Pharmaceutics

14 pages, 2255 KB

Open AccessEditor’s ChoiceArticle

Camellia sinensis (L.) Kuntze Extract Attenuates Ovalbumin-Induced Allergic Asthma by Regulating Airway Inflammation and Mucus Hypersecretion

by Sohi Kang, Hyun-Yong Kim, A Yeong Lee, Hyo Seon Kim, Jun Hong Park, Byeong Cheol Moon, Hyeon Hwa Nam, Sung-Wook Chae, Bokyung Jung, Changjong Moon, In Sik Shin, Joong Sun Kim and Yun-Soo Seo

Pharmaceutics 2023, 15(9), 2355; https://doi.org/10.3390/pharmaceutics15092355 - 20 Sep 2023

Cited by 4 | Viewed by 2255

Abstract

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects [...] Read more.

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects of Camellia sinensis (L.) Kuntze extract (CE) on ovalbumin-induced allergic asthma. The components of CE were analyzed using high-performance liquid chromatography (HPLC) chromatogram patterns, and asthmatic animal models were induced via ovalbumin treatment. The antioxidant and anti-inflammatory effects of CE were evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), and nitric oxide (NO) assays. Seven compounds were detected in the CE chromatogram. In the ovalbumin-induced mouse model, CE treatment significantly decreased the inflammation index in the lung tissue. CE also significantly decreased eosinophilia and the production of inflammatory cytokines and OVA-specific IgE in animals with asthma. Collectively, our results indicate that CE has anti-inflammatory and antioxidant activities, and that CE treatment suppresses asthmatic progression, including mucin accumulation, inflammation, and OVA-specific IgE production. Full article

(This article belongs to the Special Issue New Approach to Anti-inflammation, Antibacterial and Anti-cancer Therapy: Natural Extracts)

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12 pages, 2232 KB

Open AccessEditor’s ChoiceArticle

A New Paclitaxel Formulation Based on Secretome Isolated from Mesenchymal Stem Cells Shows a Significant Cytotoxic Effect on Osteosarcoma Cell Lines

by Alessia Giovanna Santa Banche Niclot, Elena Marini, Ivana Ferrero, Francesco Barbero, Elena Rosso, Ivana Fenoglio, Alessandro Barge, Augusto Pessina, Valentina Coccè, Francesca Paino, Katia Mareschi and Franca Fagioli

Pharmaceutics 2023, 15(9), 2340; https://doi.org/10.3390/pharmaceutics15092340 - 19 Sep 2023

Cited by 5 | Viewed by 1975

Abstract

Background: Osteosarcoma (OS) represents a rare cancer with an unfavorable prognosis that needs innovative treatment. The aim was to isolate a secretome from mesenchymal stem cells (MSCs) that are treated with paclitaxel (PTX)-containing microvesicles as a drug delivery system and analyze its cytotoxic [...] Read more.

Background: Osteosarcoma (OS) represents a rare cancer with an unfavorable prognosis that needs innovative treatment. The aim was to isolate a secretome from mesenchymal stem cells (MSCs) that are treated with paclitaxel (PTX)-containing microvesicles as a drug delivery system and analyze its cytotoxic effects on OS cell lines (SJSA, MG63, and HOS). Methods: Three batches of secretome (SECR-1, SECR-2, and SECR-3) were produced from three bone marrow (BM) MSCs samples treated for 24 h with 15 µg/mL of PTX or with a standard medium. The viability of the OS cell lines after 5 days of exposure to SECR-1-2-3 (pure and diluted to 1:2 and 1:4) was analyzed with an MTT assay. The same SECR batches were analyzed with high-performance liquid chromatography (HPLC) and with a nanoparticle tracking assay (NTA). Results: A statistically significant decrease in the viability of all OS cell lines was observed after treatment with SECR-PTX 1-2-3 in a dose–response manner. The NTA analyses showed the presence of nanoparticles (NPs) with a mean size comparable to that of extracellular vesicles (EVs). The HPLC analyses detected the presence of PTX in minimal doses in all SECR batches. Conclusions: This proof-of-concept study showed that the conditioned medium isolated from MSCs loaded with PTX had a strong cytotoxic effect on OS cell lines, due to the presence of EV and PTX. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cell-Based-Delivery for Clinical Applications)

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53 pages, 8211 KB

Open AccessEditor’s ChoiceReview

Cyclodextrin Inclusion Complexes for Improved Drug Bioavailability and Activity: Synthetic and Analytical Aspects

by Álvaro Sarabia-Vallejo, María del Mar Caja, Ana I. Olives, M. Antonia Martín and J. Carlos Menéndez

Pharmaceutics 2023, 15(9), 2345; https://doi.org/10.3390/pharmaceutics15092345 - 19 Sep 2023

Cited by 120 | Viewed by 12639

Abstract

Many active pharmaceutical ingredients show low oral bioavailability due to factors such as poor solubility and physical and chemical instability. The formation of inclusion complexes with cyclodextrins, as well as cyclodextrin-based polymers, nanosponges, and nanofibers, is a valuable tool to improve the oral [...] Read more.

Many active pharmaceutical ingredients show low oral bioavailability due to factors such as poor solubility and physical and chemical instability. The formation of inclusion complexes with cyclodextrins, as well as cyclodextrin-based polymers, nanosponges, and nanofibers, is a valuable tool to improve the oral bioavailability of many drugs. The microencapsulation process modifies key properties of the included drugs including volatility, dissolution rate, bioavailability, and bioactivity. In this context, we present relevant examples of the stabilization of labile drugs through the encapsulation in cyclodextrins. The formation of inclusion complexes with drugs belonging to class IV in the biopharmaceutical classification system as an effective solution to increase their bioavailability is also discussed. The stabilization and improvement in nutraceuticals used as food supplements, which often have low intestinal absorption due to their poor solubility, is also considered. Cyclodextrin-based nanofibers, which are polymer-free and can be generated using environmentally friendly technologies, lead to dramatic bioavailability enhancements. The synthesis of chemically modified cyclodextrins, polymers, and nanosponges based on cyclodextrins is discussed. Analytical techniques that allow the characterization and verification of the formation of true inclusion complexes are also considered, taking into account the differences in the procedures for the formation of inclusion complexes in solution and in the solid state. Full article

(This article belongs to the Special Issue Development of Chitosan/Cyclodextrins in Drug Delivery Field)

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33 pages, 8301 KB

Open AccessEditor’s ChoiceReview

Photothermal Effect of Gold Nanoparticles as a Nanomedicine for Diagnosis and Therapeutics

by Panangattukara Prabhakaran Praveen Kumar and Dong-Kwon Lim

Pharmaceutics 2023, 15(9), 2349; https://doi.org/10.3390/pharmaceutics15092349 - 19 Sep 2023

Cited by 67 | Viewed by 7696

Abstract

Gold nanoparticles (AuNPs) have received great attention for various medical applications due to their unique physicochemical properties. AuNPs with tunable optical properties in the visible and near-infrared regions have been utilized in a variety of applications such as in vitro diagnostics, in vivo [...] Read more.

Gold nanoparticles (AuNPs) have received great attention for various medical applications due to their unique physicochemical properties. AuNPs with tunable optical properties in the visible and near-infrared regions have been utilized in a variety of applications such as in vitro diagnostics, in vivo imaging, and therapeutics. Among the applications, this review will pay more attention to recent developments in diagnostic and therapeutic applications based on the photothermal (PT) effect of AuNPs. In particular, the PT effect of AuNPs has played an important role in medical applications utilizing light, such as photoacoustic imaging, photon polymerase chain reaction (PCR), and hyperthermia therapy. First, we discuss the fundamentals of the optical properties in detail to understand the background of the PT effect of AuNPs. For diagnostic applications, the ability of AuNPs to efficiently convert absorbed light energy into heat to generate enhanced acoustic waves can lead to significant enhancements in photoacoustic signal intensity. Integration of the PT effect of AuNPs with PCR may open new opportunities for technological innovation called photonic PCR, where light is used to enable fast and accurate temperature cycling for DNA amplification. Additionally, beyond the existing thermotherapy of AuNPs, the PT effect of AuNPs can be further applied to cancer immunotherapy. Controlled PT damage to cancer cells triggers an immune response, which is useful for obtaining better outcomes in combination with immune checkpoint inhibitors or vaccines. Therefore, this review examines applications to nanomedicine based on the PT effect among the unique optical properties of AuNPs, understands the basic principles, the advantages and disadvantages of each technology, and understands the importance of a multidisciplinary approach. Based on this, it is expected that it will help understand the current status and development direction of new nanoparticle-based disease diagnosis methods and treatment methods, and we hope that it will inspire the development of new innovative technologies. Full article

(This article belongs to the Special Issue Advances in Cancer Nanotechnology for Photodynamic and Photothermal Therapy)

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14 pages, 3158 KB

Open AccessEditor’s ChoiceArticle

Caco-2 Cell Sheet Partially Laminated with HT29-MTX Cells as a Novel In Vitro Model of Gut Epithelium Drug Permeability

by Yi Cheng, Chie Watanabe, Yusuke Ando, Satoshi Kitaoka, Yuya Egawa, Tomoya Takashima, Akihiro Matsumoto and Masahiro Murakami

Pharmaceutics 2023, 15(9), 2338; https://doi.org/10.3390/pharmaceutics15092338 - 18 Sep 2023

Cited by 16 | Viewed by 5527

Abstract

The intestinal epithelial Caco-2 cell monolayer is a well-established in vitro model useful for predicting intestinal drug absorption in humans. Coculture models of Caco-2 and goblet-cell-like HT29-MTX cells have been developed to overcome the lack of a mucus layer; however, those models are [...] Read more.

The intestinal epithelial Caco-2 cell monolayer is a well-established in vitro model useful for predicting intestinal drug absorption in humans. Coculture models of Caco-2 and goblet-cell-like HT29-MTX cells have been developed to overcome the lack of a mucus layer; however, those models are much leakier compared to the intestinal epithelium. Here, we developed a partially laminated culture model where HT29-MTX cells were superimposed onto a Caco-2 monolayer to overcome this issue. A morphological study showed that the piled HT29-MTX cells were voluntarily incorporated into the Caco-2 monolayer, and mucus production was confirmed via periodic acid-Schiff and mucin protein 2 staining. Permeability was evaluated in terms of transepithelial electrical resistance (TEER) and the apparent permeability of paracellular markers with different molecular sizes. The partially laminated model maintained the high barrier function of the Caco-2 monolayer, whose permeability appeared adjustable according to the HT29-MTX/Caco-2 cell ratio. In contrast, the coculture models showed abnormally high permeability of those markers, correlated with low TEER. Thus, the partially laminated model enabled in vitro recapitulation of effective mucosal barrier function. Consequently, this novel model may be useful as an in vitro high-throughput evaluation system for enteral mucosal permeability and mucus-penetrating efficiency of drugs and nanocarriers. Full article

(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)

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17 pages, 3931 KB

Open AccessEditor’s ChoiceArticle

Conjugation with Tris Decreases the Risk of Ketoprofen-Induced Mucosal Damage and Reduces Inflammation-Associated Methane Production in a Rat Model of Colitis

by Melinda Ugocsai, Anett Bársony, Réka Anna Varga, Ámos Gajda, Noémi Vida, Norbert Lajkó, Benedek Rónaszéki, Gábor Tóth, Mihály Boros, Dániel Érces and Gabriella Varga

Pharmaceutics 2023, 15(9), 2329; https://doi.org/10.3390/pharmaceutics15092329 - 16 Sep 2023

Cited by 1 | Viewed by 1660

Abstract

We have designed a new compound from the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (Ket) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors, with the aim to reduce the gastrointestinal (GI) side effects of NSAID therapies. We investigated mucosal reactions in a standard rat model of colitis together [...] Read more.

We have designed a new compound from the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (Ket) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors, with the aim to reduce the gastrointestinal (GI) side effects of NSAID therapies. We investigated mucosal reactions in a standard rat model of colitis together with methane generation as a possible indicator of pro-inflammatory activation under this condition (approval number: V./148/2013). Whole-body methane production (photoacoustic spectroscopy) and serosal microcirculation (intravital videomicroscopy) were measured, and mucosal damage was assessed (conventional histology; in vivo laser-scanning endomicroscopy). Inflammatory markers were measured from tissue and blood samples. Colitis induced an inflammatory response, morphological colonic damage and increased methane output. Ket treatment lowered inflammatory activation and colonic mucosal injury, but macroscopic gastric bleeding and increased methane output were present. Ket-Tris reduced inflammatory activation, methane emission and colonic mucosal damage, without inducing gastric injury. Conjugation with Tris reduces the GI side effects of Ket and still decreases the inflammatory response in experimental colitis. Methane output correlates with the mucosal inflammatory response and non-invasively demonstrates the effects of anti-inflammatory treatments. Full article

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28 pages, 3985 KB

Open AccessEditor’s ChoiceArticle

Intracellular Fate of the Photosensitizer Chlorin e4 with Different Carriers and Induced Metabolic Changes Studied by ¹H NMR Spectroscopy

by Martina Vermathen, Tobias Kämpfer, Jean-Marc Nuoffer and Peter Vermathen

Pharmaceutics 2023, 15(9), 2324; https://doi.org/10.3390/pharmaceutics15092324 - 15 Sep 2023

Cited by 3 | Viewed by 1748

Abstract

Porphyrinic photosensitizers (PSs) and their nano-sized polymer-based carrier systems are required to exhibit low dark toxicity, avoid side effects, and ensure high in vivo tolerability. Yet, little is known about the intracellular fate of PSs during the dark incubation period and how it [...] Read more.

Porphyrinic photosensitizers (PSs) and their nano-sized polymer-based carrier systems are required to exhibit low dark toxicity, avoid side effects, and ensure high in vivo tolerability. Yet, little is known about the intracellular fate of PSs during the dark incubation period and how it is affected by nanoparticles. In a systematic study, high-resolution magic angle spinning NMR spectroscopy combined with statistical analyses was used to study the metabolic profile of cultured HeLa cells treated with different concentrations of PS chlorin e4 (Ce4) alone or encapsulated in carrier systems. For the latter, either polyvinylpyrrolidone (PVP) or the micelle-forming polyethylene glycol (PEG)-polypropylene glycol triblock copolymer Kolliphor P188 (KP) were used. Diffusion-edited spectra indicated Ce4 membrane localization evidenced by Ce4 concentration-dependent chemical shift perturbation of the cellular phospholipid choline resonance. The effect was also visible in the presence of KP and PVP but less pronounced. The appearance of the PEG resonance in the cell spectra pointed towards cell internalization of KP, whereas no conclusion could be drawn for PVP that remained NMR-invisible. Multivariate statistical analyses of the cell spectra (PCA, PLS-DA, and oPLS) revealed a concentration-dependent metabolic response upon exposure to Ce4 that was attenuated by KP and even more by PVP. Significant Ce4-concentration-dependent alterations were mainly found for metabolites involved in the tricarboxylic acid cycle and the phosphatidylcholine metabolism. The data underline the important protective role of the polymeric carriers following cell internalization. Moreover, to our knowledge, for the first time, the current study allowed us to trace intracellular PS localization on an atomic level by NMR methods. Full article

(This article belongs to the Section Gene and Cell Therapy)

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12 pages, 2399 KB

Open AccessEditor’s ChoiceArticle

Nanosuspension-Based Dissolvable Microneedle Arrays to Enhance Diclofenac Skin Delivery

by Luca Casula, Rosa Pireddu, Maria Cristina Cardia, Elena Pini, Donatella Valenti, Michele Schlich, Chiara Sinico, Salvatore Marceddu, Nina Dragićević, Anna Maria Fadda and Francesco Lai

Pharmaceutics 2023, 15(9), 2308; https://doi.org/10.3390/pharmaceutics15092308 - 13 Sep 2023

Cited by 16 | Viewed by 2950

Abstract

Applying a formulation on the skin represents a patient-acceptable and therapeutically effective way to administer drugs locally and systemically. However, the stratum corneum stands as an impermeable barrier that only allows a very limited number of drugs to be distributed in the underlying [...] Read more.

Applying a formulation on the skin represents a patient-acceptable and therapeutically effective way to administer drugs locally and systemically. However, the stratum corneum stands as an impermeable barrier that only allows a very limited number of drugs to be distributed in the underlying tissues, limiting the feasibility of this administration route. Microneedle arrays are minimally invasive platforms that allow the delivery of drugs within/across the skin through the temporary mechanical disruption of the stratum corneum. In this work, microneedle arrays were combined with nanosuspensions, a technology for solubility enhancement of water insoluble molecules, for the skin delivery of diclofenac. Nanosuspensions were prepared using a top-down method and loaded in the tips of 500 µm or 800 µm high microneedles. The quality of the combined platform was assessed using electron microscopy and spectroscopic and calorimetry techniques, demonstrating the ability to load high amounts of the hydrophobic drug and the compatibility between excipients. Lastly, the application of nanosuspension-loaded microneedles on the skin in vitro allowed the delivery of diclofenac within and across the stratum corneum, proving the potential of this combination to enhance skin delivery of scarcely soluble drugs. Full article

(This article belongs to the Special Issue Nanosuspensions for the Improvement of Drug Bioavailability, 2nd Edition)

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17 pages, 3726 KB

Open AccessEditor’s ChoiceArticle

A Nucleus-Targeting WT1 Antagonistic Peptide Encapsulated in Polymeric Nanomicelles Combats Refractory Chronic Myeloid Leukemia

by Mengting Chen, Xiaocui Fang, Rong Du, Jie Meng, Jingyi Liu, Mingpeng Liu, Yanlian Yang and Chen Wang

Pharmaceutics 2023, 15(9), 2305; https://doi.org/10.3390/pharmaceutics15092305 - 12 Sep 2023

Cited by 3 | Viewed by 1939

Abstract

Chronic myeloid leukemia (CML) is recognized as a classic clonal myeloproliferative disorder. Given the limited treatment options for CML patients in the accelerated phase (AP) and blast phase (BP), there is an evident need to develop new therapeutic strategies. This has the potential [...] Read more.

Chronic myeloid leukemia (CML) is recognized as a classic clonal myeloproliferative disorder. Given the limited treatment options for CML patients in the accelerated phase (AP) and blast phase (BP), there is an evident need to develop new therapeutic strategies. This has the potential to improve outcomes for individuals in the advanced stages of CML. A promising therapeutic target is Wilms’ tumor 1 (WT1), which is highly expressed in BP-CML cells and plays a crucial role in CML progression. In this study, a chemically synthesized nucleus-targeting WT1 antagonistic peptide termed WIP2W was identified. The therapeutic implications of both the peptide and its micellar formulation, M—WIP2W, were evaluated in WT1⁺ BP-CML cell lines and in mice. The findings indicate that WIP2W can bind specifically to the WT1 protein, inducing cell cycle arrest and notable cytotoxicity in WT1⁺ BP-CML cells. Moreover, subcutaneous injections of M—WIP2W were observed to significantly enhance intra-tumoral accumulation and to effectively inhibit tumor growth. Thus, WIP2W stands out as a potent and selective WT1 inhibitor, and the M—WIP2W nanoformulation appears promising for the therapeutic treatment of refractory CML as well as other WT1-overexpressing malignant cancers. Full article

(This article belongs to the Special Issue Functional Peptide-Based Biomaterials for Biomedical Applications)

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16 pages, 6648 KB

Open AccessEditor’s ChoiceArticle

Negr1-Derived Peptides Trigger ALK Degradation and Halt Neuroblastoma Progression In Vitro and In Vivo

by Francesca Pischedda, Alessia Ghirelli, Vasvi Tripathi and Giovanni Piccoli

Pharmaceutics 2023, 15(9), 2307; https://doi.org/10.3390/pharmaceutics15092307 - 12 Sep 2023

Cited by 4 | Viewed by 2143

Abstract

Neuroblastoma is among the most common childhood cancers. Neuroblastoma in advanced stages is one of the most intractable pediatric cancers, notwithstanding the recent therapeutic advances. ALK mutations are among the leading cause of hereditary neuroblastoma and account for more than 14% of the [...] Read more.

Neuroblastoma is among the most common childhood cancers. Neuroblastoma in advanced stages is one of the most intractable pediatric cancers, notwithstanding the recent therapeutic advances. ALK mutations are among the leading cause of hereditary neuroblastoma and account for more than 14% of the somatically acquired alterations. ALK kinase activity is currently one of the main targets for pharmacological strategies. However, evidence from ALK fusion-positive lung cancer studies has shown that resistance to ALK inhibition arises during the therapy, causing a relapse within several years. IgLONs are membrane-bound proteins involved in cell-to-cell adhesion. The expression of the IgLON family results altered in different cancers. We found that the IgLON member Negr1 is downregulated in neuroblastoma. The ectopic overexpression of Negr1 impairs neuroblastoma growth in vitro and in vivo. Negr1 exists as a GPI-anchored membrane-bound protein and as a soluble protein released upon metalloprotease cleavage. We generated and characterized a panel of Negr1-derived peptides. The treatment with Negr1 protein and derived peptides induce ALK downregulation and halt neuroblastoma progression in vitro and in vivo. Full article

(This article belongs to the Special Issue State of Art in Protein Degraders and Autophagy Modulators in the Cancer Treatment)

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14 pages, 3462 KB

Open AccessEditor’s ChoiceArticle

Combining MSC Exosomes and Cerium Oxide Nanocrystals for Enhanced Dry Eye Syndrome Therapy

by Ying Tian, Yiquan Zhang, Jiawei Zhao, Fuxiao Luan, Yingjie Wang, Fan Lai, Defang Ouyang and Yong Tao

Pharmaceutics 2023, 15(9), 2301; https://doi.org/10.3390/pharmaceutics15092301 - 11 Sep 2023

Cited by 12 | Viewed by 3125

Abstract

Dry eye syndrome (DES) is a prevalent ocular disorder involving diminishe·d tear production and increased tear evaporation, leading to ocular discomfort and potential surface damage. Inflammation and reactive oxygen species (ROS) have been implicated in the pathophysiology of DES. Inflammation is one core [...] Read more.

Dry eye syndrome (DES) is a prevalent ocular disorder involving diminishe·d tear production and increased tear evaporation, leading to ocular discomfort and potential surface damage. Inflammation and reactive oxygen species (ROS) have been implicated in the pathophysiology of DES. Inflammation is one core cause of the DES vicious cycle. Moreover, there are ROS that regulate inflammation in the cycle from the upstream, which leads to treatment failure in current therapies that merely target inflammation. In this study, we developed a novel therapeutic nanoparticle approach by growing cerium oxide (Ce) nanocrystals in situ on mesenchymal stem cell-derived exosomes (MSCExos), creating MSCExo-Ce. The combined properties of MSCExos and cerium oxide nanocrystals aim to target the “inflammation-ROS-injury” pathological mechanism in DES. We hypothesized that this approach would provide a new treatment option for patients with DES. Our analysis confirmed the successful in situ crystallization of cerium onto MSCExos, and MSCExo-Ce displayed excellent biocompatibility. In vitro and in vivo experiments have demonstrated that MSCExo-Ce promotes corneal cell growth, scavenges ROS, and more effectively suppresses inflammation compared with MSCExos alone. MSCExo-Ce also demonstrated the ability to alleviate DES symptoms and reverse pathological alterations at both the cellular and tissue levels. In conclusion, our findings highlight the potential of MSCExo-Ce as a promising therapeutic candidate for the treatment of DES. Full article

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

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15 pages, 4885 KB

Open AccessEditor’s ChoiceArticle

Chlorhexidine–Silver Nanoparticle Conjugation Leading to Antimicrobial Synergism but Enhanced Cytotoxicity

by Nadezhda Ivanova, Neli Ermenlieva, Lora Simeonova, Iliyan Kolev, Iliya Slavov, Daniela Karashanova and Velichka Andonova

Pharmaceutics 2023, 15(9), 2298; https://doi.org/10.3390/pharmaceutics15092298 - 9 Sep 2023

Cited by 13 | Viewed by 2634

Abstract

This study explored the potential synergism within chlorhexidine–silver nanoparticle conjugates against Influenza type A, Staphylococcus aureus, Escherichia coli, and Candida albicans. Silver nanoparticles (SN) were obtained by the reduction of silver ions with green tea total phenolic extract and conjugated [...] Read more.

This study explored the potential synergism within chlorhexidine–silver nanoparticle conjugates against Influenza type A, Staphylococcus aureus, Escherichia coli, and Candida albicans. Silver nanoparticles (SN) were obtained by the reduction of silver ions with green tea total phenolic extract and conjugated with chlorhexidine (Cx). The particles were characterized by UV-Vis and FTIR spectroscopies, dynamic light scattering, X-ray diffraction, and transmission electron microscopy. A stable negatively charged nano-silver colloid (ζ = −50.01) was obtained with an average hydrodynamic diameter of 92.34 nm. In the presence of chlorhexidine, the spectral data and the shift of the zeta potential to positive values (ζ = +44.59) revealed the successful sorption of the drug onto the silver surface. The conjugates (SN-Cx) demonstrated potentiation in their effects against S. aureus and C. albicans and synergism against E. coli with minimal inhibitory concentrations of SN at 5.5 µg/mL + Cx 8.8 µg/mL. The SN showed excellent virucidal properties, increasing with time, and demonstrated low toxicity. However, the coupling of the cationic chlorhexidine with nano-silver did not reduce its intrinsic cytotoxicity on various cell lines (MDCK, BJ, and A549). The newly synthesized antimicrobial agent exhibited an extended and promising therapeutic spectrum and needs to be further evaluated regarding the designated route of administration in three-dimensional cell models (e.g., nasal, bronchial, dermal, ocular, etc.). Full article

(This article belongs to the Special Issue Advances in Nano-Scale Drug Delivery Systems)

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13 pages, 2431 KB

Open AccessEditor’s ChoiceArticle

In Vitro and In Vivo Evaluation of Inhalable Ciprofloxacin Sustained Release Formulations

by Changzhi Shi, Kewei Guo, Li Zhang, Yi Guo, Yu Feng, Sandra Cvijić, Dongmei Cun and Mingshi Yang

Pharmaceutics 2023, 15(9), 2287; https://doi.org/10.3390/pharmaceutics15092287 - 6 Sep 2023

Cited by 8 | Viewed by 2683

Abstract

Respiratory antibiotics delivery has been appreciated for its high local concentration at the infection sites. Certain formulation strategies are required to improve pulmonary drug exposure and to achieve effective antimicrobial activity, especially for highly permeable antibiotics. This study aimed to investigate lung exposure [...] Read more.

Respiratory antibiotics delivery has been appreciated for its high local concentration at the infection sites. Certain formulation strategies are required to improve pulmonary drug exposure and to achieve effective antimicrobial activity, especially for highly permeable antibiotics. This study aimed to investigate lung exposure to various inhalable ciprofloxacin (CIP) formulations with different drug release rates in a rat model. Four formulations were prepared, i.e., CIP-loaded PLGA micro-particles (CHPM), CIP microcrystalline dry powder (CMDP), CIP nanocrystalline dry powder (CNDP), and CIP spray-dried powder (CHDP), which served as a reference. The physicochemical properties, drug dissolution rate, and aerosolization performance of these powders were characterized in vitro. Pharmacokinetic profiles were evaluated in rats. All formulations were suitable for inhalation (mass median aerodynamic diameter < 5 µm). CIP in CHPM and CHDP was amorphous, whereas the drug in CMDP and CNDP remained predominantly crystalline. CHDP exhibited the fastest drug release rate, while CMDP and CNDP exhibited much slower drug release. In addition, CMDP and CNDP exhibited significantly higher in vivo lung exposure to CIP compared with CHDP and CHPM. This study suggests that lung exposure to inhaled drugs with high permeability is governed by drug release rate, implying that lung exposure of inhaled antibiotics could be improved by a sustained-release formulation strategy. Full article

(This article belongs to the Special Issue Nanoformulation of Drug Delivery Systems for Natural Products)

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25 pages, 892 KB

Open AccessEditor’s ChoiceReview

Therapeutic Implications of Renin–Angiotensin System Modulators in Alzheimer’s Dementia

by Daniela-Carmen Ababei, Veronica Bild, Ioana Macadan, Alexandru Vasincu, Răzvan-Nicolae Rusu, Mihaela Blaj, Gabriela Dumitrița Stanciu, Radu-Marian Lefter and Walther Bild

Pharmaceutics 2023, 15(9), 2290; https://doi.org/10.3390/pharmaceutics15092290 - 6 Sep 2023

Cited by 13 | Viewed by 3598

Abstract

The Renin–Angiotensin System (RAS) has attracted considerable interest beyond its traditional cardiovascular role due to emerging data indicating its potential involvement in neurodegenerative diseases, including Alzheimer’s dementia (AD). This review investigates the therapeutic implications of RAS modulators, specifically focusing on angiotensin-converting enzyme inhibitors [...] Read more.

The Renin–Angiotensin System (RAS) has attracted considerable interest beyond its traditional cardiovascular role due to emerging data indicating its potential involvement in neurodegenerative diseases, including Alzheimer’s dementia (AD). This review investigates the therapeutic implications of RAS modulators, specifically focusing on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors in AD. ACEIs, commonly used for hypertension, show promise in AD by reducing angiotensin (Ang) II levels. This reduction is significant as Ang II contributes to neuroinflammation, oxidative stress, and β-amyloid (Aβ) accumulation, all implicated in AD pathogenesis. ARBs, known for vasodilation, exhibit neuroprotection by blocking Ang II receptors, improving cerebral blood flow and cognitive decline in AD models. Renin inhibitors offer a novel approach by targeting the initial RAS step, displaying anti-inflammatory and antioxidant effects that mitigate AD degeneration. Preclinical studies demonstrate RAS regulation’s favorable impact on neuroinflammation, neuronal damage, cognitive function, and Aβ metabolism. Clinical trials on RAS modulators in AD are limited, but with promising results, ARBs being more effective that ACEIs in reducing cognitive decline. The varied roles of ACEIs, ARBs, and renin inhibitors in RAS modulation present a promising avenue for AD therapeutic intervention, requiring further research to potentially transform AD treatment strategies. Full article

(This article belongs to the Special Issue Perspective Insights into Therapeutic Approaches in Alzheimer’s Disease)

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12 pages, 2007 KB

Open AccessEditor’s ChoiceArticle

Evaluation of Two Osmosis-Based Methods for the Preparation of Drug Delivery Systems Based on Red Blood Cells

by Carmen Gutierrez-Millan, Celia Barez Diaz, Lydia Alvarez Vizan and Clara I. Colino

Pharmaceutics 2023, 15(9), 2281; https://doi.org/10.3390/pharmaceutics15092281 - 5 Sep 2023

Cited by 2 | Viewed by 3512

Abstract

Erythrocytes have been thoroughly investigated as drug delivery systems for a wide range of therapeutic molecules and using different kinds of loading methods, outstanding the osmosis-based methods as the most used ones. Most of them involve too much handling of blood components and [...] Read more.

Erythrocytes have been thoroughly investigated as drug delivery systems for a wide range of therapeutic molecules and using different kinds of loading methods, outstanding the osmosis-based methods as the most used ones. Most of them involve too much handling of blood components and the immediate obtention of fresh blood. Based on our group’s considerable experience in dialysis-based carrier erythrocyte preparation, this study details a simple method based on hypotonic dilution and subsequent resealing that has been developed for stavudine using packed erythrocytes from a local blood bank. Properties of the obtained carrier erythrocytes were studied in comparison to those prepared by dialysis. Erythrocytes’ morphology, osmotic fragility, hematological parameters, and in vitro release profiles were evaluated. Loaded erythrocytes obtained with the proposed method did not show impaired properties in comparison with those obtained with our reference method, provided that the buffer composition remained the same. In the present work, we have optimized a simplified method for erythrocytes’ drug loading, which can use blood transfusion products and could be easily automatized and scalable. Full article

(This article belongs to the Special Issue Novel Cell and Bioinspired Drug Delivery Systems)

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18 pages, 1282 KB

Open AccessEditor’s ChoiceReview

Elucidating Berberine’s Therapeutic and Photosensitizer Potential through Nanomedicine Tools

by Célia Marques, Maria Helena Fernandes and Sofia A. Costa Lima

Pharmaceutics 2023, 15(9), 2282; https://doi.org/10.3390/pharmaceutics15092282 - 5 Sep 2023

Cited by 18 | Viewed by 4194

Abstract

Berberine, an isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been gaining interest due to anti-inflammatory and antioxidant activities, as well as neuro and cardiovascular protective effects in animal models. Recently, photodynamic therapy demonstrated successful application in many fields of medicine. [...] Read more.

Berberine, an isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been gaining interest due to anti-inflammatory and antioxidant activities, as well as neuro and cardiovascular protective effects in animal models. Recently, photodynamic therapy demonstrated successful application in many fields of medicine. This innovative, non-invasive treatment modality requires a photosensitizer, light, and oxygen. In particular, the photosensitizer can selectively accumulate in diseased tissues without damaging healthy cells. Berberine’s physicochemical properties allow its use as a photosensitising agent for photodynamic therapy, enabling reactive oxygen species production and thus potentiating treatment efficacy. However, berberine exhibits poor aqueous solubility, low oral bioavailability, poor cellular permeability, and poor gastrointestinal absorption that hamper its therapeutic and photodynamic efficacy. Nanotechnology has been used to minimize berberine’s limitations with the design of drug delivery systems. Different nanoparticulate delivery systems for berberine have been used, as lipid-, inorganic- and polymeric-based nanoparticles. These berberine nanocarriers improve its therapeutic properties and photodynamic potential. More specifically, they extend its half-life, increase solubility, and allow a high permeation and targeted delivery. This review describes different nano strategies designed for berberine delivery as well as berberine’s potential as a photosensitizer for photodynamic therapy. To benefit from berberine’s overall potential, nanotechnology has been applied for berberine-mediated photodynamic therapy. Full article

(This article belongs to the Special Issue Frontiers in the Application of Nanomaterials in Drug Delivery)

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30 pages, 1006 KB

Open AccessEditor’s ChoiceReview

Exosomes: Potential Next-Generation Nanocarriers for the Therapy of Inflammatory Diseases

by Tosca Mori, Lisa Giovannelli, Anna Rita Bilia and Francesca Margheri

Pharmaceutics 2023, 15(9), 2276; https://doi.org/10.3390/pharmaceutics15092276 - 4 Sep 2023

Cited by 18 | Viewed by 4683

Abstract

Inflammatory diseases are common pathological processes caused by various acute and chronic factors, and some of them are autoimmune diseases. Exosomes are fundamental extracellular vesicles secreted by almost all cells, which contain a series of constituents, i.e., cytoskeletal and cytosolic proteins (actin, tubulin, [...] Read more.

Inflammatory diseases are common pathological processes caused by various acute and chronic factors, and some of them are autoimmune diseases. Exosomes are fundamental extracellular vesicles secreted by almost all cells, which contain a series of constituents, i.e., cytoskeletal and cytosolic proteins (actin, tubulin, and histones), nucleic acids (mRNA, miRNA, and DNA), lipids (diacylglycerophosphates, cholesterol, sphingomyelin, and ceramide), and other bioactive components (cytokines, signal transduction proteins, enzymes, antigen presentation and membrane transport/fusion molecules, and adhesion molecules). This review will be a synopsis of the knowledge on the contribution of exosomes from different cell sources as possible therapeutic agents against inflammation, focusing on several inflammatory diseases, neurological diseases, rheumatoid arthritis and osteoarthritis, intestinal bowel disease, asthma, and liver and kidney injuries. Current knowledge indicates that the role of exosomes in the therapy of inflammation and in inflammatory diseases could be distinctive. The main limitations to their clinical translation are still production, isolation, and storage. Additionally, there is an urgent need to personalize the treatments in terms of the selection of exosomes; their dosages and routes of administration; and a deeper knowledge about their biodistribution, type and incidence of adverse events, and long-term effects of exosomes. In conclusion, exosomes can be a very promising next-generation therapeutic option, superior to synthetic nanocarriers and cell therapy, and can represent a new strategy of effective, safe, versatile, and selective delivery systems in the future. Full article

(This article belongs to the Special Issue Recent Advances in Exosomes as Drug Carriers)

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18 pages, 2415 KB

Open AccessEditor’s ChoiceArticle

Improved Pharmacokinetic Feasibilities of Mirabegron-1,2-Ethanedisulfonic Acid, Mirabegron-1,5-Naphthalenedisulfonic Acid, and Mirabegron-L-Pyroglutamic Acid as Co-Amorphous Dispersions in Rats and Mice

by Seo-Yeon Kim, Byung Hoon You, Mingoo Bae, Seung Yon Han, Kiwon Jung and Young Hee Choi

Pharmaceutics 2023, 15(9), 2277; https://doi.org/10.3390/pharmaceutics15092277 - 4 Sep 2023

Cited by 4 | Viewed by 2571

Abstract

Mirabegron (MBR) is a β₃-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic [...] Read more.

Mirabegron (MBR) is a β₃-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic acid (MBR-EFA), MBR-1,5-naphthalenedisulfonic acid (MBR-NDA), and MBR-L-pyroglutamic acid (MBR-PG), have been developed, showing improved solubility and thermodynamic stability. Nevertheless, the pharmacokinetic feasibility of these co-amorphous dispersions has not been evaluated. Therefore, this study aimed to characterize the pharmacokinetic profiles of MBR-EFA, MBR-NDA, and MBR-PG in rats and mice. Our results exhibited that relative F_24h and AUC_0–24h values of MBR in MBR-EFA, MBR-NDA, and MBR-PG rats were increased by 143–195% compared with the MBR rats. The absolute F_24h, relative F_24h, and AUC_0–24h values of MBR in MBR-EFA and MBR-NDA mice were enhanced by 178–234% compared with the MBR mice. In tissue distribution, MBR was extensively distributed in the gastrointestinal tract, liver, kidneys, lung, and heart of mice. Notably, MBR distribution in the liver, kidneys, and lung was considerably high in MBR-EFA, MBR-NDA, or MBR-PG mice compared with MBR mice. These findings highlight the potential of these co-amorphous dispersions to enhance oral F of MBR. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)

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35 pages, 7519 KB

Open AccessEditor’s ChoiceReview

Optical Methods for Non-Invasive Determination of Skin Penetration: Current Trends, Advances, Possibilities, Prospects, and Translation into In Vivo Human Studies

by Maxim E. Darvin

Pharmaceutics 2023, 15(9), 2272; https://doi.org/10.3390/pharmaceutics15092272 - 3 Sep 2023

Cited by 25 | Viewed by 6624

Abstract

Information on the penetration depth, pathways, metabolization, storage of vehicles, active pharmaceutical ingredients (APIs), and functional cosmetic ingredients (FCIs) of topically applied formulations or contaminants (substances) in skin is of great importance for understanding their interaction with skin targets, treatment efficacy, and risk [...] Read more.

Information on the penetration depth, pathways, metabolization, storage of vehicles, active pharmaceutical ingredients (APIs), and functional cosmetic ingredients (FCIs) of topically applied formulations or contaminants (substances) in skin is of great importance for understanding their interaction with skin targets, treatment efficacy, and risk assessment—a challenging task in dermatology, cosmetology, and pharmacy. Non-invasive methods for the qualitative and quantitative visualization of substances in skin in vivo are favored and limited to optical imaging and spectroscopic methods such as fluorescence/reflectance confocal laser scanning microscopy (CLSM); two-photon tomography (2PT) combined with autofluorescence (2PT-AF), fluorescence lifetime imaging (2PT-FLIM), second-harmonic generation (SHG), coherent anti-Stokes Raman scattering (CARS), and reflectance confocal microscopy (2PT-RCM); three-photon tomography (3PT); confocal Raman micro-spectroscopy (CRM); surface-enhanced Raman scattering (SERS) micro-spectroscopy; stimulated Raman scattering (SRS) microscopy; and optical coherence tomography (OCT). This review summarizes the state of the art in the use of the CLSM, 2PT, 3PT, CRM, SERS, SRS, and OCT optical methods to study skin penetration in vivo non-invasively (302 references). The advantages, limitations, possibilities, and prospects of the reviewed optical methods are comprehensively discussed. The ex vivo studies discussed are potentially translatable into in vivo measurements. The requirements for the optical properties of substances to determine their penetration into skin by certain methods are highlighted. Full article

(This article belongs to the Special Issue Topical Delivery Illuminated: Penetration Monitoring for New Age Medicines)

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13 pages, 2412 KB

Open AccessEditor’s ChoiceArticle

Injectable pH and Thermo-Responsive Hydrogel Scaffold with Enhanced Osteogenic Differentiation of Preosteoblasts for Bone Regeneration

by Jasmine L. King, Roopali Shrivastava, Pooja D. Shah, Panita Maturavongsadit and Soumya Rahima Benhabbour

Pharmaceutics 2023, 15(9), 2270; https://doi.org/10.3390/pharmaceutics15092270 - 2 Sep 2023

Cited by 7 | Viewed by 2514

Abstract

Bone fractures are common in the geriatric population and pose a great economic burden worldwide. While traditional methods for repairing bone defects have primarily been autografts, there are several drawbacks limiting its use. Bone graft substitutes have been used as alternative strategies to [...] Read more.

Bone fractures are common in the geriatric population and pose a great economic burden worldwide. While traditional methods for repairing bone defects have primarily been autografts, there are several drawbacks limiting its use. Bone graft substitutes have been used as alternative strategies to improve bone healing. However, there remain several impediments to achieving the desired healing outcomes. Injectable hydrogels have become attractive scaffold materials for bone regeneration, given their high performance in filling irregularly sized bone defects and their ability to encapsulate cells and bioactive molecules and mimic the native ECM of bone. We investigated the use of an injectable chitosan-based hydrogel scaffold to promote the differentiation of preosteoblasts in vitro. The hydrogels were characterized by evaluating cell homogeneity, cell viability, rheological and mechanical properties, and differentiation ability of preosteoblasts in hydrogel scaffolds. Cell-laden hydrogel scaffolds exhibited shear thinning behavior and the ability to maintain shape fidelity after injection. The CNC-CS hydrogels exhibited higher mechanical strength and significantly upregulated the osteogenic activity and differentiation of preosteoblasts, as shown by ALP activity assays and histological analysis of hydrogel scaffolds. These results suggest that this injectable hydrogel is suitable for cell survival, can promote osteogenic differentiation of preosteoblasts, and structurally support new bone growth. Full article

(This article belongs to the Special Issue Novel Preclinical Drug Formulation and Delivery Approaches: Developments and Challenges)

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22 pages, 1576 KB

Open AccessEditor’s ChoiceCommunication

Concept for a Unidirectional Release Mucoadhesive Buccal Tablet for Oral Delivery of Antidiabetic Peptide Drugs Such as Insulin, Glucagon-like Peptide 1 (GLP-1), and their Analogs

by Anubhav Pratap-Singh, Yigong Guo, Alberto Baldelli and Anika Singh

Pharmaceutics 2023, 15(9), 2265; https://doi.org/10.3390/pharmaceutics15092265 - 1 Sep 2023

Cited by 11 | Viewed by 5395

Abstract

Injectable peptides such as insulin, glucagon-like peptide 1 (GLP-1), and their agonists are being increasingly used for the treatment of diabetes. Currently, the most common route of administration is injection, which is linked to patient discomfort as well as being subjected to refrigerated [...] Read more.

Injectable peptides such as insulin, glucagon-like peptide 1 (GLP-1), and their agonists are being increasingly used for the treatment of diabetes. Currently, the most common route of administration is injection, which is linked to patient discomfort as well as being subjected to refrigerated storage and the requirement for efficient supply chain logistics. Buccal and sublingual routes are recognized as valid alternatives due to their high accessibility and easy administration. However, there can be several challenges, such as peptide selection, drug encapsulation, and delivery system design, which are linked to the enhancement of drug efficacy and efficiency. By using hydrophobic polymers that do not dissolve in saliva, and by using neutral or positively charged nanoparticles that show better adhesion to the negative charges generated by the sialic acid in the mucus, researchers have attempted to improve drug efficiency and efficacy in buccal delivery. Furthermore, unidirectional films and tablets seem to show the highest bioavailability as compared to sprays and other buccal delivery vehicles. This advantageous attribute can be attributed to their capability to mitigate the impact of saliva and inadvertent gastrointestinal enzymatic digestion, thereby minimizing drug loss. This is especially pertinent as these formulations ensure a more directed drug delivery trajectory, leading to heightened therapeutic outcomes. This communication describes the current state of the art with respect to the creation of nanoparticles containing peptides such as insulin, glucagon-like peptide 1 (GLP-1), and their agonists, and theorizes the production of mucoadhesive unidirectional release buccal tablets or films. Such an approach is more patient-friendly and can improve the lives of millions of diabetics around the world; in addition, these shelf-stable formulations ena a more environmentally friendly and sustainable supply chain network. Full article

(This article belongs to the Special Issue Micronutrient Delivery Systems: Potential Health-Promoting Applications)

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25 pages, 4505 KB

Open AccessEditor’s ChoiceArticle

Twin Screw Melt Granulation: A Single Step Approach for Developing Self-Emulsifying Drug Delivery System for Lipophilic Drugs

by Dinesh Nyavanandi, Preethi Mandati, Sagar Narala, Abdullah Alzahrani, Praveen Kolimi, Sateesh Kumar Vemula and Michael A. Repka

Pharmaceutics 2023, 15(9), 2267; https://doi.org/10.3390/pharmaceutics15092267 - 1 Sep 2023

Cited by 15 | Viewed by 2528

Abstract

The current research aims to improve the solubility of the poorly soluble drug, i.e., ibuprofen, by developing self-emulsifying drug delivery systems (SEDDS) utilizing a twin screw melt granulation (TSMG) approach. Gelucire^® 44/14, Gelucire^® 48/16, and Transcutol^® HP were screened as [...] Read more.

The current research aims to improve the solubility of the poorly soluble drug, i.e., ibuprofen, by developing self-emulsifying drug delivery systems (SEDDS) utilizing a twin screw melt granulation (TSMG) approach. Gelucire^® 44/14, Gelucire^® 48/16, and Transcutol^® HP were screened as suitable excipients for developing the SEDDS formulations. Initially, liquid SEDDS (L-SEDDS) were developed with oil concentrations between 20–50% w/w and surfactant to co-surfactant ratios of 2:1, 4:1, 6:1. The stable formulations of L-SEDDS were transformed into solid SEDDS (S-SEDDS) using a suitable adsorbent carrier and compressed into tablets (T-SEDDS). The S-SEDDS has improved flow, drug release profiles, and permeability compared to pure drugs. The existence of the drug in an amorphous state was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction analysis (PXRD). The formulations with 20% w/w and 30% w/w of oil concentration and a 4:1 ratio of surfactant to co-surfactant have resulted in a stable homogeneous emulsion with a globule size of 14.67 ± 0.23 nm and 18.54 ± 0.55 nm. The compressed tablets were found stable after six months of storage at accelerated and long-term conditions. This shows the suitability of the TSMG approach as a single-step continuous manufacturing process for developing S-SEDDS formulations. Full article

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15 pages, 2537 KB

Open AccessEditor’s ChoiceReview

Cyclodextrins as Multi-Functional Ingredients in Dentistry

by Susana Santos Braga

Pharmaceutics 2023, 15(9), 2251; https://doi.org/10.3390/pharmaceutics15092251 - 31 Aug 2023

Cited by 7 | Viewed by 3566

Abstract

Cyclodextrins are present in a variety of oral hygiene compositions. The present work describes the role of cyclodextrins in several toothpastes and mouthwashes that are already available in the market, as well as their prospective use in other applications as investigated in studies [...] Read more.

Cyclodextrins are present in a variety of oral hygiene compositions. The present work describes the role of cyclodextrins in several toothpastes and mouthwashes that are already available in the market, as well as their prospective use in other applications as investigated in studies in the literature. Moreover, cyclodextrins are under study for the development of materials used in various techniques of dental repair, such as fillings, cements and binders therein. Their role in each of the innovative materials is presented. Finally, the prospect of the use of cyclodextrin-based delivery systems for the oral cavity is introduced, with a focus on new cyclodextrin molecules with dual action as bone-targeting agents and osteogenic drugs, and on new cross-linked cyclodextrin particles with a high drug loading and sustained drug delivery profile for the treatment of diseases that require prolonged action, such as periodontitis. In conclusion, cyclodextrins are herein demonstrated to act as versatile and multi-action ingredients with a broad range of applications in dentistry. Full article

(This article belongs to the Special Issue Biomaterials and Agents: Pharmaceutical and Biomedical Applications in Dental Research)

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15 pages, 3770 KB

Open AccessEditor’s ChoiceArticle

A NIR-Activated and Mild-Temperature-Sensitive Nanoplatform with an HSP90 Inhibitor for Combinatory Chemotherapy and Mild Photothermal Therapy in Cancel Cells

by Yingying Peng, Hanlin Jiang, Bifei Li, Yue Liu, Bing Guo and Wei Gan

Pharmaceutics 2023, 15(9), 2252; https://doi.org/10.3390/pharmaceutics15092252 - 31 Aug 2023

Cited by 7 | Viewed by 2153

Abstract

Mild photothermal therapy (PTT) shows great potential to treat cancers while avoiding unwanted damage to surrounding normal cells. However, the efficacy of mild PTT is normally moderate because of the low hyperthermia temperature and limited light penetration depth. Chemotherapy has unlimited penetration but [...] Read more.

Mild photothermal therapy (PTT) shows great potential to treat cancers while avoiding unwanted damage to surrounding normal cells. However, the efficacy of mild PTT is normally moderate because of the low hyperthermia temperature and limited light penetration depth. Chemotherapy has unlimited penetration but often suffers from unsatisfactory efficacy in view of the occurrence of drug resistance, suboptimal drug delivery and release profile. As a result, the combinatory of chemotherapy and mild PTT would integrate their advantages and overcome the shortcomings. Herein, we synthesized an NIR-activatable and mild-temperature-sensitive nanoplatform (BDPII-gel@TSL) composed of temperature-sensitive liposomes (TSL), heat shock protein 90 (HSP90) inhibitor (geldanamycin) and photothermal agent (BDPII), for dual chemotherapy and mild PTT in cancer cells. BDPII, constructed with donor-acceptor moieties, acts as an excellent near-infrared (NIR) photothermal agent (PTA) with a high photothermal conversion efficiency (80.75%). BDPII-containing TSLs efficiently produce a mild hyperthermia effect (42 °C) under laser irradiation (808 nm, 0.5 W cm⁻²). Importantly, the phase transformation of TSL leads to burst release of geldanamycin from BDPII-gel@TSL, and this contributes to down-regulation of the overexpression of HSP90, ensuring efficient inhibition of cancer cell growth. This research provides a dual-sensitive synergistic therapeutic strategy for cancer cell treatment. Full article

(This article belongs to the Special Issue Recent Progress in Reactive Oxygen Species-Related Therapy for Disease Treatment)

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21 pages, 2013 KB

Open AccessEditor’s ChoiceReview

Modulation of Human Dendritic Cell Functions by Phosphodiesterase-4 Inhibitors: Potential Relevance for the Treatment of Respiratory Diseases

by Hoang Oanh Nguyen, Laura Tiberio, Fabrizio Facchinetti, Giulia Ripari, Valentina Violi, Gino Villetti, Valentina Salvi and Daniela Bosisio

Pharmaceutics 2023, 15(9), 2254; https://doi.org/10.3390/pharmaceutics15092254 - 31 Aug 2023

Cited by 5 | Viewed by 3519

Abstract

Inhibitors of phosphodiesterase-4 (PDE4) are small-molecule drugs that, by increasing the intracellular levels of cAMP in immune cells, elicit a broad spectrum of anti-inflammatory effects. As such, PDE4 inhibitors are actively studied as therapeutic options in a variety of human diseases characterized by [...] Read more.

Inhibitors of phosphodiesterase-4 (PDE4) are small-molecule drugs that, by increasing the intracellular levels of cAMP in immune cells, elicit a broad spectrum of anti-inflammatory effects. As such, PDE4 inhibitors are actively studied as therapeutic options in a variety of human diseases characterized by an underlying inflammatory pathogenesis. Dendritic cells (DCs) are checkpoints of the inflammatory and immune responses, being responsible for both activation and dampening depending on their activation status. This review shows evidence that PDE4 inhibitors modulate inflammatory DC activation by decreasing the secretion of inflammatory and Th1/Th17-polarizing cytokines, although preserving the expression of costimulatory molecules and the CD4+ T cell-activating potential. In addition, DCs activated in the presence of PDE4 inhibitors induce a preferential Th2 skewing of effector T cells, retain the secretion of Th2-attracting chemokines and increase the production of T cell regulatory mediators, such as IDO1, TSP-1, VEGF-A and Amphiregulin. Finally, PDE4 inhibitors selectively induce the expression of the surface molecule CD141/Thrombomodulin/BDCA-3. The result of such fine-tuning is immunomodulatory DCs that are distinct from those induced by classical anti-inflammatory drugs, such as corticosteroids. The possible implications for the treatment of respiratory disorders (such as COPD, asthma and COVID-19) by PDE4 inhibitors will be discussed. Full article

(This article belongs to the Special Issue Immunotherapeutic Strategies in Cancer and Chronic Infection)

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23 pages, 7929 KB

Open AccessEditor’s ChoiceArticle

Mesoporous Composite Bioactive Compound Delivery System for Wound-Healing Processes

by Bogdan Purcăreanu, Manuela Diana Ene, Alina Moroșan, Dan Eduard Mihaiescu, Mihai Alexandru Florea, Adelina Ghica, Roxana Andreea Nita, Veronica Drumea, Mihai Alexandru Grigoroscuta, Andrei Kuncser, Petre Badica and Laura Olariu

Pharmaceutics 2023, 15(9), 2258; https://doi.org/10.3390/pharmaceutics15092258 - 31 Aug 2023

Cited by 3 | Viewed by 1923

Abstract

Currently, the treatment of wounds is still a challenge for healthcare professionals due to high complication incidences and social impacts, and the development of biocompatible and efficient medicines remains a goal. In this regard, mesoporous materials loaded with bioactive compounds from natural extracts [...] Read more.

Currently, the treatment of wounds is still a challenge for healthcare professionals due to high complication incidences and social impacts, and the development of biocompatible and efficient medicines remains a goal. In this regard, mesoporous materials loaded with bioactive compounds from natural extracts have a high potential for wound treatment due to their nontoxicity, high loading capacity and slow drug release. MCM-41-type mesoporous material was synthesized by using sodium trisilicate as a silica source at room temperature and normal pressure. The synthesized mesoporous silica was characterized by using Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), N₂ absorption–desorption (BET), Dynamic Light Scattering (DLS) and Fourier transform infrared spectroscopy (FT-IR), revealing a high surface area (BET, 1244 m²/g); pore diameter of approx. 2 nm; and a homogenous, ordered and hexagonal geometry (TEM images). Qualitative monitoring of the desorption degree of the Salvia officinalis (SO) extract, rich in ursolic acid and oleanolic acid, and Calendula officinalis (CO) extract, rich in polyphenols and flavones, was performed via the continuous recording of the UV-VIS spectra at predetermined intervals. The active ingredients in the new composite MCM-41/sage and marigold (MCM-41/SO&CO) were quantified by using HPLC-DAD and LC-MS-MS techniques. The evaluation of the biological composites’ activity on the wound site was performed on two cell lines, HS27 and HaCaT, naturally involved in tissue-regeneration processes. The experimental results revealed the ability to stimulate collagen biosynthesis, the enzymatic activity of the main metalloproteinases (MMP-2 and MMP-9) involved in tissue remodeling processes and the migration rate in the wound site, thus providing insights into the re-epithelializing properties of mesoporous composites. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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23 pages, 4963 KB

Open AccessEditor’s ChoiceArticle

A Species-Specific Anti-Human P2X7 Monoclonal Antibody Reduces Graft-versus-Host Disease in Humanised Mice

by Amal Elhage, Peter Cuthbertson, Chloe Sligar, Debbie Watson and Ronald Sluyter

Pharmaceutics 2023, 15(9), 2263; https://doi.org/10.3390/pharmaceutics15092263 - 31 Aug 2023

Cited by 4 | Viewed by 2495

Abstract

Graft-versus-host disease (GVHD) is a T cell-mediated inflammatory disorder that arises from allogeneic haematopoietic stem cell transplantation and is often fatal. The P2X7 receptor is an extracellular adenosine 5′-triphosphate-gated cation channel expressed on immune cells. Blockade of this receptor with small molecule inhibitors [...] Read more.

Graft-versus-host disease (GVHD) is a T cell-mediated inflammatory disorder that arises from allogeneic haematopoietic stem cell transplantation and is often fatal. The P2X7 receptor is an extracellular adenosine 5′-triphosphate-gated cation channel expressed on immune cells. Blockade of this receptor with small molecule inhibitors impairs GVHD in a humanised mouse model. A species-specific blocking monoclonal antibody (mAb) (clone L4) for human P2X7 is available, affording the opportunity to determine whether donor (human) P2X7 contributes to the development of GVHD in humanised mice. Using flow cytometric assays of human RPMI 8266 and murine J774 cells, this study confirmed that this mAb bound and impaired human P2X7. Furthermore, this mAb prevented the loss of human regulatory T cells (hTregs) and natural killer (hNK) T cells in vitro. NOD-scid IL2Rγ^null mice were injected with 10 × 10⁶ human peripheral blood mononuclear cells (Day 0) and an anti-hP2X7 or control mAb (100 μg i.p. per mouse, Days 0, 2, 4, 6, and 8). The anti-hP2X7 mAb increased hTregs and hNK cells at Day 21. Moreover, anti-hP2X7 mAb-treatment reduced clinical and histological GVHD in the liver and lung compared to the control treatment at disease endpoint. hTregs, hNK, and hNK T cell proportions were increased, and human T helper 17 cell proportions were decreased at endpoint. These studies indicate that blockade of human (donor) P2X7 reduces GVHD development in humanised mice, providing the first direct evidence of a role for donor P2X7 in GVHD. Full article

(This article belongs to the Section Biologics and Biosimilars)

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14 pages, 2818 KB

Open AccessEditor’s ChoiceArticle

Virus-like Silica Nanoparticles Improve Permeability of Macromolecules across the Blood–Brain Barrier In Vitro

by Yuran Feng, Yuxue Cao, Zhi Qu, Taskeen Iqbal Janjua and Amirali Popat

Pharmaceutics 2023, 15(9), 2239; https://doi.org/10.3390/pharmaceutics15092239 - 30 Aug 2023

Cited by 9 | Viewed by 3398

Abstract

The presence of the blood–brain barrier (BBB) limits the delivery of therapies into the brain. There has been significant interest in overcoming the BBB for the effective delivery of therapies to the brain. Inorganic nanomaterials, especially silica nanoparticles with varying surface chemistry and [...] Read more.

The presence of the blood–brain barrier (BBB) limits the delivery of therapies into the brain. There has been significant interest in overcoming the BBB for the effective delivery of therapies to the brain. Inorganic nanomaterials, especially silica nanoparticles with varying surface chemistry and surface topology, have been recently used as permeation enhancers for oral protein delivery. In this context, nanoparticles with varying sizes and surface chemistries have been employed to overcome this barrier; however, there is no report examining the effect of nanoscale roughness on BBB permeability. This paper reports the influence of nanoscale surface roughness on the integrity and permeability of the BBB in vitro, using smooth surface Stöber silica nanoparticles (60 nm) compared to rough surface virus-like silica nanoparticles (VSNP, 60 nm). Our findings reveal that VSNP (1 mg/mL) with virus-mimicking-topology spiky surface have a greater effect on transiently opening endothelial tight junctions of the BBB than the same dose of Stöber silica nanoparticles (1 mg/mL) by increasing the FITC-Dextran (70 kDa) permeability 1.9-fold and by decreasing the trans-endothelial electrical resistance (TEER) by 2.7-fold. This proof-of-concept research paves the way for future studies to develop next-generation tailored surface-modified silica nanoparticles, enabling safe and efficient macromolecule transport across the BBB. Full article

(This article belongs to the Special Issue Nanodelivery and Nanodiagnostics for Nucleic Acids)

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14 pages, 3587 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Spheroid Formation and Recovery Using Superhydrophobic Coating for Regenerative Purposes

by María del Carmen Morán, Francesca Cirisano and Michele Ferrari

Pharmaceutics 2023, 15(9), 2226; https://doi.org/10.3390/pharmaceutics15092226 - 29 Aug 2023

Cited by 6 | Viewed by 1899

Abstract

Cell therapies commonly pursue tissue stimulation for regenerative purposes by replacing cell numbers or supplying for functional deficiencies. To this aim, monodispersed cells are usually transplanted for incorporation by local injection. The limitations of this strategy include poor success associated with cell death, [...] Read more.

Cell therapies commonly pursue tissue stimulation for regenerative purposes by replacing cell numbers or supplying for functional deficiencies. To this aim, monodispersed cells are usually transplanted for incorporation by local injection. The limitations of this strategy include poor success associated with cell death, insufficient retention, or cell damage due to shear forces associated with the injection. Spheroids have recently emerged as a model that mimics an in vivo environment with more representative cell-to-cell interactions and better intercellular communication. Nevertheless, cost-effective and lab friendly fabrication and effectively performed recovery are challenges that restrict the broad application of spheroids. In this work, glass surfaces were modified with an environmentally friendly superhydrophobic coating. The superhydrophobic surfaces were used for the 3D spheroid preparation of fibroblasts (3T3 cell line) and keratinocytes (HaCaT cell line). The effectiveness of the spheroids to be recovered and grown under 2D culture conditions was evaluated. The morphology of the migrated cells from the 3D spheroids was characterized at the nano-microscale through 3D profilometry. The results demonstrated improved adhesion and proliferation in the migrated cells, both advanced properties for regenerative applications. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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42 pages, 4436 KB

Open AccessEditor’s ChoiceReview

Polysaccharide-Based Coatings as Drug Delivery Systems

by Anita Ioana Visan and Rodica Cristescu

Pharmaceutics 2023, 15(9), 2227; https://doi.org/10.3390/pharmaceutics15092227 - 29 Aug 2023

Cited by 51 | Viewed by 5401

Abstract

Therapeutic polysaccharide-based coatings have recently emerged as versatile strategies to transform a conventional medical implant into a drug delivery system. However, the translation of these polysaccharide-based coatings into the clinic as drug delivery systems still requires a deeper understanding of their drug degradation/release [...] Read more.

Therapeutic polysaccharide-based coatings have recently emerged as versatile strategies to transform a conventional medical implant into a drug delivery system. However, the translation of these polysaccharide-based coatings into the clinic as drug delivery systems still requires a deeper understanding of their drug degradation/release profiles. This claim is supported by little or no data. In this review paper, a comprehensive description of the benefits and challenges generated by the polysaccharide-based coatings is provided. Moreover, the latest advances made towards the application of the most important representative coatings based on polysaccharide types for drug delivery are debated. Furthermore, suggestions/recommendations for future research to speed up the transition of polysaccharide-based drug delivery systems from the laboratory testing to clinical applications are given. Full article

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

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12 pages, 2716 KB

Open AccessEditor’s ChoiceArticle

Spray-Dried Inhalable Microparticles Combining Remdesivir and Ebselen against SARS-CoV-2 Infection

by Tushar Saha, Shubhra Sinha, Rhodri Harfoot, Miguel E. Quiñones-Mateu and Shyamal C. Das

Pharmaceutics 2023, 15(9), 2229; https://doi.org/10.3390/pharmaceutics15092229 - 29 Aug 2023

Cited by 11 | Viewed by 2699

Abstract

There is a continuous effort to develop efficient treatments for coronavirus disease 2019 (COVID-19) and other viral respiratory diseases. Among the different strategies, inhaled treatment is considered one of the most logical and efficient approaches to treating COVID-19, as the causative “SARS-CoV-2 virus [...] Read more.

There is a continuous effort to develop efficient treatments for coronavirus disease 2019 (COVID-19) and other viral respiratory diseases. Among the different strategies, inhaled treatment is considered one of the most logical and efficient approaches to treating COVID-19, as the causative “SARS-CoV-2 virus RNA” predominantly infects the respiratory tract. COVID-19 treatments initially relied on repurposed drugs, with a few additional strategies developed during the last two years, and all of them are based on monotherapy. However, drug combinations have been found to be more effective than monotherapy in other viral diseases such as HIV, influenza, and hepatitis C virus. In the case of SARS-CoV-2 infection, in vitro studies have shown synergistic antiviral activity combining remdesivir with ebselen, an organoselenium compound. Therefore, these drug combinations could ensure better therapeutic outcomes than the individual agents. In this study, we developed a dry powder formulation containing remdesivir and ebselen using a spray-drying technique and used L-leucine as an aerosolization enhancer. The prepared dry powders were spherical and crystalline, with a mean particle size between 1 and 3 µm, indicating their suitability for inhalation. The emitted dose (ED) and fine particle fraction (FPF) of remdesivir- and ebselen-containing dry powders were ~80% and ~57% when prepared without L-leucine. The ED as well as the FPF significantly increased with values of >86% and >67%, respectively, when L-leucine was incorporated. More importantly, the single and combinational dry powder of remdesivir and ebselen showed minimal cytotoxicity (CC₅₀ > 100 μM) in Calu-3 cells, retaining their anti-SARS-CoV-2 properties (EC₅₀ 2.77 to 18.64 μM). In summary, we developed an inhalable dry powder combination of remdesivir and ebselen using a spray-drying technique. The spray-dried inhalable microparticles retained their limited cytotoxicity and specific antiviral properties. Future in vivo studies are needed to verify the potential use of these remdesivir/ebselen combinational spray-dried inhalable microparticles to block the SARS-CoV-2 replication in the respiratory tract. Full article

(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)

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19 pages, 10032 KB

Open AccessEditor’s ChoiceArticle

3D Printing of Personalised Carvedilol Tablets Using Selective Laser Sintering

by Atabak Ghanizadeh Tabriz, Quentin Gonot-Munck, Arnaud Baudoux, Vivek Garg, Richard Farnish, Orestis L. Katsamenis, Ho-Wah Hui, Nathan Boersen, Sandra Roberts, John Jones and Dennis Douroumis

Pharmaceutics 2023, 15(9), 2230; https://doi.org/10.3390/pharmaceutics15092230 - 29 Aug 2023

Cited by 16 | Viewed by 2767

Abstract

Selective laser sintering (SLS) has drawn attention for the fabrication of three-dimensional oral dosage forms due to the plurality of drug formulations that can be processed. The aim of this work was to employ SLS with a CO₂ laser for the manufacturing [...] Read more.

Selective laser sintering (SLS) has drawn attention for the fabrication of three-dimensional oral dosage forms due to the plurality of drug formulations that can be processed. The aim of this work was to employ SLS with a CO₂ laser for the manufacturing of carvedilol personalised dosage forms of various strengths. Carvedilol (CVD) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) blends of various ratios were sintered to produce CVD tablets of 3.125, 6.25, and 12.5 mg. The tuning of the SLS processing laser intensity parameter improved printability and impacted the tablet hardness, friability, CVD dissolution rate, and the total amount of drug released. Physicochemical characterization showed the presence of CVD in the amorphous state. X-ray micro-CT analysis demonstrated that the applied CO₂ intensity affected the total tablet porosity, which was reduced with increased laser intensity. The study demonstrated that SLS is a suitable technology for the development of personalised medicines that meet the required specifications and patient needs. Full article

(This article belongs to the Special Issue Recent Non-oral Dosage Form Development: Focus on 3D-Printed Formulations)

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22 pages, 6497 KB

Open AccessEditor’s ChoiceArticle

Development of Simvastatin-Loaded Particles Using Spray Drying Method for Ex Tempore Preparation of Cartridges for 2D Printing Technology

by Barbara Sterle Zorec and Rok Dreu

Pharmaceutics 2023, 15(9), 2221; https://doi.org/10.3390/pharmaceutics15092221 - 28 Aug 2023

Cited by 1 | Viewed by 1867

Abstract

In this work, a spray drying method was developed to produce drug/polymer (simvastatin/polycaprolactone) microparticles that have the potential to be used as a pre-formulation for ex tempore preparation of 2D printing cartridges. An experimental model was designed with the process parameters set to [...] Read more.

In this work, a spray drying method was developed to produce drug/polymer (simvastatin/polycaprolactone) microparticles that have the potential to be used as a pre-formulation for ex tempore preparation of 2D printing cartridges. An experimental model was designed with the process parameters set to predict the smallest particle size required for successful 2D printing. Three different types of particles (lactose, nanocellulose/lactose, calcium silicate) were produced, and the average size of the dry particles varied depending on the sampling location (cyclone, collection vessel). The encapsulation efficiency of simvastatin was highest with nanocellulose/lactose from the collection vessel. The one-month stability of simvastatin in the particles showed low content, but the addition of ascorbic acid as an antioxidant increased the chemical stability of the drug. Interestingly, the addition of antioxidants decreased the stability of simvastatin in the calcium silicate particles from the collection vessel. Dispersion of the particles in three different propylene glycol and water mixtures (10/90, 50/50, and 90/10% (v/v)), representing a printable ink medium with three different viscosity and surface tension properties, showed that nanocellulose/lactose was the most suitable antiadhesive in terms of dispersed particle size (˂1 µm). After one month of storage, the dispersed particles remained in the same size range without undesirable particle agglomeration. Full article

(This article belongs to the Special Issue Recent Advances in Solid Dosage Form)

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16 pages, 3209 KB

Open AccessEditor’s ChoiceArticle

Development of a Hydroxypropyl-β-Cyclodextrin-Based Liquid Formulation for the Oral Administration of Propranolol in Pediatric Therapy

by Marzia Cirri, Paola Mura, Simona Benedetti and Susanna Buratti

Pharmaceutics 2023, 15(9), 2217; https://doi.org/10.3390/pharmaceutics15092217 - 27 Aug 2023

Cited by 10 | Viewed by 3133

Abstract

Propranolol (PPN) is widely used in children to treat various cardiovascular diseases. The availability of a suitable PPN solution should avoid recourse to extemporaneous preparations of unknown/limited stability, as commonly made in hospital pharmacies. However, the development of pediatric PPN solutions is hindered [...] Read more.

Propranolol (PPN) is widely used in children to treat various cardiovascular diseases. The availability of a suitable PPN solution should avoid recourse to extemporaneous preparations of unknown/limited stability, as commonly made in hospital pharmacies. However, the development of pediatric PPN solutions is hindered by their instability to light and stability at pH ≈ 3, bitter taste, and the need to improve palatability and avoid co-solvents, flavoring agents, or preservatives that are potentially toxic. In this study, cyclodextrin (CD) complexation has been exploited to develop a safe, stable, and palatable oral pediatric solution of PPN. An initial screening among various CDs allowed us to select HPβCD for its good complexing ability and no toxicity. Drug-HPβCD physical mixtures or co-ground systems (1:1 or 1:2 mol:mol) were used to prepare 0.2% w/v drug solutions. Photo stability studies evidenced the protective effect of HPβCD, revealing a reduction of up to 75% in the drug degradation rate after 1 h of exposure to UV radiation. Storage stability studies showed unchanged physical–chemical properties and almost constant drug concentration after 6 months and under accelerated conditions (40 °C), despite the less aggressive pH (≈5.5) of the solution. The electronic tongue test proved that the HPβCD taste-masking properties improved the formulation palatability, with a 30% reduction in drug bitterness. Full article

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

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21 pages, 4738 KB

Open AccessEditor’s ChoiceArticle

Characterization and In Vivo Antiangiogenic Activity Evaluation of Morin-Based Cyclodextrin Inclusion Complexes

by Federica De Gaetano, Fatima Margani, Vincenzina Barbera, Valeria D’Angelo, Maria Paola Germanò, Venerando Pistarà and Cinzia Anna Ventura

Pharmaceutics 2023, 15(9), 2209; https://doi.org/10.3390/pharmaceutics15092209 - 26 Aug 2023

Cited by 16 | Viewed by 1868

Abstract

Morin (MRN) is a natural compound with antiangiogenic, antioxidant, anti-inflammatory, and anticancer activity. However, it shows a very low water solubility (28 μg/mL) that reduces its oral absorption, making bioavailability low and unpredictable. To improve MRN solubility and positively affect its biological activity, [...] Read more.

Morin (MRN) is a natural compound with antiangiogenic, antioxidant, anti-inflammatory, and anticancer activity. However, it shows a very low water solubility (28 μg/mL) that reduces its oral absorption, making bioavailability low and unpredictable. To improve MRN solubility and positively affect its biological activity, particularly its antiangiogenic activity, in this work, we prepared the inclusion complexes of MNR with sulfobutylether-β-cyclodextrin (SBE-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complexes obtained by the freeze-drying method were extensively characterized in solution (phase-solubility studies, UV–Vis titration, and NMR spectroscopy) and in the solid state (TGA, DSC, and WAXD analysis). The complexation significantly increased the water solubility by about 100 times for MRN/HP-β-CD and 115 times for MRN/SBE-β-CD. Furthermore, quantitative dissolution of the complexes was observed within 60 min, whilst 1% of the free drug dissolved in the same experimental time. ¹H NMR and UV–Vis titration studies demonstrated both CDs well include the benzoyl moiety of the drug. Additionally, SBE-β-CD could interact with the cinnamoyl moiety of MRN too. The complexes are stable in solution, showing a high value of association constant, that is, 3380 M⁻¹ for MRN/HP-β-CD and 2870 M⁻¹ for MRN/SBE-β-CD. In vivo biological studies on chick embryo chorioallantoic membrane (CAM) and zebrafish embryo models demonstrated the high biocompatibility of the inclusion complexes and the effective increase in antiangiogenic activity of complexed MRN with respect to the free drug. Full article

(This article belongs to the Collection Women in Pharmaceutics)

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29 pages, 7593 KB

Open AccessEditor’s ChoiceArticle

Do Mixtures of Beads with Different Sizes Improve Wet Stirred Media Milling of Drug Suspensions?

by Gulenay Guner, Mirsad Mehaj, Natasha Seetharaman, Sherif Elashri, Helen F. Yao, Donald J. Clancy and Ecevit Bilgili

Pharmaceutics 2023, 15(9), 2213; https://doi.org/10.3390/pharmaceutics15092213 - 26 Aug 2023

Cited by 8 | Viewed by 3712

Abstract

The impacts of bead sizes and bead mixtures on breakage kinetics, the number of milling cycles applied to prevent overheating, and power consumption during the nanomilling of drug (griseofulvin) suspensions were investigated from both an experimental and theoretical perspective. Narrowly sized zirconia beads [...] Read more.

The impacts of bead sizes and bead mixtures on breakage kinetics, the number of milling cycles applied to prevent overheating, and power consumption during the nanomilling of drug (griseofulvin) suspensions were investigated from both an experimental and theoretical perspective. Narrowly sized zirconia beads with nominal sizes of 100, 200, and 400 µm and their half-and-half binary mixtures were used at 3000 and 4000 rpm with two bead loadings of 0.35 and 0.50. Particle size evolution was measured during the 3 h milling experiments using laser diffraction. An nth-order breakage model was fitted to the experimental median particle size evolution, and various microhydrodynamic parameters were calculated. In general, the beads and their mixtures with smaller median sizes achieved faster breakage. While the microhydrodynamic model explained the impacts of process parameters, it was limited in describing bead mixtures. For additional test runs performed, the kinetics model augmented with a decision tree model using process parameters outperformed that augmented with an elastic-net regression model using the microhydrodynamic parameters. The evaluation of the process merit scores suggests that the use of bead mixtures did not lead to notable process improvement; 100 µm beads generally outperformed bead mixtures and coarser beads in terms of fast breakage, low power consumption and heat generation, and low intermittent milling cycles. Full article

(This article belongs to the Collection Feature Papers in Pharmaceutical Technology)

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23 pages, 5070 KB

Open AccessEditor’s ChoiceArticle

Novel Tripodal Polyamine Tris-Pyrene: DNA/RNA Binding and Photodynamic Antiproliferative Activity

by Marta Jurković, Marijana Radić Stojković, Ksenija Božinović, Davor Nestić, Dragomira Majhen, Estefanía Delgado-Pinar, Mario Inclán, Enrique García-España and Ivo Piantanida

Pharmaceutics 2023, 15(9), 2197; https://doi.org/10.3390/pharmaceutics15092197 - 25 Aug 2023

Cited by 1 | Viewed by 1735

Abstract

A novel tri-pyrene polyamine (TAL3PYR) bearing net five positive charges at biorelevant conditions revealed strong intramolecular interactions in aqueous medium between pyrenes, characterised by pronounced excimer fluorescence. A novel compound revealed strong binding to ds-DNA and ds-RNA, along with pronounced thermal [...] Read more.

A novel tri-pyrene polyamine (TAL3PYR) bearing net five positive charges at biorelevant conditions revealed strong intramolecular interactions in aqueous medium between pyrenes, characterised by pronounced excimer fluorescence. A novel compound revealed strong binding to ds-DNA and ds-RNA, along with pronounced thermal stabilisation of DNA/RNA and extensive changes in DNA/RNA structure, as evidenced by circular dichroism. New dye caused pronounced ds-DNA or ds-RNA condensation, which was attributed to a combination of electrostatic interactions between 5+ charge of dye and negatively charged polynucleotide backbone, accompanied by aromatic and hydrophobic interactions of pyrenes within polynucleotide grooves. New dye also showed intriguing antiproliferative activity, strongly enhanced upon photo-induced activation of pyrenes, and is thus a promising lead compound for theranostic applications on ds-RNA or ds-DNA targets, applicable as a new strategy in cancer and gene therapy. Full article

(This article belongs to the Special Issue The Delivery of RNA-Based Therapeutics: New Strategies in Cancer and Gene Therapy)

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17 pages, 5051 KB

Open AccessEditor’s ChoiceArticle

Gold Nanomaterial System That Enables Dual Photothermal and Chemotherapy for Breast Cancer

by Lijun Wang, Binita Shrestha, Eric M. Brey and Liang Tang

Pharmaceutics 2023, 15(9), 2198; https://doi.org/10.3390/pharmaceutics15092198 - 25 Aug 2023

Cited by 3 | Viewed by 1830

Abstract

This study involves the fabrication and characterization of a multifunctional therapeutic nanocomposite system, as well as an assessment of its in vitro efficacy for breast cancer treatment. The nanocomposite system combines gold nanorods (GNRs) and gold nanoclusters (GNCs) to enable a combination of [...] Read more.

This study involves the fabrication and characterization of a multifunctional therapeutic nanocomposite system, as well as an assessment of its in vitro efficacy for breast cancer treatment. The nanocomposite system combines gold nanorods (GNRs) and gold nanoclusters (GNCs) to enable a combination of photothermal therapy and doxorubicin-based chemotherapy. GNRs of various sizes but exhibiting similar absorbance spectra were synthesized and screened for photothermal efficiency. GNRs exhibiting the highest photothermal efficiency were selected for further experiments. GNCs were synthesized in bovine serum albumin (BSA) and integrated into citrate-capped GNRs using layer-by-layer assembly. Glutaraldehyde crosslinking with the lysine residues in BSA was employed to immobilize the GNCs onto the GNRs, forming a stable “soft gel-like” structure. This structure provided binding sites for doxorubicin through electrostatic interactions and enhanced the overall structural stability of the nanocomposite. Additionally, the presence of GNCs allowed the nanocomposite system to emit robust fluorescence in the range of ~520 nm to 700 nm for self-detection. Hyaluronic acid was functionalized on the exterior surface of the nanocomposite as a targeting moiety for CD44 to improve the cellular internalization and specificity for breast cancer cells. The developed nanocomposite system demonstrated good stability in vitro and exhibited a pH- and near-infrared-responsive drug release behavior. In vitro studies showed the efficient internalization of the nanocomposite system and reduced cellular viability following NIR irradiation in MDA-MB-231 breast cancer cells. Together, these results highlight the potential of this nanocomposite system for targeted breast cancer therapy. Full article

(This article belongs to the Special Issue Multifunctional Nanoparticles for Combinational Cancer Therapy)

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19 pages, 3899 KB

Open AccessEditor’s ChoiceArticle

Long-Term Survival and Induction of Operational Tolerance to Murine Islet Allografts by Co-Transplanting Cyclosporine A Microparticles and CTLA4-Ig

by Purushothaman Kuppan, Jordan Wong, Sandra Kelly, Jiaxin Lin, Jessica Worton, Chelsea Castro, Joy Paramor, Karen Seeberger, Nerea Cuesta-Gomez, Colin C. Anderson, Gregory S. Korbutt and Andrew R. Pepper

Pharmaceutics 2023, 15(9), 2201; https://doi.org/10.3390/pharmaceutics15092201 - 25 Aug 2023

Cited by 5 | Viewed by 2336

Abstract

One strategy to prevent islet rejection is to create a favorable immune-protective local environment at the transplant site. Herein, we utilize localized cyclosporine A (CsA) delivery to islet grafts via poly(lactic-co-glycolic acid) (PLGA) microparticles to attenuate allograft rejection. CsA-eluting PLGA microparticles were prepared [...] Read more.

One strategy to prevent islet rejection is to create a favorable immune-protective local environment at the transplant site. Herein, we utilize localized cyclosporine A (CsA) delivery to islet grafts via poly(lactic-co-glycolic acid) (PLGA) microparticles to attenuate allograft rejection. CsA-eluting PLGA microparticles were prepared using a single emulsion (oil-in-water) solvent evaporation technique. CsA microparticles alone significantly delayed islet allograft rejection compared to islets alone (p < 0.05). Over 50% (6/11) of recipients receiving CsA microparticles and short-term cytotoxic T lymphocyte-associated antigen 4-Ig (CTLA4-Ig) therapy displayed prolonged allograft survival for 214 days, compared to 25% (2/8) receiving CTLA4-Ig alone. CsA microparticles alone and CsA microparticles + CTLA4-Ig islet allografts exhibited reduced T-cell (CD4⁺ and CD8⁺ cells, p < 0.001) and macrophage (CD68⁺ cells, p < 0.001) infiltration compared to islets alone. We observed the reduced mRNA expression of proinflammatory cytokines (IL-6, IL-10, INF-γ, and TNF-α; p < 0.05) and chemokines (CCL2, CCL5, CCL22, and CXCL10; p < 0.05) in CsA microparticles + CTLA4-Ig allografts compared to islets alone. Long-term islet allografts contained insulin⁺ and intra-graft FoxP3⁺ T regulatory cells. The rapid rejection of third-party skin grafts (C3H) in islet allograft recipients suggests that CsA microparticles + CTLA4-Ig therapy induced operational tolerance. This study demonstrates that localized CsA drug delivery plus short-course systemic immunosuppression promotes an immune protective transplant niche for allogeneic islets. Full article

(This article belongs to the Topic Recent Advancement in Biotechnology and Drug Development Using Cutting-Edge Platforms)

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23 pages, 7521 KB

Open AccessEditor’s ChoiceArticle

Continuous Manufacturing of Solvent-Free Cyclodextrin Inclusion Complexes for Enhanced Drug Solubility via Hot-Melt Extrusion: A Quality by Design Approach

by Siva Ram Munnangi, Ahmed Adel Ali Youssef, Nagarjuna Narala, Preethi Lakkala, Sateesh Kumar Vemula, Rohit Alluri, Feng Zhang and Micheal A. Repka

Pharmaceutics 2023, 15(9), 2203; https://doi.org/10.3390/pharmaceutics15092203 - 25 Aug 2023

Cited by 16 | Viewed by 3476

Abstract

Conventional cyclodextrin complexation enhances the solubility of poorly soluble drugs but is solvent-intensive and environmentally unfavorable. This study evaluated solvent-free hot-melt extrusion (HME) for forming cyclodextrin inclusion complexes to improve the solubility and dissolution of ibuprofen (IBU). Molecular docking confirmed IBU’s hosting in [...] Read more.

Conventional cyclodextrin complexation enhances the solubility of poorly soluble drugs but is solvent-intensive and environmentally unfavorable. This study evaluated solvent-free hot-melt extrusion (HME) for forming cyclodextrin inclusion complexes to improve the solubility and dissolution of ibuprofen (IBU). Molecular docking confirmed IBU’s hosting in Hydroxypropyl-β-cyclodextrin (HPβ-CD), while phase solubility revealed its complex stoichiometry and stability. In addition, an 11 mm twin-screw co-rotating extruder with PVP VA-64 as an auxiliary substance aided the complex formation and extrusion. Using QbD and the Box–Behnken design, we studied variables (barrel temperature, screw speed, and polymer concentration) and their impact on solubility and dissolution. The high polymer concentration and high screw speeds positively affected the dependent variables. However, higher temperatures had a negative effect. The lowest barrel temperature set near the Tg of the polymer, when combined with high polymer concentrations, resulted in high torques in HME and halted the extrusion process. Therefore, the temperature and polymer concentration should be selected to provide sufficient melt viscosities to aid the complex formation and extrusion process. Studies such as DSC and XRD revealed the amorphous conversion of IBU, while the inclusion complex formation was demonstrated by ATR and NMR studies. The dissolution of ternary inclusion complexes (TIC) produced from HME was found to be ≥85% released within 30 min. This finding implied the high solubility of IBU, according to the US FDA 2018 guidance for highly soluble compounds containing immediate-release solid oral dosage forms. Overall, the studies revealed the effect of various process parameters on the formation of CD inclusion complexes via HME. Full article

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

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16 pages, 3908 KB

Open AccessEditor’s ChoiceArticle

Superparamagnetic Nanocrystals Clustered Using Poly(ethylene glycol)-Crosslinked Amphiphilic Copolymers for the Diagnosis of Liver Cancer

by Ling Jiang, Jiaying Chi, Jiahui Wang, Shaobin Fang, Tingting Peng, Guilan Quan, Daojun Liu, Zhongjie Huang and Chao Lu

Pharmaceutics 2023, 15(9), 2205; https://doi.org/10.3390/pharmaceutics15092205 - 25 Aug 2023

Cited by 2 | Viewed by 1701

Abstract

Superparamagnetic iron oxide (SPIO) nanocrystals have been extensively studied as theranostic nanoparticles to increase transverse (T₂) relaxivity and enhance contrast in magnetic resonance imaging (MRI). To improve the blood circulation time and enhance the diagnostic sensitivity of MRI contrast agents, we [...] Read more.

Superparamagnetic iron oxide (SPIO) nanocrystals have been extensively studied as theranostic nanoparticles to increase transverse (T₂) relaxivity and enhance contrast in magnetic resonance imaging (MRI). To improve the blood circulation time and enhance the diagnostic sensitivity of MRI contrast agents, we developed an amphiphilic copolymer, PCPZL, to effectively encapsulate SPIO nanocrystals. PCPZL was synthesized by crosslinking a polyethylene glycol (PEG)-based homobifunctional linker with a hydrophobic star-like poly(ε-benzyloxycarbonyl-L-lysine) segment. Consequently, it could self-assemble into shell-crosslinked micelles with enhanced colloidal stability in bloodstream circulation. Notably, PCPZL could effectively load SPIO nanocrystals with a high loading capacity of 66.0 ± 0.9%, forming SPIO nanoclusters with a diameter of approximately 100 nm, a high cluster density, and an impressive T₂ relaxivity value 5.5 times higher than that of Resovist^®. In vivo MRI measurements highlighted the rapid accumulation and contrast effects of SPIO-loaded PCPZL micelles in the livers of both healthy mice and nude mice with an orthotopic hepatocellular carcinoma tumor model. Moreover, the magnetic micelles remarkably enhanced the relative MRI signal difference between the tumor and normal liver tissues. Overall, our findings demonstrate that PCPZL significantly improves the stability and magnetic properties of SPIO nanocrystals, making SPIO-loaded PCPZL micelles promising MRI contrast agents for diagnosing liver diseases and cancers. Full article

(This article belongs to the Special Issue Polymeric Micelles for Drug Delivery and Cancer Therapy)

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12 pages, 5143 KB

Open AccessEditor’s ChoiceArticle

Modified mRNA Formulation and Stability for Cardiac and Skeletal Muscle Delivery

by Magdalena M. Żak, Keerat Kaur, Jimeen Yoo, Ann Anu Kurian, Matthew Adjmi, Gayatri Mainkar, Seonghun Yoon and Lior Zangi

Pharmaceutics 2023, 15(9), 2176; https://doi.org/10.3390/pharmaceutics15092176 - 22 Aug 2023

Cited by 7 | Viewed by 3901

Abstract

Directly injecting naked or lipid nanoparticle (LNP)-encapsulated modified mRNA (modRNA) allows rapid and efficient protein expression. This non-viral technology has been used successfully in modRNA vaccines against SARS-CoV-2. The main challenges in using modRNA vaccines were the initial requirement for an ultra-cold storage [...] Read more.

Directly injecting naked or lipid nanoparticle (LNP)-encapsulated modified mRNA (modRNA) allows rapid and efficient protein expression. This non-viral technology has been used successfully in modRNA vaccines against SARS-CoV-2. The main challenges in using modRNA vaccines were the initial requirement for an ultra-cold storage to preserve their integrity and concerns regarding unwanted side effects from this new technology. Here, we showed that naked modRNA maintains its integrity when stored up to 7 days at 4 °C, and LNP-encapsulated modRNA for up to 7 days at room temperature. Naked modRNA is predominantly expressed at the site of injection when delivered into cardiac or skeletal muscle. In comparison, LNP-encapsulated modRNA granted superior protein expression but also additional protein expression beyond the cardiac or skeletal muscle injection site. To overcome this challenge, we developed a skeletal-muscle-specific modRNA translation system (skeletal muscle SMRTs) for LNP-encapsulated modRNA. This system allows controlled protein translation predominantly at the site of injection to prevent potentially detrimental leakage and expression in major organs. Our study revealed the potential of the SMRTs platform for controlled expression of mRNA payload delivered intramuscularly. To conclude, our SMRTs platform for LNP-encapsulated modRNA can provide safe, stable, efficient and targeted gene expression at the site of injection. Full article

(This article belongs to the Special Issue Progress and Innovation on Nanosystems for Gene Therapy)

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14 pages, 2207 KB

Open AccessEditor’s ChoiceArticle

On-Demand Release of Anti-Infective Silver from a Novel Implant Coating Using High-Energy Focused Shock Waves

by Jan Puetzler, Julian Hasselmann, Melanie Nonhoff, Manfred Fobker, Silke Niemann, Christoph Theil, Georg Gosheger and Martin Schulze

Pharmaceutics 2023, 15(9), 2179; https://doi.org/10.3390/pharmaceutics15092179 - 22 Aug 2023

Cited by 8 | Viewed by 1634

Abstract

Implant-related infections are a significant concern in orthopedic surgery. A novel anti-infective implant coating made of bioresorbable polymer with silver nitrate was developed. A controlled release of silver ions into the vicinity of the prosthesis can be triggered on-demand by extracorporeal shock waves [...] Read more.

Implant-related infections are a significant concern in orthopedic surgery. A novel anti-infective implant coating made of bioresorbable polymer with silver nitrate was developed. A controlled release of silver ions into the vicinity of the prosthesis can be triggered on-demand by extracorporeal shock waves to effectively combat all clinically relevant microorganisms. Microscopy techniques were used to examine the effects of shock wave application on coated titanium discs. Cytotoxicity was measured using a fibroblast proliferation assay. The anti-infective effect was assessed by monitoring the growth curves of three bacterial strains and by conventional culture. Microscopic analysis confirmed surface disruption of the coatings, with a complete release of silver in the focus area after shock wave application. Spectrometry detected an increase in silver concentration in the surrounding of the discs that surpassed the minimum inhibitory concentration (MIC) for both S. epidermidis RP62A and E. coli ATCC 25922. The released silver demonstrated an anti-infective effect, significantly inhibiting bacterial growth, especially at 6% and 8% silver concentrations. Cytotoxicity testing showed decreasing fibroblast viability with increasing silver concentration in the coating, with 6% silver maintaining viability above 25%. Compared to a commonly used electroplated silver coating on the market, the new coating demonstrated superior antimicrobial efficacy and lower cytotoxicity. Full article

(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery, 3rd Edition)

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36 pages, 2575 KB

Open AccessEditor’s ChoiceReview

Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy

by Kenneth K. W. To and William C. Cho

Pharmaceutics 2023, 15(8), 2166; https://doi.org/10.3390/pharmaceutics15082166 - 21 Aug 2023

Cited by 7 | Viewed by 4812

Abstract

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of [...] Read more.

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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21 pages, 3750 KB

Open AccessEditor’s ChoiceReview

An Insight on the Possible Association between Inflammatory Bowel Disease and Biologic Therapy with IL-17 Inhibitors in Psoriasis Patients

by Olguța Anca Orzan, Cristian George Țieranu, Andrei Ovidiu Olteanu, Alexandra Maria Dorobanțu, Anca Cojocaru, Mara Mădălina Mihai, Liliana Gabriela Popa, Ana Maria Gheorghiu, Călin Giurcăneanu and Ana Ion

Pharmaceutics 2023, 15(8), 2171; https://doi.org/10.3390/pharmaceutics15082171 - 21 Aug 2023

Cited by 9 | Viewed by 4398

Abstract

Psoriasis is a chronic, inflammatory, multisystemic disease which affects approximately 2–3% of the population globally, whose onset is triggered by genetic and environmental factors which activate both dendritic cells and keratinocytes, resulting in the production of proinflammatory cytokines such as tumor necrosis factor [...] Read more.

Psoriasis is a chronic, inflammatory, multisystemic disease which affects approximately 2–3% of the population globally, whose onset is triggered by genetic and environmental factors which activate both dendritic cells and keratinocytes, resulting in the production of proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 17, interleukin 23, interleukin 22, and interleukin 1β. An in-depth understanding of the pathophysiology of psoriasis led to significant advances in the development of safe and efficient novel therapeutic options, with four classes of biologic therapy being approved for the management of moderate to severe psoriasis: tumor necrosis factor alpha inhibitors, interleukin 23 inhibitors, anti-interleukin 12/23 agents, anti-interleukin 17 agents, as well as small-molecule inhibitors, such as apremilast. Psoriasis is associated with comorbid conditions, namely psoriatic arthritis, cardiovascular disease, metabolic syndrome, psychiatric disorders, malignancy, as well as inflammatory bowel disease. For patients affected by both psoriasis and inflammatory bowel disease, there is a strong recommendation to avoid IL-17 inhibitors since they may play a part in the exacerbation of the gastrointestinal disease. Our aim was to perform a thorough literature review regarding the development of inflammatory bowel disease lesions in psoriasis patients treated with IL-17 inhibitors, along with a case presentation to emphasize the need for close follow-up of these patients. Full article

(This article belongs to the Special Issue Targeted Therapies for Skin Diseases)

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27 pages, 6312 KB

Open AccessEditor’s ChoiceReview

Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload

by Aleksei Kondrashov, Surendra Sapkota, Aditya Sharma, Ivy Riano, Razelle Kurzrock and Jacob J. Adashek

Pharmaceutics 2023, 15(8), 2160; https://doi.org/10.3390/pharmaceutics15082160 - 19 Aug 2023

Cited by 25 | Viewed by 6066

Abstract

Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific [...] Read more.

Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs’ effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies. Full article

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

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22 pages, 2692 KB

Open AccessEditor’s ChoiceReview

Exploring the Antioxidant Potential of Gellan and Guar Gums in Wound Healing

by Gianina Dodi, Rosina E. Sabau, Bianca E.-B. Crețu and Ioannis Gardikiotis

Pharmaceutics 2023, 15(8), 2152; https://doi.org/10.3390/pharmaceutics15082152 - 17 Aug 2023

Cited by 19 | Viewed by 3965

Abstract

It is acknowledged that the presence of antioxidants boosts the wound-healing process. Many biopolymers have been explored over the years for their antioxidant potential in wound healing, but limited research has been performed on gum structures and their derivatives. This review aims to [...] Read more.

It is acknowledged that the presence of antioxidants boosts the wound-healing process. Many biopolymers have been explored over the years for their antioxidant potential in wound healing, but limited research has been performed on gum structures and their derivatives. This review aims to evaluate whether the antioxidant properties of gellan and guar gums and wound healing co-exist. PubMed was the primary platform used to explore published reports on the antioxidant wound-healing interconnection, wound dressings based on gellan and guar gum, as well as the latest review papers on guar gum. The literature search disclosed that some wound-healing supports based on gellan gum hold considerable antioxidant properties, as evident from the results obtained using different antioxidant assays. It has emerged that the antioxidant properties of guar gum are overlooked in the wound-healing field, in most cases, even if this feature improves the healing outcome. This review paper is the first that examines guar gum vehicles throughout the wound-healing process. Further research is needed to design and evaluate customized wound dressings that can scavenge excess reactive oxygen species, especially in clinical practice. Full article

(This article belongs to the Special Issue The Study of Plant Compounds in Antioxidant Activity and Anticancer Activity)

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20 pages, 4967 KB

Open AccessEditor’s ChoiceArticle

Antibiofilm Effect of Lavandula multifida Essential Oil: A New Approach for Chronic Infections

by Jorge Alves-Silva, Mónica Zuzarte, Carlos Cavaleiro and Lígia Salgueiro

Pharmaceutics 2023, 15(8), 2142; https://doi.org/10.3390/pharmaceutics15082142 - 15 Aug 2023

Cited by 7 | Viewed by 2327

Abstract

Fungal infections are associated with high morbidity and mortality rates, being highly prevalent in patients with underlying health complications such as chronic lung disease, HIV, cancer, and diabetes mellitus. To mitigate these infections, the development of effective antifungals is imperative, with plants standing [...] Read more.

Fungal infections are associated with high morbidity and mortality rates, being highly prevalent in patients with underlying health complications such as chronic lung disease, HIV, cancer, and diabetes mellitus. To mitigate these infections, the development of effective antifungals is imperative, with plants standing out as promising sources of bioactive compounds. In the present study, we focus on the antibiofilm potential of Lavandula multifida essential oil (EO) against dermatophyte strains and Candida albicans. The EO was characterized using GC and GC–MS, and its antifungal effect was assessed on both biofilm formation and disruption. Biofilm mass, extracellular matrix, and viability were quantified using crystal violet, safranin, and XTT assays, respectively, and morphological alterations were confirmed using optical and scanning electron microscopy. L. multifida EO showed very high amounts of carvacrol and was very effective in inhibiting and disrupting fungal biofilms. The EO significantly decreased biofilm mass and viability in all tested fungi. In addition, a reduction in dermatophytes’ extracellular matrix was observed, particularly during biofilm formation. Morphological alterations were evident in mature biofilms, with a clear decrease in hypha diameter. These promising results support the use of L. multifida EO in the development of effective plant-based antifungal products. Full article

(This article belongs to the Special Issue Essential Oil in Pharmaceutical Products for the Management of Chronic Diseases)

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17 pages, 2749 KB

Open AccessEditor’s ChoiceArticle

Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab

by Blaise Pasquiers, Salih Benamara, Mathieu Felices, David Ternant, Xavier Declèves and Alicja Puszkiel

Pharmaceutics 2023, 15(8), 2129; https://doi.org/10.3390/pharmaceutics15082129 - 14 Aug 2023

Cited by 4 | Viewed by 4195

Abstract

Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding [...] Read more.

Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding inter-species translation during preclinical and clinical development steps of mAbs. The objective of this study was to develop a generic PBPK translational approach for mAbs using the open-source software (PK-Sim^® and Mobi^®). The translation of bevacizumab based on data in non-human primates (NHP), healthy volunteers (HV), and cancer patients was used as a case example for model demonstration purpose. A PBPK model for bevacizumab concentration-time data was developed using data from literature and the Open Systems Pharmacology (OSP) Suite version 10. PK-sim^® was used to build the linear part of bevacizumab PK (mainly FcRn-mediated), whereas MoBi^® was used to develop the target-mediated part. The model was first developed for NHP and used for a priori PK prediction in HV. Then, the refined model obtained in HV was used for a priori prediction in cancer patients. A priori predictions were within 2-fold prediction error (predicted/observed) for both area under the concentration-time curve (AUC) and maximum concentration (C_max) and all the predicted concentrations were within 2-fold average fold error (AFE) and average absolute fold error (AAFE). Sensitivity analysis showed that FcRn-mediated distribution and elimination processes must be accounted for at all mAb concentration levels, whereas the lower the mAb concentration, the more significant the target-mediated elimination. This project is the first step to generalize the full PBPK translational approach in Model-Informed Drug Development (MIDD) of mAbs using OSP Suite. Full article

(This article belongs to the Special Issue Applications of Physiologically-Based Pharmacokinetic (PBPK) Modeling, 2nd Edition)

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17 pages, 796 KB

Open AccessEditor’s ChoiceReview

Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma

by Jieun Bang, Mihyeon Jun, Soyun Lee, Hyuk Moon and Simon Weonsang Ro

Pharmaceutics 2023, 15(8), 2130; https://doi.org/10.3390/pharmaceutics15082130 - 14 Aug 2023

Cited by 44 | Viewed by 6403

Abstract

Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways [...] Read more.

Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/AKT/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we explore recent advancements in understanding the role of the EGFR/PI3K/AKT/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies. Full article

(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)

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