinetic Potential of Granules and Optimization of the Pelletization Method Using the Quality by Design Approach

by Azza A. K. Mahmoud, Alharith A. A. Hassan, Dorina Gabriella Dobó, Krisztina Ludasi, László Janovák, Géza Regdon, Jr., Ildikó Csóka and Katalin Kristó

Pharmaceutics 2024, 16(7), 848; https://doi.org/10.3390/pharmaceutics16070848 - 22 Jun 2024

Cited by 1 | Viewed by 4866

Abstract

The preparation of pellets using a high-shear granulator in a rapid single-step is considered a good economic alternative to the extrusion spheronization process. As process parameters and material attributes greatly affect pellet qualities, successful process optimization plays a vital role in producing pellet [...] Read more.

The preparation of pellets using a high-shear granulator in a rapid single-step is considered a good economic alternative to the extrusion spheronization process. As process parameters and material attributes greatly affect pellet qualities, successful process optimization plays a vital role in producing pellet dosage forms with the required critical quality attributes. This study was aimed at the development and optimization of the pelletization technique with the Pro-CepT granulator. According to the quality by design (QbD) and screening design results, chopper speed, the volume of the granulating liquid, binder amount, and impeller speed were selected as the highest risk variables for a two-level full factorial design and central composite design, which were applied to the formula of microcrystalline cellulose, mannitol, and with a binding aqueous polyvinylpyrrolidone solution. The design space was estimated based on physical response results, including the total yield of the required size, hardness, and aspect ratio. The optimized point was tested with two different types of active ingredients. Amlodipine and hydrochlorothiazide were selected as model drugs and were loaded into an optimized formulation. The kinetics of the release of the active agent was examined and found that the results show a correlation with the electrokinetic potential because amlodipine besylate can be adsorbed on the surface of the MCC, while hydrochlorothiazide less so; therefore, in this case, the release of the active agent increases. The research results revealed no significant differences between plain and model drug pellets, except for hydrochlorothiazide yield percent, in addition to acceptable content uniformity and dissolution enhancement. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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46 pages, 3156 KB

Open AccessEditor’s ChoiceReview

An Overview on the Physiopathology of the Blood–Brain Barrier and the Lipid-Based Nanocarriers for Central Nervous System Delivery

by Francesca Susa, Silvia Arpicco, Candido Fabrizio Pirri and Tania Limongi

Pharmaceutics 2024, 16(7), 849; https://doi.org/10.3390/pharmaceutics16070849 - 22 Jun 2024

Cited by 20 | Viewed by 5440

Abstract

The state of well-being and health of our body is regulated by the fine osmotic and biochemical balance established between the cells of the different tissues, organs, and systems. Specific districts of the human body are defined, kept in the correct state of [...] Read more.

The state of well-being and health of our body is regulated by the fine osmotic and biochemical balance established between the cells of the different tissues, organs, and systems. Specific districts of the human body are defined, kept in the correct state of functioning, and, therefore, protected from exogenous or endogenous insults of both mechanical, physical, and biological nature by the presence of different barrier systems. In addition to the placental barrier, which even acts as a linker between two different organisms, the mother and the fetus, all human body barriers, including the blood–brain barrier (BBB), blood–retinal barrier, blood–nerve barrier, blood–lymph barrier, and blood–cerebrospinal fluid barrier, operate to maintain the physiological homeostasis within tissues and organs. From a pharmaceutical point of view, the most challenging is undoubtedly the BBB, since its presence notably complicates the treatment of brain disorders. BBB action can impair the delivery of chemical drugs and biopharmaceuticals into the brain, reducing their therapeutic efficacy and/or increasing their unwanted bioaccumulation in the surrounding healthy tissues. Recent nanotechnological innovation provides advanced biomaterials and ad hoc customized engineering and functionalization methods able to assist in brain-targeted drug delivery. In this context, lipid nanocarriers, including both synthetic (liposomes, solid lipid nanoparticles, nanoemulsions, nanostructured lipid carriers, niosomes, proniosomes, and cubosomes) and cell-derived ones (extracellular vesicles and cell membrane-derived nanocarriers), are considered one of the most successful brain delivery systems due to their reasonable biocompatibility and ability to cross the BBB. This review aims to provide a complete and up-to-date point of view on the efficacy of the most varied lipid carriers, whether FDA-approved, involved in clinical trials, or used in in vitro or in vivo studies, for the treatment of inflammatory, cancerous, or infectious brain diseases. Full article

(This article belongs to the Special Issue Nanotechnology-Based Pharmaceutical Treatments)

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13 pages, 3238 KB

Open AccessEditor’s ChoiceArticle

Derivatization of Hyaluronan to Target Neuroblastoma and Neuroglioma Expressing CD44

by Giau Van Vo, Kummara Madhusudana Rao, Ildoo Chung, Chang-Sik Ha, Seong Soo A. An and Yang H. Yun

Pharmaceutics 2024, 16(6), 836; https://doi.org/10.3390/pharmaceutics16060836 - 20 Jun 2024

Cited by 3 | Viewed by 2544

Abstract

Therapeutics for actively targeting over-expressed receptors are of great interest because the majority of diseased tissues originate from normal cells and do not possess a unique receptor from which they can be differentiated. One such receptor is CD44, which has been shown to [...] Read more.

Therapeutics for actively targeting over-expressed receptors are of great interest because the majority of diseased tissues originate from normal cells and do not possess a unique receptor from which they can be differentiated. One such receptor is CD44, which has been shown to be highly overexpressed in many breast cancers and other types of cancer cells. While CD44 has been documented to express low levels in normal adult neurons, astrocytes, and microglia, this receptor may be overexpressed by neuroblastoma and neuroglioma. If differential expression exists between normal and cancerous cells, hyaluronan (HA) could be a useful carrier that targets carcinomas. Thus, HA was conjugated with resveratrol (HA-R), and its efficacy was tested on cortical–neuroblastoma hybrid, neuroblastoma, and neuroglioma cells. Confocal and flow cytometry showed these cells express CD44 and are able to bind and uptake HA-R. The toxicity of HA-R correlated well with CD44 expression in this study. Therefore, conjugating resveratrol and other chemotherapeutics to HA could minimize the side effects for normal cells within the brain and nervous system and could be a viable strategy for developing targeted therapies. Full article

(This article belongs to the Special Issue Carbohydrate-Based Carriers for Drug Delivery)

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10 pages, 1763 KB

Open AccessEditor’s ChoiceArticle

The Distinctive Role of Gluconic Acid in Retarding Percutaneous Drug Permeation: Formulation of Lidocaine-Loaded Chitosan Nanoparticles

by Amnon C. Sintov

Pharmaceutics 2024, 16(6), 831; https://doi.org/10.3390/pharmaceutics16060831 - 19 Jun 2024

Cited by 1 | Viewed by 1688

Abstract

The objective of the present investigation was to evidence the skin retardation phenomenon of lidocaine by gluconic acid as an inactive ingredient involved in citrate-crosslinking chitosan nanoparticles. Lidocaine hydrochloride was loaded in nanoparticles based on chitosan, fabricated by using a water-in-oil microemulsion as [...] Read more.

The objective of the present investigation was to evidence the skin retardation phenomenon of lidocaine by gluconic acid as an inactive ingredient involved in citrate-crosslinking chitosan nanoparticles. Lidocaine hydrochloride was loaded in nanoparticles based on chitosan, fabricated by using a water-in-oil microemulsion as a template and citric acid as an ionic cross-linker. Gluconic acid (pentahydroxy hexanoic acid) was added during the fabrication and compared with caproic acid, a non-hydroxy hexanoic acid. The chitosan nanoparticulate systems were characterized for mean particle size, particle size distribution, and zeta potential. The pentahydroxy hexanoic acid decreased the zeta potential to a significantly lower value than those obtained from both plain citrate and citrate–hexanoic acid formulations. The relatively lower value implies that gluconate ions are partly attached to the nanoparticle’s surface and mask its positively charged groups. It was also noted that the in vitro percutaneous permeation flux of lidocaine significantly decreased when gluconate-containing chitosan nanoparticles were applied, i.e., 6.1 ± 1.5 μg‧cm⁻²‧h⁻¹ without gluconic acid to 3.4 ± 2.3 μg‧cm⁻²‧h⁻¹ with gluconic acid. According to this result, it is suggested that gluconate ions played a role in retarding drug permeation through the skin, probably by calcium chelation in the stratum granulosum, which in turn stimulated lamellar body secretion, lipid synthesis, and intracellular release of Ca²⁺ from the endoplasmic reticulum. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications, 2nd Edition)

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20 pages, 2999 KB

Open AccessEditor’s ChoiceArticle

Acid-Responsive Decomposable Nanomedicine Based on Zeolitic Imidazolate Frameworks for Near-Infrared Fluorescence Imaging/Chemotherapy Combined Tumor Theranostics

by Heze Guo, Vincent Mukwaya, Daikun Wu, Shuhan Xiong and Hongjing Dou

Pharmaceutics 2024, 16(6), 823; https://doi.org/10.3390/pharmaceutics16060823 - 18 Jun 2024

Cited by 7 | Viewed by 2650

Abstract

Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) are gaining traction in tumor theranostics for their effectiveness in encapsulating both imaging agents and therapeutic drugs. While typically, similar hydrophilic molecules are encapsulated in either pure aqueous or organic environments, few studies have explored co-encapsulation of [...] Read more.

Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) are gaining traction in tumor theranostics for their effectiveness in encapsulating both imaging agents and therapeutic drugs. While typically, similar hydrophilic molecules are encapsulated in either pure aqueous or organic environments, few studies have explored co-encapsulation of chemotherapeutic drugs and imaging agents with varying hydrophilicity and, consequently, constructed multifunctional ZIF-8 composite NPs for acid-responsive, near-infrared fluorescence imaging/chemotherapy combined tumor theranostics. Here, we present a one-pot method for the synthesis of uniform Cy5.5&DOX@ZIF-8 nanoparticles in mixed solvents, efficiently achieving simultaneous encapsulation of hydrophilic doxorubicin (DOX) and hydrophobic Cyanine-5.5 (Cy5.5). Surface decoration with dextran (Dex) enhanced colloidal stability and biocompatibility. The method significantly facilitated co-loading of Cy5.5 dyes and DOX drugs, endowing the composite NPs with notable fluorescent imaging capabilities and pH-responsive chemotherapy capacities. In vivo near-infrared fluorescence (NIRF) imaging in A549 tumor-bearing mice demonstrated significant accumulation of Cy5.5 at tumor sites due to enhanced permeability and retention (EPR) effects, with fluorescence intensities approximately 48-fold higher than free Cy5.5. Enhanced therapeutic efficiency was observed in composite NPs compared to free DOX, validating tumor-targeted capability. These findings suggest ZIF-8-based nanomedicines as promising platforms for multifunctional tumor theranostics. Full article

(This article belongs to the Topic Application of Nanomaterials and Nanobiotechnology in Cancer)

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23 pages, 7648 KB

Open AccessEditor’s ChoiceArticle

Multistage Nanocarrier Based on an Oil Core–Graphene Oxide Shell

by Immacolata Tufano, Raffaele Vecchione, Valeria Panzetta, Edmondo Battista, Costantino Casale, Giorgia Imparato and Paolo Antonio Netti

Pharmaceutics 2024, 16(6), 827; https://doi.org/10.3390/pharmaceutics16060827 - 18 Jun 2024

Viewed by 2013

Abstract

Potent synthetic drugs, as well as biomolecules extracted from plants, have been investigated for their selectivity toward cancer cells. The main limitation in cancer treatment is the ability to bring such molecules within each single cancer cell, which requires accumulation in the peritumoral [...] Read more.

Potent synthetic drugs, as well as biomolecules extracted from plants, have been investigated for their selectivity toward cancer cells. The main limitation in cancer treatment is the ability to bring such molecules within each single cancer cell, which requires accumulation in the peritumoral region followed by homogeneous spreading within the entire tissue. In the last decades, nanotechnology has emerged as a powerful tool due to its ability to protect the drug during blood circulation and allow enhanced accumulation around the leaky regions of the tumor vasculature. However, the ideal size for accumulation of around 100 nm is too large for effective penetration into the dense collagen matrix. Therefore, we propose a multistage system based on graphene oxide nanosheet-based quantum dots (GOQDs) with dimensions that are 12 nm, functionalized with hyaluronic acid (GOQDs-HA), and deposited using the layer-by-layer technique onto an oil-in-water nanoemulsion (O/W NE) template that is around 100 nm in size, previously stabilized by a biodegradable polymer, chitosan. The choice of a biodegradable core for the nanocarrier is to degrade once inside the tumor, thus promoting the release of smaller compounds, GOQDs-HA, carrying the adsorbed anticancer compound, which in this work is represented by curcumin as a model bioactive anticancer molecule. Additionally, modification with HA aims to promote active targeting of stromal and cancer cells. Cell uptake experiments and preliminary penetration experiments in three-dimensional microtissues were performed to assess the proposed multistage nanocarrier. Full article

(This article belongs to the Special Issue Smart Nanocarriers for Drug Delivery in Cancer Therapy)

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14 pages, 8407 KB

Open AccessEditor’s ChoiceArticle

Stability of Multicomponent Antidote Parenteral Formulations for Autoinjectors against Chemical War Agents (Neurotoxics)

by María José Rodríguez Fernández, Daniel Hernández, Brayan Javier Anaya, Dolores R. Serrano and Juan José Torrado

Pharmaceutics 2024, 16(6), 820; https://doi.org/10.3390/pharmaceutics16060820 - 17 Jun 2024

Viewed by 1629

Abstract

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, [...] Read more.

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, and midazolam); (ii) pH (3 versus 4); and (iii) type of elastomeric sealing material (PH 701/50 C BLACK versus 4023/50 GRAY). Syringes were stored at three different temperatures: 4, 25, and 40 °C. Samples were assayed at different time points to study the physical appearance, drug sorption on the sealing elastomeric materials, and drug content in solution. Midazolam was unstable in all tested experimental conditions. Drug adsorption was observed in both types of sealing elastomeric materials and was significantly (p < 0.01) dependent on the lipophilicity of the drug. The most stable formulation was the combination of pralidoxime and atropine at pH 4 with the elastomeric sealing material 4023/50 GRAY. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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47 pages, 3150 KB

Open AccessEditor’s ChoiceReview

Progress in Topical and Transdermal Drug Delivery Research—Focus on Nanoformulations

by Dominique Lunter, Victoria Klang, Adina Eichner, Sanela M. Savic, Snezana Savic, Guoping Lian and Franciska Erdő

Pharmaceutics 2024, 16(6), 817; https://doi.org/10.3390/pharmaceutics16060817 - 16 Jun 2024

Cited by 27 | Viewed by 9866

Abstract

Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The [...] Read more.

Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The skin is involved in body temperature regulation by the storage of fat and water. It is an interesting tissue in regard to the local and transdermal application of active ingredients for prevention or treatment of pathological conditions. Topical and transdermal delivery is an emerging route of drug and cosmetic administration. It is beneficial for avoiding side effects and rapid metabolism. Many pharmaceutical, technological and cosmetic innovations have been described and patented recently in the field. In this review, the main features of skin morphology and physiology are presented and are being followed by the description of classical and novel nanoparticulate dermal and transdermal drug formulations. The biophysical aspects of the penetration of drugs and cosmetics into or across the dermal barrier and their investigation in diffusion chambers, skin-on-a-chip devices, high-throughput measuring systems or with advanced analytical techniques are also shown. The current knowledge about mathematical modeling of skin penetration and the future perspectives are briefly discussed in the end, all also involving nanoparticulated systems. Full article

(This article belongs to the Special Issue Nanoparticles for Local Drug Delivery)

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17 pages, 2761 KB

Open AccessEditor’s ChoiceReview

Development, Optimization, and Clinical Relevance of Lactoferrin Delivery Systems: A Focus on Ocular Delivery

by Erika Ponzini, Gloria Astolfi, Rita Grandori, Silvia Tavazzi and Piera Versura

Pharmaceutics 2024, 16(6), 804; https://doi.org/10.3390/pharmaceutics16060804 - 14 Jun 2024

Cited by 9 | Viewed by 3072

Abstract

Lactoferrin (Lf), a multifunctional protein found abundantly in secretions, including tears, plays a crucial role in ocular health through its antimicrobial, immunoregulatory, anti-inflammatory, and antioxidant activities. Advanced delivery systems are desirable to fully leverage its therapeutic potential in treating ocular diseases. The process [...] Read more.

Lactoferrin (Lf), a multifunctional protein found abundantly in secretions, including tears, plays a crucial role in ocular health through its antimicrobial, immunoregulatory, anti-inflammatory, and antioxidant activities. Advanced delivery systems are desirable to fully leverage its therapeutic potential in treating ocular diseases. The process of Lf quantification for diagnostic purposes underscores the importance of developing reliable, cost-effective detection methods, ranging from conventional techniques to advanced nano-based sensors. Despite the ease and non-invasiveness of topical administration for ocular surface diseases, challenges such as rapid drug elimination necessitate innovations, such as Lf-loaded contact lenses and biodegradable polymeric nanocapsules, to enhance drug stability and bioavailability. Furthermore, overcoming ocular barriers for the treatment of posterior segment disease calls for nano-formulations. The scope of this review is to underline the advancements in nanotechnology-based Lf delivery methods, emphasizing the pivotal role of multidisciplinary approaches and cross-field strategies in improving ocular drug delivery and achieving better therapeutic outcomes for a wide spectrum of eye conditions. Full article

(This article belongs to the Special Issue Application Progress of Lactoferrin in Biomedicine)

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54 pages, 4234 KB

Open AccessEditor’s ChoiceReview

Lipid Biomimetic Models as Simple Yet Complex Tools to Predict Skin Permeation and Drug–Membrane Biophysical Interactions

by Eduarda Fernandes, Carla M. Lopes and Marlene Lúcio

Pharmaceutics 2024, 16(6), 807; https://doi.org/10.3390/pharmaceutics16060807 - 14 Jun 2024

Cited by 2 | Viewed by 2980

Abstract

The barrier function of the skin is primarily determined by its outermost layer, the Stratum Corneum (SC). The SC consists of corneocytes embedded in a lipid matrix composed mainly of ceramides, cholesterol, and free fatty acids in equimolar proportions and is organised in [...] Read more.

The barrier function of the skin is primarily determined by its outermost layer, the Stratum Corneum (SC). The SC consists of corneocytes embedded in a lipid matrix composed mainly of ceramides, cholesterol, and free fatty acids in equimolar proportions and is organised in a complex lamellar structure with different periodicities and lateral packings. This matrix provides a diffusion pathway across the SC for bioactive compounds that are administered to the skin. In this regard, and as the skin administration route has grown in popularity, there has been an increase in the use of lipid mixtures that closely resemble the SC lipid matrix, either for a deeper biophysical understanding or for pharmaceutical and cosmetic purposes. This review focuses on a systematic analysis of the main outcomes of using lipid mixtures as SC lipid matrix models for pharmaceutical and cosmetic purposes. Thus, a methodical evaluation of the main outcomes based on the SC structure is performed, as well as the main recent developments in finding suitable new in vitro tools for permeation testing based on lipid models. Full article

(This article belongs to the Topic New Challenges in the Cosmetics Industry)

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21 pages, 4436 KB

Open AccessEditor’s ChoiceArticle

Benznidazole-Loaded Polymeric Nanoparticles for Oral Chemotherapeutic Treatment of Chagas Disease

by Lucas Resende Dutra Sousa, Thays Helena Chaves Duarte, Viviane Flores Xavier, Aline Coelho das Mercês, Gabriel Maia Vieira, Maximiliano Delany Martins, Cláudia Martins Carneiro, Viviane Martins Rebello dos Santos, Orlando David Henrique dos Santos and Paula Melo de Abreu Vieira

Pharmaceutics 2024, 16(6), 800; https://doi.org/10.3390/pharmaceutics16060800 - 13 Jun 2024

Cited by 4 | Viewed by 2169

Abstract

Chagas disease (CD) is a worldwide public health problem. Benznidazole (BZ) is the drug used to treat it. However, in its commercial formulation, it has significant side effects and is less effective in the chronic phase of the infection. The development of particulate [...] Read more.

Chagas disease (CD) is a worldwide public health problem. Benznidazole (BZ) is the drug used to treat it. However, in its commercial formulation, it has significant side effects and is less effective in the chronic phase of the infection. The development of particulate systems containing BZ is therefore being promoted. The objective of this investigation was to develop polymeric nanoparticles loaded with BZ and examine their trypanocidal impact in vitro. Two formulas (BNP1 and BNP2) were produced through double emulsification and freeze drying. Subsequent to physicochemical and morphological assessment, both formulations exhibited adequate yield, average particle diameter, and zeta potential for oral administration. Cell viability was assessed in H9C2 and RAW 264.7 cells in vitro, revealing no cytotoxicity in cardiomyocytes or detrimental effects in macrophages at specific concentrations. BNP1 and BNP2 enhanced the effect of BZ within 48 h using a treatment of 3.90 μg/mL. The formulations notably improved NO reduction, particularly BNP2. The findings imply that the compositions are suitable for preclinical research, underscoring their potential as substitutes for treating CD. This study aids the quest for new BZ formulations, which are essential in light of the disregard for the treatment of CD and the unfavorable effects associated with its commercial product. Full article

(This article belongs to the Special Issue Nanoparticles: Technology and Therapeutic Applications in Human Infectious and Parasitic Diseases)

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12 pages, 3160 KB

Open AccessEditor’s ChoiceReview

Nano-Delivery of Immunogenic Cell Death Inducers and Immune Checkpoint Blockade Agents: Single-Nanostructure Strategies for Enhancing Immunotherapy

by Yujeong Moon, Hanhee Cho and Kwangmeyung Kim

Pharmaceutics 2024, 16(6), 795; https://doi.org/10.3390/pharmaceutics16060795 - 12 Jun 2024

Cited by 6 | Viewed by 4070

Abstract

Cancer immunotherapy has revolutionized oncology by harnessing the patient’s immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically ‘cold’ tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers [...] Read more.

Cancer immunotherapy has revolutionized oncology by harnessing the patient’s immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically ‘cold’ tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers and advanced drug delivery systems represents a promising solution. This review discusses the development and application of various nanocarriers, including polymeric nanoparticles, liposomes, peptide-based nanoparticles, and inorganic nanoparticles, designed to deliver ICD inducers and ICBs effectively. These nanocarriers improve therapeutic outcomes by converting cold tumors into hot tumors, thus enhancing immune responses and reducing systemic toxicity. By focusing on single-nanoparticle systems that co-deliver both ICD inducers and ICBs, this review highlights their potential in achieving higher drug concentrations at tumor sites, improving pharmacokinetics and pharmacodynamics, and facilitating clinical translation. Future research should aim to optimize these nanocarrier systems for better in vivo performance and clinical applications, ultimately advancing cancer immunotherapy. Full article

(This article belongs to the Special Issue Nanomedicines in Cancer Therapy)

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19 pages, 4927 KB

Open AccessEditor’s ChoiceArticle

Synthesis of Gd-DTPA Carborane-Containing Compound and Its Immobilization on Iron Oxide Nanoparticles for Potential Application in Neutron Capture Therapy

by Ilya V. Korolkov, Alexander Zaboronok, Kairat A. Izbasar, Zhangali A. Bekbol, Lana I. Lissovskaya, Alexandr V. Zibert, Rafael I. Shakirzyanov, Luiza N. Korganbayeva, Haolan Yang, Eiichi Ishikawa and Maxim V. Zdorovets

Pharmaceutics 2024, 16(6), 797; https://doi.org/10.3390/pharmaceutics16060797 - 12 Jun 2024

Cited by 5 | Viewed by 2426

Abstract

Cancer is one of the leading causes of global mortality, and its incidence is increasing annually. Neutron capture therapy (NCT) is a unique anticancer modality capable of selectively eliminating tumor cells within normal tissues. The development of accelerator-based, clinically mountable neutron sources has [...] Read more.

Cancer is one of the leading causes of global mortality, and its incidence is increasing annually. Neutron capture therapy (NCT) is a unique anticancer modality capable of selectively eliminating tumor cells within normal tissues. The development of accelerator-based, clinically mountable neutron sources has stimulated a worldwide search for new, more effective compounds for NCT. We synthesized magnetic iron oxide nanoparticles (NPs) that concurrently incorporate boron and gadolinium, potentially enhancing the effectiveness of NCT. These magnetic nanoparticles underwent sequential modifications through silane polycondensation and allylamine graft polymerization, enabling the creation of functional amino groups on their surface. Characterization was performed using Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), energy dispersive X-ray (EDX), dynamic light scattering (DLS), thermal gravimetric analysis (TGA), and transmission electron microscopy (TEM). ICP-AES measurements indicated that boron (B) content in the NPs reached 3.56 ppm/mg, while gadolinium (Gd) averaged 0.26 ppm/mg. Gadolinium desorption was observed within 4 h, with a peak rate of 61.74%. The biocompatibility of the NPs was confirmed through their relatively low cytotoxicity and sufficient cellular tolerability. Using NPs at non-toxic concentrations, we obtained B accumulation of up to 5.724 × 10¹⁰ atoms per cell, sufficient for successful NCT. Although limited by its content in the NP composition, the Gd amount may also contribute to NCT along with its diagnostic properties. Further development of the NPs is ongoing, focusing on increasing the boron and gadolinium content and creating active tumor targeting. Full article

(This article belongs to the Special Issue Development of Novel Tumor-Targeting Nanoparticles, 2nd Edition)

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22 pages, 11192 KB

Open AccessEditor’s ChoiceArticle

Identification and Characterization of Critical Processing Parameters in the Fabrication of Double-Emulsion Poly(lactic-co-glycolic) Acid Microparticles

by Elizabeth R. Bentley, Stacia Subick, Michael Pezzillo, Stephen C. Balmert, Aidan Herbert and Steven R. Little

Pharmaceutics 2024, 16(6), 796; https://doi.org/10.3390/pharmaceutics16060796 - 12 Jun 2024

Cited by 3 | Viewed by 3442

Abstract

In the past several decades, polymeric microparticles (MPs) have emerged as viable solutions to address the limitations of standard pharmaceuticals and their corresponding delivery methods. While there are many preclinical studies that utilize polymeric MPs as a delivery vehicle, there are limited FDA-approved [...] Read more.

In the past several decades, polymeric microparticles (MPs) have emerged as viable solutions to address the limitations of standard pharmaceuticals and their corresponding delivery methods. While there are many preclinical studies that utilize polymeric MPs as a delivery vehicle, there are limited FDA-approved products. One potential barrier to the clinical translation of these technologies is a lack of understanding with regard to the manufacturing process, hindering batch scale-up. To address this knowledge gap, we sought to first identify critical processing parameters in the manufacturing process of blank (no therapeutic drug) and protein-loaded double-emulsion poly(lactic-co-glycolic) acid MPs through a quality by design approach. We then utilized the design of experiments as a tool to systematically investigate the impact of these parameters on critical quality attributes (e.g., size, surface morphology, release kinetics, inner occlusion size, etc.) of blank and protein-loaded MPs. Our results elucidate that some of the most significant CPPs impacting many CQAs of double-emulsion MPs are those within the primary or single-emulsion process (e.g., inner aqueous phase volume, solvent volume, etc.) and their interactions. Furthermore, our results indicate that microparticle internal structure (e.g., inner occlusion size, interconnectivity, etc.) can heavily influence protein release kinetics from double-emulsion MPs, suggesting it is a crucial CQA to understand. Altogether, this study identifies several important considerations in the manufacturing and characterization of double-emulsion MPs, potentially enhancing their translation. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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14 pages, 2993 KB

Open AccessEditor’s ChoiceArticle

Evaluation of Novel Nasal Mucoadhesive Nanoformulations Containing Lipid-Soluble EGCG for Long COVID Treatment

by Nicolette Frank, Douglas Dickinson, Garrison Lovett, Yutao Liu, Hongfang Yu, Jingwen Cai, Bo Yao, Xiaocui Jiang and Stephen Hsu

Pharmaceutics 2024, 16(6), 791; https://doi.org/10.3390/pharmaceutics16060791 - 11 Jun 2024

Cited by 6 | Viewed by 2880

Abstract

Following recovery from the acute infection stage of the SARS-CoV-2 virus (COVID-19), survivors can experience a wide range of persistent Post-Acute Sequelae of COVID-19 (PASC), also referred to as long COVID. According to the US National Research Action Plan on Long COVID 2022, [...] Read more.

Following recovery from the acute infection stage of the SARS-CoV-2 virus (COVID-19), survivors can experience a wide range of persistent Post-Acute Sequelae of COVID-19 (PASC), also referred to as long COVID. According to the US National Research Action Plan on Long COVID 2022, up to 23.7 million Americans suffer from long COVID, and approximately one million workers may be out of the workforce each day due to these symptoms, leading to a USD 50 billion annual loss of salary. Neurological symptoms associated with long COVID result from persistent infection with SARS-CoV-2 in the nasal neuroepithelial cells, leading to inflammation in the central nervous system (CNS). As of today, there is no evidence that vaccines or medications can clear the persistent viral infection in olfactory mucosa. Recently published clinical data demonstrate that only 5% of long COVID anosmia patients have fully recovered during the past 2 years, and 10.4% of COVID patients are still symptomatic 18 months post-infection. Our group demonstrated that epigallocatechin-3-gallate-monopalmitate (EC16m) nanoformulations possess strong antiviral activity against human coronavirus, suggesting that this green-tea-derived compound in nanoparticle formulations could be developed as an intranasally delivered new drug targeting the persistent SARS-CoV-2 infection, as well as inflammation and oxidative stress in the CNS, leading to restoration of neurologic functions. The objective of the current study was to evaluate the mucociliary safety of the EC16m nasal nanoformulations and their efficacy against human coronavirus. Methods: Nanoparticle size and Zeta potential were measured using the ZetaView Nanoparticle Tracking Analysis system; mucociliary safety was determined using the MucilAir human nasal model; contact antiviral activity and post-infection inhibition against the OC43 viral strain were assessed by the TCID50 assay for cytopathic effect on MRC-5 cells. Results: The saline-based EC16 mucoadhesive nanoformulations containing 0.005 to 0.02% w/v EC16m have no significant difference compared to saline (0.9% NaCl) with respect to tissue integrity, cytotoxicity, and cilia beat frequency. A 5 min contact resulted in 99.9% inactivation of β-coronavirus OC43. OC43 viral replication was inhibited by >90% after infected MRC-5 cells were treated with the formulations. Conclusion: The saline-based novel EC16m mucoadhesive nasal nanoformulations rapidly inactivated human coronavirus with mucociliary safety properties comparable to saline, a solution widely used for nasal applications. Full article

(This article belongs to the Special Issue Nanoparticle-Mediated Targeted Drug Delivery Systems)

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26 pages, 4460 KB

Open AccessEditor’s ChoiceArticle

A Physiologically Based Pharmacokinetic (PBPK) Study to Assess the Adjuvanticity of Three Peptides in an Oral Vaccine

by Leonor Saldanha, Ülo Langel and Nuno Vale

Pharmaceutics 2024, 16(6), 780; https://doi.org/10.3390/pharmaceutics16060780 - 8 Jun 2024

Cited by 3 | Viewed by 1613

Abstract

Following up on the first PBPK model for an oral vaccine built for alpha-tocopherol, three peptides are explored in this article to verify if they could support an oral vaccine formulation as adjuvants using the same PBPK modeling approach. A literature review was [...] Read more.

Following up on the first PBPK model for an oral vaccine built for alpha-tocopherol, three peptides are explored in this article to verify if they could support an oral vaccine formulation as adjuvants using the same PBPK modeling approach. A literature review was conducted to verify what peptides have been used as adjuvants in the last decades, and it was noticed that MDP derivatives have been used, with one of them even being commercially approved and used as an adjuvant when administered intravenously in oncology. The aim of this study was to build optimized models for three MDP peptides (MDP itself, MTP-PE, and murabutide) and to verify if they could act as adjuvants for an oral vaccine. Challenges faced by peptides in an oral delivery system are taken into consideration, and improvements to the formulations to achieve better results are described in a step-wise approach to reach the most-optimized model. Once simulations are performed, results are compared to determine what would be the best peptide to support as an oral adjuvant. According to our results, MTP-PE, the currently approved and commercialized peptide, could have potential to be incorporated into an oral formulation. It would be interesting to proceed with further in vivo experiments to determine the behavior of this peptide when administered orally with a proper formulation to overcome the challenges of oral delivery systems. Full article

(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)

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27 pages, 6940 KB

Open AccessEditor’s ChoiceArticle

Evidence That a Peptide-Drug/p53 Gene Complex Promotes Cognate Gene Expression and Inhibits the Viability of Glioblastoma Cells

by Ana Neves, Tânia Albuquerque, Rúben Faria, Cecília R. A. Santos, Eric Vivès, Prisca Boisguérin, Diana Carneiro, Daniel F. Bruno, Maria D. Pavlaki, Susana Loureiro, Ângela Sousa and Diana Costa

Pharmaceutics 2024, 16(6), 781; https://doi.org/10.3390/pharmaceutics16060781 - 8 Jun 2024

Cited by 2 | Viewed by 2931

Abstract

Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Conventional therapies are followed by poor patient survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Gene therapy has emerged as an exciting and innovative tool in cancer [...] Read more.

Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Conventional therapies are followed by poor patient survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Gene therapy has emerged as an exciting and innovative tool in cancer therapy. Its combination with chemotherapy has significantly improved therapeutic outcomes. In line with this, our team has developed temozolomide–transferrin (Tf) peptide (WRAP5)/p53 gene nanometric complexes that were revealed to be biocompatible with non-cancerous cells and in a zebrafish model and were able to efficiently target and internalize into SNB19 and U373 glioma cell lines. The transfection of these cells, mediated by the formulated peptide-drug/gene complexes, resulted in p53 expression. The combined action of the anticancer drug with p53 supplementation in cancer cells enhances cytotoxicity, which was correlated to apoptosis activation through quantification of caspase-3 activity. In addition, increased caspase-9 levels revealed that the intrinsic or mitochondrial pathway of apoptosis was implicated. This assumption was further evidenced by the presence, in glioma cells, of Bax protein overexpression—a core regulator of this apoptotic pathway. Our findings demonstrated the great potential of peptide TMZ/p53 co-delivery complexes for cellular transfection, p53 expression, and apoptosis induction, holding promising therapeutic value toward glioblastoma. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

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