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Pharmaceutics, Volume 15, Issue 7 (July 2023) – 235 articles

Cover Story (view full-size image): In oral absorption, dissolution limitations can occur if the time required for dissolution is longer than the small intestinal transit time and/or if dissolution is slower than the drug’s permeation through the gut wall. A standard method for overcoming dissolution issues is to reduce the particle size of the (solid) drug. Building on the refined Developability Classification System (rDCS), this work establishes a novel set of equations with which the degree of particle size reduction needed to mitigate dissolution limitations can be calculated. According to the type of data available, the appropriate equation(s) for each situation can be applied. Three example drugs, representing a wide range of physicochemical characteristics, are used to illustrate the implementation of the equations: voriconazole, lemborexant and istradefylline. View this paper
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20 pages, 7560 KiB  
Article
Dual-Ligand Synergistic Targeting Anti-Tumor Nanoplatforms with Cascade-Responsive Drug Release
Pharmaceutics 2023, 15(7), 2014; https://doi.org/10.3390/pharmaceutics15072014 - 24 Jul 2023
Viewed by 1078
Abstract
Dual-ligand targeting drug delivery nanoplatforms are considered a promising tool for enhancing the specificity of chemotherapy. However, serious off-target delivery has been observed in current dual-ligand targeting nanoplatforms, as each ligand can independently recognize receptors on the cell membrane surface and guide drug [...] Read more.
Dual-ligand targeting drug delivery nanoplatforms are considered a promising tool for enhancing the specificity of chemotherapy. However, serious off-target delivery has been observed in current dual-ligand targeting nanoplatforms, as each ligand can independently recognize receptors on the cell membrane surface and guide drug nanocarriers to different cells. To overcome this barrier, a dual-ligand synergistic targeting (DLST) nanoplatform is developed, which can guide chemotherapy treatment specifically to cancer cells simultaneously overexpressing two receptors. This nanoplatform consists of a singlet oxygen (1O2) photosensitizer-loaded nanocarrier and a drug-loaded nanocarrier with 1O2 responsiveness, which were, respectively, decorated with a pair of complementary DNA sequences and two different ligands. For cancer cells overexpressing both receptors, two nanocarriers can be internalized in larger quantities to cause DNA hybridization-induced nanocarrier aggregation, which further activates 1O2-triggered drug release under light irradiation. For cells overexpressing a single receptor, only one type of nanocarrier can be internalized in a large quantity, leading to blocked drug release due to the ultrashort action radius of 1O2. In vivo evaluation showed this DLST nanoplatform displayed highly specific tumor treatment with minimized long-term toxicity. This is a highly efficient drug delivery system for DLST chemotherapy, holding great potential for clinical applications. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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34 pages, 5182 KiB  
Review
The Spicy Science of Dendrimers in the Realm of Cancer Nanomedicine: A Report from the COST Action CA17140 Nano2Clinic
Pharmaceutics 2023, 15(7), 2013; https://doi.org/10.3390/pharmaceutics15072013 - 24 Jul 2023
Cited by 1 | Viewed by 1013
Abstract
COST Action CA17140 Cancer Nanomedicine—from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their [...] Read more.
COST Action CA17140 Cancer Nanomedicine—from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their initial design, preclinical testing of efficacy, pharmacokinetics and toxicity to the preparation of detailed protocols needed for the first phase of their clinical studies. By promoting scientific exchanges, technological implementation, and innovative solutions, the action aims at providing a timely instrument to rationalize and focus research efforts at the European level in dealing with the grand challenge of nanomedicine translation in cancer, one of the major and societal-burdening human pathologies. Within CA17140, dendrimers in all their forms (from covalent to self-assembling dendrons) play a vital role as powerful nanotheranostic agents in oncology; therefore, the purpose of this review work is to gather and summarize the major results in the field stemming from collaborative efforts in the framework of the European Nano2Clinic COST Action. Full article
(This article belongs to the Special Issue Dendrimers for Drug Delivery)
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18 pages, 3308 KiB  
Article
A Moexitecan Magnetic Liposomal Strategy for Ferroptosis-Enhanced Chemotherapy
Pharmaceutics 2023, 15(7), 2012; https://doi.org/10.3390/pharmaceutics15072012 - 24 Jul 2023
Cited by 2 | Viewed by 910
Abstract
Moexitecan (Mex) is a novel camptothecin derivative that retains the potent antitumor properties of camptothecin drugs and has improved hydrophilicity to enhance biocompatibility in vitro. However, single-drug therapy still has limitations. In this study, magnetic liposomes loaded with both moexitecan and superparamagnetic iron [...] Read more.
Moexitecan (Mex) is a novel camptothecin derivative that retains the potent antitumor properties of camptothecin drugs and has improved hydrophilicity to enhance biocompatibility in vitro. However, single-drug therapy still has limitations. In this study, magnetic liposomes loaded with both moexitecan and superparamagnetic iron oxide nanoparticles (SPIO) have been fabricated by a film hydration and filtration method, which is abbreviated as Mex@MLipo. By using liposomes as drug carriers, Mex can be delivered specifically to the target site, resulting in improved therapeutic efficacy and reduced toxicity. Morphology characterization results show that Mex@MLipo has a mean diameter of 180–200 nm with a round morphology. The loading efficiencies of Mex and SPIO are 65.86% and 76.86%, respectively. Cell toxicity, in vitro cell uptake, and in vivo fluorescence imaging experiments showed that Mex@MLipo was the most effective in killing HT-29 cells compared with HepG-2 and PC-3 cells, due to its ability to combine chemotherapy and induce ferroptosis, resulting in a strong anti-tumor effect. Thus, this study developed an innovative nanoscale drug delivery system that paves the way for clinical applications of moexitecan. Full article
(This article belongs to the Section Gene and Cell Therapy)
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25 pages, 1758 KiB  
Review
Bio-Inspired Nanocarriers Derived from Stem Cells and Their Extracellular Vesicles for Targeted Drug Delivery
Pharmaceutics 2023, 15(7), 2011; https://doi.org/10.3390/pharmaceutics15072011 - 24 Jul 2023
Cited by 3 | Viewed by 1378
Abstract
With their seemingly limitless capacity for self-improvement, stem cells have a wide range of potential uses in the medical field. Stem-cell-secreted extracellular vesicles (EVs), as paracrine components of stem cells, are natural nanoscale particles that transport a variety of biological molecules and facilitate [...] Read more.
With their seemingly limitless capacity for self-improvement, stem cells have a wide range of potential uses in the medical field. Stem-cell-secreted extracellular vesicles (EVs), as paracrine components of stem cells, are natural nanoscale particles that transport a variety of biological molecules and facilitate cell-to-cell communication which have been also widely used for targeted drug delivery. These nanocarriers exhibit inherent advantages, such as strong cell or tissue targeting and low immunogenicity, which synthetic nanocarriers lack. However, despite the tremendous therapeutic potential of stem cells and EVs, their further clinical application is still limited by low yield and a lack of standardized isolation and purification protocols. In recent years, inspired by the concept of biomimetics, a new approach to biomimetic nanocarriers for drug delivery has been developed through combining nanotechnology and bioengineering. This article reviews the application of biomimetic nanocarriers derived from stem cells and their EVs in targeted drug delivery and discusses their advantages and challenges in order to stimulate future research. Full article
(This article belongs to the Special Issue Biomimetic Nanoparticles for Disease Treatment and Diagnosis)
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13 pages, 2461 KiB  
Article
Sodium Alginate/Chitosan-Coated Liposomes for Oral Delivery of Hydroxy-α-Sanshool: In Vitro and In Vivo Evaluation
Pharmaceutics 2023, 15(7), 2010; https://doi.org/10.3390/pharmaceutics15072010 - 24 Jul 2023
Viewed by 1058
Abstract
Background: Hydroxy-α-Sanshool (HAS) possesses various pharmacological properties, such as analgesia and regulating gastrointestinal function. However, the low oral bioavailability of HAS has limited its oral delivery in clinical application. Methods and Results: To enhance its oral bioavailability, a nanocomposite delivery system based on [...] Read more.
Background: Hydroxy-α-Sanshool (HAS) possesses various pharmacological properties, such as analgesia and regulating gastrointestinal function. However, the low oral bioavailability of HAS has limited its oral delivery in clinical application. Methods and Results: To enhance its oral bioavailability, a nanocomposite delivery system based on chitosan (CH, as the polycation) and sodium alginate (SA, as the polyanion) was prepared using a layer-by-layer coating technique. The morphology, thermal behavior and Fourier transform infrared spectrum (FTIR) showed that the obtained sodium alginate/chitosan-coated HAS-loaded liposomes (SA/CH-HAS-LIP) with core-shell structures have been successfully covered with polymers. When compared with HAS-loaded liposomes (HAS-LIP), SA/CH-HAS-LIP displayed obvious pH sensitivity and a sustained-release behavior in in vitro studies, which fitted well to Weibull model. In vivo, the half-life of HAS from SA/CH-HAS-LIP remarkably extended after oral administration compared to the free drug. Additionally, it allowed a 4.6-fold and 4.2-fold increase in oral bioavailability, respectively, compared with free HAS and HAS-LIP. Conclusions: SA/CH-HAS-LIP could be a promising release vehicle for the oral delivery of HAS to increase its oral bioavailability. Full article
(This article belongs to the Special Issue Nanotechnology-Based Drug Formulations and Drug Delivery Systems)
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17 pages, 2749 KiB  
Article
The Use of a Barley-Based Well to Define Cationic Betaglucan to Study Mammalian Cell Toxicity Associated with Interactions with Biological Structures
Pharmaceutics 2023, 15(7), 2009; https://doi.org/10.3390/pharmaceutics15072009 - 23 Jul 2023
Cited by 1 | Viewed by 840
Abstract
Among potential macromolecule-based pharmaceuticals, polycations seem particularly interesting due to their proven antimicrobial properties and use as vectors in gene therapy. This makes an understanding of the mechanisms of these molecules’ interaction with living structures important, so the goal of this paper was [...] Read more.
Among potential macromolecule-based pharmaceuticals, polycations seem particularly interesting due to their proven antimicrobial properties and use as vectors in gene therapy. This makes an understanding of the mechanisms of these molecules’ interaction with living structures important, so the goal of this paper was to propose and carry out experiments that will allow us to characterize these phenomena. Of particular importance is the question of toxicity of such structures to mammalian cells and, in the work presented here, two lines, normal fibroblasts 3T3-L1 and A549 lung cancer, were used to determine this. In this work, three well-defined cationic derivatives of barley-derived betaglucans obtained in a reaction with glycidyltrimethylammonium chloride (BBGGTMAC) with different degrees of cationization (50, 70, and 100% per one glucose unit) and electrostatic charge were studied. The studies address interactions of these polymers with proteins (bovine serum proteins and BSA), nucleic acids (DNA), glycosaminoglycans (heparin), and biological membranes. The results described in this study make it possible to indicate that toxicity is most strongly influenced by interactions with biological membranes and is closely related to the electrostatic charge of the macromolecule. The presentation of this observation was the goal of this publication. This paper also shows, using fluorescently labeled variants of polymers, the penetration and impact on cell structure (only for the polymer with the highest substitution binding to cell membranes is observed) by using confocal and SEM (for the polymer with the highest degree of substitution, and the appearance of additional structures on the surface of the cell membrane is observed). The labeled polymers are also tools used together with dynamic light scattering and calorimetric titration to study their interaction with other biopolymers. As for the interactions with biological membranes, lipid Langmuir monolayers as model membrane systems were used. Full article
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13 pages, 4320 KiB  
Article
Curcumin–Triterpene Type Hybrid as Effective Sonosensitizers for Sonodynamic Therapy in Oral Squamous Cell Carcinoma
Pharmaceutics 2023, 15(7), 2008; https://doi.org/10.3390/pharmaceutics15072008 - 23 Jul 2023
Cited by 1 | Viewed by 983
Abstract
Sonodynamic therapy (SDT) is a non-invasive therapeutic modality in cancer treatment that combines low-intensity ultrasound (US) and sonosensitizers. Tumor cells are destroyed through the synergistic effects of ultrasound and a chemical sonosensitizer. This study focused on the synthesis and in vitro evaluation of [...] Read more.
Sonodynamic therapy (SDT) is a non-invasive therapeutic modality in cancer treatment that combines low-intensity ultrasound (US) and sonosensitizers. Tumor cells are destroyed through the synergistic effects of ultrasound and a chemical sonosensitizer. This study focused on the synthesis and in vitro evaluation of the sonodynamic effect of natural curcumin, triterpene oleanolic acid, and their semi-synthetic derivatives on tongue cancer SCC-25 and hypopharyngeal FaDu cell lines. The combination of the tested compounds with sonication showed a synergistic increase in cytotoxicity. In the group of oleanolic acid derivatives, oleanoyl hydrogen succinate (6) showed the strongest cytotoxic effect both in the SCC-25 and FaDu cell lines. Comparing curcumin (4) and its pyrazole derivative (5), curcumin showed a better cytotoxic effect on SCC-25 cells, while curcumin pyrazole was more potent on FaDu cells. The highest sonotherapeutic activity, compared to its individual components, was demonstrated by a structural linker mode hybrid containing both curcumin pyrazole-oleanoyl hydrogen succinate units within one complex molecule (7). This study can be beneficial in the context of new perspectives in the search for effective sonosensitizers among derivatives of natural organic compounds. Full article
(This article belongs to the Special Issue Advances in Phototherapy and Sonodynamic Therapy)
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17 pages, 5126 KiB  
Article
Preparation and Evaluation of Auxiliary Permeable Microneedle Patch Composed of Polyvinyl Alcohol and Eudragit NM30D Aqueous Dispersion
Pharmaceutics 2023, 15(7), 2007; https://doi.org/10.3390/pharmaceutics15072007 - 22 Jul 2023
Cited by 1 | Viewed by 1693
Abstract
Poor transdermal permeability limits the possibility of most drug delivery through the skin. Auxiliary permeable microneedles (AP-MNs) with a three-dimensional network structure can effectively break the skin stratum corneum barrier and assist in the transdermal delivery of active ingredients. Herein, we propose a [...] Read more.
Poor transdermal permeability limits the possibility of most drug delivery through the skin. Auxiliary permeable microneedles (AP-MNs) with a three-dimensional network structure can effectively break the skin stratum corneum barrier and assist in the transdermal delivery of active ingredients. Herein, we propose a simple method for preparing AP-MNs using polyvinyl alcohol and Eudragit NM30D for the first time. To optimize the formulation of microneedles, the characteristics of swelling properties, skin insertion, solution viscosity, and needle integrity were systematically examined. Additionally, the morphology, mechanical strength, formation mechanism, skin permeability, swelling performance, biocompatibility, and in vitro transdermal drug delivery of AP-MNs were evaluated. The results indicated that the microneedles exhibited excellent mechanical-strength and hydrogel-forming properties after swelling. Further, it proved that a continuous and unblockable network channel was created based on physical entanglement and encapsulation of two materials. The 24 h cumulative permeation of acidic and alkaline model drugs, azelaic acid and matrine, were 51.73 ± 2.61% and 54.02 ± 2.85%, respectively, significantly enhancing the transdermal permeability of the two drugs. In summary, the novel auxiliary permeable microneedles prepared through a simple blending route of two materials was a promising and valuable way to improve drug permeation efficiency. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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22 pages, 12114 KiB  
Article
An In Vivo Electroencephalographic Analysis of the Effect of Riluzole against Limbic and Absence Seizure and Comparison with Glutamate Antagonists
Pharmaceutics 2023, 15(7), 2006; https://doi.org/10.3390/pharmaceutics15072006 - 22 Jul 2023
Viewed by 1080
Abstract
Background: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. Methods: In the [...] Read more.
Background: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. Methods: In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague–Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. Results: In Sprague–Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. Conclusions: these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors. Full article
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32 pages, 1171 KiB  
Review
Next-Generation Nanomedicine Approaches for the Management of Retinal Diseases
Pharmaceutics 2023, 15(7), 2005; https://doi.org/10.3390/pharmaceutics15072005 - 22 Jul 2023
Cited by 1 | Viewed by 1880
Abstract
Retinal diseases are one of the leading causes of blindness globally. The mainstay treatments for these blinding diseases are laser photocoagulation, vitrectomy, and repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) or steroids. Unfortunately, these therapies are associated with ocular complications like [...] Read more.
Retinal diseases are one of the leading causes of blindness globally. The mainstay treatments for these blinding diseases are laser photocoagulation, vitrectomy, and repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) or steroids. Unfortunately, these therapies are associated with ocular complications like inflammation, elevated intraocular pressure, retinal detachment, endophthalmitis, and vitreous hemorrhage. Recent advances in nanomedicine seek to curtail these limitations, overcoming ocular barriers by developing non-invasive or minimally invasive delivery modalities. These modalities include delivering therapeutics to specific cellular targets in the retina, providing sustained delivery of drugs to avoid repeated intravitreal injections, and acting as a scaffold for neural tissue regeneration. These next-generation nanomedicine approaches could potentially revolutionize the treatment landscape of retinal diseases. This review describes the availability and limitations of current treatment strategies and highlights insights into the advancement of future approaches using next-generation nanomedicines to manage retinal diseases. Full article
(This article belongs to the Special Issue Novel Nanoparticle Formulations for Retinal Drug Delivery)
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63 pages, 5895 KiB  
Review
Hacking the Immune Response to Solid Tumors: Harnessing the Anti-Cancer Capacities of Oncolytic Bacteria
Pharmaceutics 2023, 15(7), 2004; https://doi.org/10.3390/pharmaceutics15072004 - 21 Jul 2023
Cited by 1 | Viewed by 3198
Abstract
Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley’s Toxin), Proteus, [...] Read more.
Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley’s Toxin), Proteus, Salmonella, and Clostridium. Advancements in techniques and methodology, including genetic engineering, create opportunities to “hijack” typical host–pathogen interactions and subsequently harness oncolytic capacities. Engineering, sometimes termed “domestication”, of oncolytic bacterial species is especially beneficial when solid tumors are inaccessible or metastasize early in development. This review examines reported oncolytic bacteria–host immune interactions and details the known mechanisms of these interactions to the protein level. A synopsis of the presented membrane surface molecules that elicit particularly promising oncolytic capacities is paired with the stimulated localized and systemic immunogenic effects. In addition, oncolytic bacterial progression toward clinical translation through engineering efforts are discussed, with thorough attention given to strains that have accomplished Phase III clinical trial initiation. In addition to therapeutic mitigation after the tumor has formed, some bacterial species, referred to as “prophylactic”, may even be able to prevent or “derail” tumor formation through anti-inflammatory capabilities. These promising species and their particularly favorable characteristics are summarized as well. A complete understanding of the bacteria–host interaction will likely be necessary to assess anti-cancer capacities and unlock the full cancer therapeutic potential of oncolytic bacteria. Full article
(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)
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21 pages, 7059 KiB  
Review
Metal-Based Nanoparticles for Cancer Metalloimmunotherapy
Pharmaceutics 2023, 15(7), 2003; https://doi.org/10.3390/pharmaceutics15072003 - 21 Jul 2023
Cited by 2 | Viewed by 1672
Abstract
Although the promise of cancer immunotherapy has been partially fulfilled with the unprecedented clinical success of several immunotherapeutic interventions, some issues, such as limited response rate and immunotoxicity, still remain. Metalloimmunotherapy offers a new form of cancer immunotherapy that utilizes the inherent immunomodulatory [...] Read more.
Although the promise of cancer immunotherapy has been partially fulfilled with the unprecedented clinical success of several immunotherapeutic interventions, some issues, such as limited response rate and immunotoxicity, still remain. Metalloimmunotherapy offers a new form of cancer immunotherapy that utilizes the inherent immunomodulatory features of metal ions to enhance anticancer immune responses. Their versatile functionalities for a multitude of direct and indirect anticancer activities together with their inherent biocompatibility suggest that metal ions can help overcome the current issues associated with cancer immunotherapy. However, metal ions exhibit poor drug-like properties due to their intrinsic physicochemical profiles that impede in vivo pharmacological performance, thus necessitating an effective pharmaceutical formulation strategy to improve their in vivo behavior. Metal-based nanoparticles provide a promising platform technology for reshaping metal ions into more drug-like formulations with nano-enabled engineering approaches. This review provides a general overview of cancer immunotherapy, the immune system and how it works against cancer cells, and the role of metal ions in the host response and immune modulation, as well as the impact of metal ions on the process via the regulation of immune cells. The preclinical studies that have demonstrated the potential of metal-based nanoparticles for cancer metalloimmunotherapy are presented for the representative nanoparticles constructed with manganese, zinc, iron, copper, calcium, and sodium ions. Lastly, the perspectives and future directions of metal-based nanoparticles are discussed, particularly with respect to their clinical applications. Full article
(This article belongs to the Special Issue Metal Nanoparticles for Cancer Therapy)
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20 pages, 2695 KiB  
Review
Methodologies to Evaluate the Hair Follicle-Targeted Drug Delivery Provided by Nanoparticles
Pharmaceutics 2023, 15(7), 2002; https://doi.org/10.3390/pharmaceutics15072002 - 21 Jul 2023
Cited by 4 | Viewed by 2474
Abstract
Nanotechnology has been investigated for treatments of hair follicle disorders mainly because of the natural accumulation of solid nanoparticles in the follicular openings following a topical application, which provides a drug “targeting effect”. Despite the promising results regarding the therapeutic efficacy of topically [...] Read more.
Nanotechnology has been investigated for treatments of hair follicle disorders mainly because of the natural accumulation of solid nanoparticles in the follicular openings following a topical application, which provides a drug “targeting effect”. Despite the promising results regarding the therapeutic efficacy of topically applied nanoparticles, the literature has often presented controversial results regarding the targeting of hair follicle potential of nanoformulations. A closer look at the published works shows that study parameters such as the type of skin model, skin sections analyzed, employed controls, or even the extraction methodologies differ to a great extent among the studies, producing either unreliable results or precluding comparisons altogether. Hence, the present study proposes to review different skin models and methods for quantitative and qualitative analysis of follicular penetration of nano-entrapped drugs and their influence on the obtained results, as a way of providing more coherent study protocols for the intended application. Full article
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21 pages, 1249 KiB  
Review
Targeting Potential of Innate Lymphoid Cells in Melanoma and Other Cancers
Pharmaceutics 2023, 15(7), 2001; https://doi.org/10.3390/pharmaceutics15072001 - 21 Jul 2023
Viewed by 1174
Abstract
Reinvigorating the killing function of tumor-infiltrating immune cells through the targeting of regulatory molecules expressed on lymphocytes has markedly improved the prognosis of cancer patients, particularly in melanoma. While initially thought to solely strengthen adaptive T lymphocyte anti-tumor activity, recent investigations suggest that [...] Read more.
Reinvigorating the killing function of tumor-infiltrating immune cells through the targeting of regulatory molecules expressed on lymphocytes has markedly improved the prognosis of cancer patients, particularly in melanoma. While initially thought to solely strengthen adaptive T lymphocyte anti-tumor activity, recent investigations suggest that other immune cell subsets, particularly tissue-resident innate lymphoid cells (ILCs), may benefit from immunotherapy treatment. Here, we describe the recent findings showing immune checkpoint expression on tissue-resident and tumor-infiltrating ILCs and how their effector function is modulated by checkpoint blockade-based therapies in cancer. We discuss the therapeutic potential of ILCs beyond the classical PD-1 and CTLA-4 regulatory molecules, exploring other possibilities to manipulate ILC effector function to further impede tumor growth and quench disease progression. Full article
(This article belongs to the Special Issue Immunotherapy of Melanoma)
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16 pages, 4607 KiB  
Article
Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation
Pharmaceutics 2023, 15(7), 2000; https://doi.org/10.3390/pharmaceutics15072000 - 21 Jul 2023
Cited by 1 | Viewed by 1018
Abstract
Small-molecule modulators of neurotensin receptor 1 (NTSR1), a class A G-protein-coupled receptor (GPCR), has emerged as promising therapeutic agent for psychiatric disorders and cancer. Interestingly, a chemical group substitution in NTSR1 modulators can launch different types of downstream regulation, highlighting the significance of [...] Read more.
Small-molecule modulators of neurotensin receptor 1 (NTSR1), a class A G-protein-coupled receptor (GPCR), has emerged as promising therapeutic agent for psychiatric disorders and cancer. Interestingly, a chemical group substitution in NTSR1 modulators can launch different types of downstream regulation, highlighting the significance of deciphering the internal fine-tuning mechanism. Here, we conducted a synergistic application of a Gaussian accelerated molecular dynamics simulation, a conventional molecular dynamics simulation, and Markov state models (MSM) to investigate the underlying mechanism of ‘driver chemical groups’ of modulators triggering inverse signaling. The results indicated that the flexibility of the leucine moiety in NTSR1 agonists contributes to the inward displacement of TM7 through a loosely coupled allosteric pathway, while the rigidity of the adamantane moiety in NTSR1 antagonists leads to unfavorable downward transduction of agonistic signaling. Furthermore, we found that R3226.54, Y3196.51, F3537.42, R1483.32, S3567.45, and S3577.46 may play a key role in inducing the activation of NTSR1. Together, our findings not only highlight the ingenious signal transduction within class A GPCRs but also lay a foundation for the development of targeted drugs harboring different regulatory functions of NTSR1. Full article
(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)
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27 pages, 2651 KiB  
Review
Cell-Penetrating and Targeted Peptides Delivery Systems as Potential Pharmaceutical Carriers for Enhanced Delivery across the Blood–Brain Barrier (BBB)
Pharmaceutics 2023, 15(7), 1999; https://doi.org/10.3390/pharmaceutics15071999 - 21 Jul 2023
Cited by 7 | Viewed by 3203
Abstract
Among the challenges to the 21st-century health care industry, one that demands special mention is the transport of drugs/active pharmaceutical agents across the blood–brain barrier (BBB). The epithelial-like tight junctions within the brain capillary endothelium hinder the uptake of most pharmaceutical agents. With [...] Read more.
Among the challenges to the 21st-century health care industry, one that demands special mention is the transport of drugs/active pharmaceutical agents across the blood–brain barrier (BBB). The epithelial-like tight junctions within the brain capillary endothelium hinder the uptake of most pharmaceutical agents. With an aim to understand more deeply the intricacies of cell-penetrating and targeted peptides as a powerful tool for desirable biological activity, we provide a critical review of both CPP and homing/targeted peptides as intracellular drug delivery agents, especially across the blood–brain barrier (BBB). Two main peptides have been discussed to understand intracellular drug delivery; first is the cell-penetrating peptides (CPPs) for the targeted delivery of compounds of interest (primarily peptides and nucleic acids) and second is the family of homing peptides, which specifically targets cells/tissues based on their overexpression of tumour-specific markers and are thus at the heart of cancer research. These small, amphipathic molecules demonstrate specific physical and chemical modifications aimed at increased ease of cellular internalisation. Because only a limited number of drug molecules can bypass the blood–brain barrier by free diffusion, it is essential to explore all aspects of CPPs that can be exploited for crossing this barrier. Considering siRNAs that can be designed against any target RNA, marking such molecules with high therapeutic potential, we present a synopsis of the studies on synthetic siRNA-based therapeutics using CPPs and homing peptides drugs that can emerge as potential drug-delivery systems as an upcoming requirement in the world of pharma- and nutraceuticals. Full article
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15 pages, 4235 KiB  
Article
Delicate Hybrid Laponite–Cyclic Poly(ethylene glycol) Nanoparticles as a Potential Drug Delivery System
Pharmaceutics 2023, 15(7), 1998; https://doi.org/10.3390/pharmaceutics15071998 - 21 Jul 2023
Cited by 2 | Viewed by 882
Abstract
The objective of the study was to explore the feasibility of a new drug delivery system using laponite (LAP) and cyclic poly(ethylene glycol) (cPEG). Variously shaped and flexible hybrid nanocrystals were made by both the covalent and physical attachment of chemically homogeneous cyclized [...] Read more.
The objective of the study was to explore the feasibility of a new drug delivery system using laponite (LAP) and cyclic poly(ethylene glycol) (cPEG). Variously shaped and flexible hybrid nanocrystals were made by both the covalent and physical attachment of chemically homogeneous cyclized PEG to laponite nanodisc plates. The size of the resulting, nearly spherical particles ranged from 1 to 1.5 µm, while PEGylation with linear methoxy poly (ethylene glycol) (mPEG) resulted in fragile sheets of different shapes and sizes. When infused with 10% doxorubicin (DOX), a drug commonly used in the treatment of various cancers, the LAP-cPEG/DOX formulation was transparent and maintained liquid-like homogeneity without delamination, and the drug loading efficiency of the LAP-cPEG nano system was found to be higher than that of the laponite-poly(ethylene glycol) LAP-mPEG system. Furthermore, the LAP-cPEG/DOX formulation showed relative stability in phosphate-buffered saline (PBS) with only 15% of the drug released. However, in the presence of human plasma, about 90% of the drug was released continuously over a period of 24 h for the LAP-cPEG/DOX, while the LAP-mPEG/DOX formulation released 90% of DOX in a 6 h burst. The results of the cell viability assay indicated that the LAP-cPEG/DOX formulation could effectively inhibit the proliferation of A549 lung carcinoma epithelial cells. With the DOX concentration in the range of 1–2 µM in the LAP-cPEG/DOX formulation, enhanced drug effects in both A549 lung carcinoma epithelial cells and primary lung epithelial cells were observed compared to LAP-mPEG/DOX. The unique properties and effects of cPEG nanoparticles provide a potentially better drug delivery system and generate interest for further targeting studies and applications. Full article
(This article belongs to the Special Issue Engineering and Characterisation of Novel Nanomedicine Formulations)
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17 pages, 1790 KiB  
Review
From the Discovery of Targets to Delivery Systems: How to Decipher and Improve the Metallodrugs’ Actions at a Molecular Level
Pharmaceutics 2023, 15(7), 1997; https://doi.org/10.3390/pharmaceutics15071997 - 21 Jul 2023
Cited by 2 | Viewed by 998
Abstract
Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them [...] Read more.
Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them to adjust the properties of molecules differently from organic molecules. Therefore, interest in the study of metal–drug complexes from different aspects has been aroused, and numerous approaches have been developed to characterize, activate, deliver, and clarify molecular mechanisms. The integration of these different approaches, ranging from chemoproteomics to nanoparticle systems and various activation strategies, enables the understanding of the cellular responses to metal drugs, which may form the basis for the development of new drugs and/or the modification of currently used drugs. The purpose of this review is to briefly summarize the recent advances in this field by describing the technological platforms and their potential applications for identifying protein targets for discovering the mechanisms of action of metallodrugs and improving their efficiency during delivery. Full article
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19 pages, 5750 KiB  
Article
Factors That Influence Sustained Release from Hot-Melt Extrudates
Pharmaceutics 2023, 15(7), 1996; https://doi.org/10.3390/pharmaceutics15071996 - 20 Jul 2023
Viewed by 1424
Abstract
Hot-melt extrusion is a well-established tool in the pharmaceutical industry, mostly implemented to increase the solubility of poorly soluble drugs. A less frequent application of this technique is to obtain formulations with extended release. This study investigated the influence of polymer choice, drug [...] Read more.
Hot-melt extrusion is a well-established tool in the pharmaceutical industry, mostly implemented to increase the solubility of poorly soluble drugs. A less frequent application of this technique is to obtain formulations with extended release. This study investigated the influence of polymer choice, drug loading, milling and hydrodynamics on the release of a model drug, flurbiprofen, from sustained-release hot-melt extrudates with Eudragit polymers. The choice of polymer and degree of particle size reduction of the extrudate by milling were the two key influences on the release profile: the percentage release after 12 h varied from 6% (2 mm threads) to 84% (particle size <125 µm) for Eudragit RL extrudates vs. 4.5 to 62% for the corresponding Eudragit RS extrudates. By contrast, the release profile was largely independent of drug loading and robust to hydrodynamics in the dissolution vessel. Thus, hot-melt extrusion offers the ability to tailor the release of the API to the therapeutic indication through a combination of particle size and polymer choice while providing robustness over a wide range of hydrodynamic conditions. Full article
(This article belongs to the Special Issue Solid Dispersions for Bioavailability Enhancement)
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20 pages, 1926 KiB  
Review
SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation
Pharmaceutics 2023, 15(7), 1995; https://doi.org/10.3390/pharmaceutics15071995 - 20 Jul 2023
Cited by 5 | Viewed by 3946
Abstract
Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium–glucose [...] Read more.
Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium–glucose cotransporter-2 (SGLT2) inhibitors, a novel yet already widely used therapy, may prevent the development of DKD and alter its natural progression. SGLT2 inhibitors induce systemic and glomerular hemodynamic changes, provide metabolic advantages, and reduce inflammatory and oxidative stress pathways. In T2DM patients, regardless of cardiovascular diseases, SGLT2 inhibitors may reduce albuminuria, progression of DKD, and doubling of serum creatinine levels, thus lowering the need for kidney replacement therapy by over 40%. The molecular mechanisms behind these beneficial effects of SGLT2 inhibitors extend beyond their glucose-lowering effects. The emerging studies are trying to explain these mechanisms at the genetic, epigenetic, transcriptomic, and proteomic levels. Full article
(This article belongs to the Special Issue Effective Therapies for Diabetes)
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13 pages, 2659 KiB  
Article
Natural Antimicrobials Block the Host NF-κB Pathway and Reduce Enterocytozoon hepatopenaei Infection Both In Vitro and In Vivo
Pharmaceutics 2023, 15(7), 1994; https://doi.org/10.3390/pharmaceutics15071994 - 20 Jul 2023
Viewed by 890
Abstract
The objective of this work was to investigate, for the first time, the antioxidant effect of a mixture of natural antimicrobials in an Enterocytozoon hepatopenaei (EHP) shrimp-gut model of infection and the biological mechanisms involved in their way of action. The study approach [...] Read more.
The objective of this work was to investigate, for the first time, the antioxidant effect of a mixture of natural antimicrobials in an Enterocytozoon hepatopenaei (EHP) shrimp-gut model of infection and the biological mechanisms involved in their way of action. The study approach included investigations, firstly, in vitro, on shrimp-gut primary (SGP) epithelial cells and in vivo by using EHP-challenged shrimp. Our results show that exposure of EHP spores to 0.1%, 0.5%, 1%, and 2% AuraAqua (Aq) significantly reduced spore activity at all concentrations but was more pronounced after exposure to 0.5% Aq. The Aq was able to reduce EHP infection of SGP cells regardless of cells being pretreated or cocultured during infection with Aq. The survivability of SGP cells infected with EHP spores was significantly increased in both scenarios; however, a more noticeable effect was observed when the infected cells were pre-exposed to Aq. Our data show that infection of SGP cells by EHP activates the host NADPH oxidases and the release of H2O2 produced. When Aq was used during infection, a significant reduction in H2O2 was observed concomitant with a significant increase in the levels of CAT and SOD enzymes. Moreover, in the presence of 0.5% Aq, the overproduction of CAT and SOD was correlated with the inactivation of the NF-κB pathway, which, otherwise, as we show, is activated upon EHP infection of SGP cells. In a challenge test, Aq was able to significantly reduce mortality in EHP-infected shrimp and increase the levels of CAT and SOD in the gut tissue. Conclusively, these results show, for the first time, that a mixture of natural antimicrobials (Aq) can reduce the EHP-spore activity, improve the survival rates of primary gut-shrimp epithelial cells and reduce the oxidative damage caused by EHP infection. Moreover, we show that Aq was able to stop the H2O2 activation of the NF-κB pathway of Crustins, Penaeidins, and the lysozyme, and the CAT and SOD activity both in vitro and in a shrimp challenge test. Full article
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14 pages, 4263 KiB  
Article
Intraoral Drug Delivery: Highly Thiolated κ-Carrageenan as Mucoadhesive Excipient
Pharmaceutics 2023, 15(7), 1993; https://doi.org/10.3390/pharmaceutics15071993 - 20 Jul 2023
Cited by 2 | Viewed by 1343
Abstract
Aim: This study aims to design a novel thiolated κ-carrageenan (κ-CA-SH) and evaluate its potential as an excipient for the design of mucoadhesive drug delivery systems. Methods: Native κ-carrageenan (κ-CA) was thiolated with phosphorous pentasulfide in sulfolane and characterized via 1H NMR, [...] Read more.
Aim: This study aims to design a novel thiolated κ-carrageenan (κ-CA-SH) and evaluate its potential as an excipient for the design of mucoadhesive drug delivery systems. Methods: Native κ-carrageenan (κ-CA) was thiolated with phosphorous pentasulfide in sulfolane and characterized via 1H NMR, FTIR, as well as Ellman’s test. Cytotoxicity was assessed via resazurin assay. In vitro release of the model drug, benzydamine hydrochloride, was determined. Tensile and mucosal residence time studies were performed on buccal and small intestinal mucosa. Mucoadhesive features were investigated via rheological studies with freshly isolated porcine mucus. Results: Thiolated κ-CA (κ-CA-SH) with 1213.88 ± 52 µmol/g thiol groups showed no cytotoxicity at a concentration of 1% (m/v) and low cytotoxicity up to 2% (m/v). Benzydamine hydrochloride showed slow release in solution for both polymers. Tensile studies on buccal and intestinal mucosa showed an up to 2.7-fold and 7.7-fold enhancement in the maximum detachment force (MDF) and total work of adhesion (TWA) of κ-CA-SH vs. κ-CA, respectively. The κ-CA-SH exhibited an up to 4.4-fold improved dynamic viscosity with mucus and significantly prolonged residence time on mucosa compared to native κ-CA. Conclusion: Since highly thiolated κ-CA shows a slow release of positively charged active pharmaceutical ingredients and enhanced mucoadhesive properties, it might be a promising excipient for local drug delivery in the oral cavity. Full article
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19 pages, 1019 KiB  
Review
Colour of Medicines and Children’s Acceptability? A Systematic Literature Review of Children’s Perceptions about Colours of Oral Dosage Forms
Pharmaceutics 2023, 15(7), 1992; https://doi.org/10.3390/pharmaceutics15071992 - 20 Jul 2023
Cited by 2 | Viewed by 1483
Abstract
The colour of a product plays an important role in consumer experiences, and in the context of pharmaceutical products, this could potentially affect a patient’s expectations, behaviours, and adherence. Several studies have been conducted on adults, but little is known about children’s opinions [...] Read more.
The colour of a product plays an important role in consumer experiences, and in the context of pharmaceutical products, this could potentially affect a patient’s expectations, behaviours, and adherence. Several studies have been conducted on adults, but little is known about children’s opinions on colours of medicines and to what extent medicines’ colour affects their acceptability. To address this gap, a systematic search in PubMed, Scopus, MEDLINE, and Web of Science was conducted. Two authors independently screened the titles, abstracts, and references of all articles and selected studies conducted on children (0–18 years old), assessing children’s preferences or opinions about colour of oral dosage forms as either a primary or secondary objective or as an anecdotal record. A total of 989 publications were identified and, after screening, 18 publications were included in the review. Red and pink were the most liked colours and there appeared to be a relationship between the colour of a medicine and expected taste/flavour. The review also highlighted a scarcity of information, usually collected as an anecdotal record. Several gaps in the current knowledge were underlined, emphasizing the need of patient-centred studies to understand if the use of certain colours can improve or worsen the acceptability of a paediatric medicine. This will help inform pharmaceutical manufacturers and regulators on the role and need of colours in children’s medicines beyond quality purposes. Full article
(This article belongs to the Special Issue Advance in Development of Patient-Centric Dosage Form, 2nd Edition)
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26 pages, 13094 KiB  
Article
Synthesis and Anticancer Activity of Novel Dual Inhibitors of Human Protein Kinases CK2 and PIM-1
Pharmaceutics 2023, 15(7), 1991; https://doi.org/10.3390/pharmaceutics15071991 - 20 Jul 2023
Cited by 1 | Viewed by 1318
Abstract
CK2 and PIM-1 are serine/threonine kinases involved in the regulation of many essential processes, such as proliferation, differentiation, and apoptosis. Inhibition of CK2 and PIM-1 kinase activity has been shown to significantly reduce the viability of cancer cells by inducing apoptosis. A series [...] Read more.
CK2 and PIM-1 are serine/threonine kinases involved in the regulation of many essential processes, such as proliferation, differentiation, and apoptosis. Inhibition of CK2 and PIM-1 kinase activity has been shown to significantly reduce the viability of cancer cells by inducing apoptosis. A series of novel amino alcohol derivatives of parental DMAT were designed and synthesized as potent dual CK2/PIM-1 inhibitors. Concomitantly with the inhibition studies toward recombinant CK2 and PIM-1, the influence of the obtained compounds on the viability of three human carcinoma cell lines, i.e., acute lymphoblastic leukemia (CCRF-CEM), human chronic myelogenous leukemia (K-562), and breast cancer (MCF-7), as well as non-cancerous cells (Vero), was evaluated using an MTT assay. Induction of apoptosis and cell cycle progression after treatment with the most active compound and a lead compound were studied by flow-cytometry-based assay. Additionally, autophagy induction in K-562 cells and intracellular inhibition of CK2 and PIM-1 in all the tested cell lines were evaluated by qualitative/quantitative fluorescence-based assay and Western blot method, respectively. Among the newly developed inhibitors, 1,1,1-trifluoro-3-[(4,5,6,7-tetrabromo-1H-benzimidazol-2-yl)amino]propan-2-ol demonstrates the highest selectivity and the most prominent proapoptotic properties towards the studied cancer cells, especially towards acute lymphoblastic leukemia, in addition to inducing autophagy in K-562 cells. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)
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19 pages, 9411 KiB  
Article
Nanofibrous Polycaprolactone Membrane with Bioactive Glass and Atorvastatin for Wound Healing: Preparation and Characterization
Pharmaceutics 2023, 15(7), 1990; https://doi.org/10.3390/pharmaceutics15071990 - 20 Jul 2023
Viewed by 1158
Abstract
Skin wound healing is one of the most challenging processes for skin reconstruction, especially after severe injuries. In our study, nanofiber membranes were prepared for wound healing using an electrospinning process, where the prepared nanofibers were made of different weight ratios of polycaprolactone [...] Read more.
Skin wound healing is one of the most challenging processes for skin reconstruction, especially after severe injuries. In our study, nanofiber membranes were prepared for wound healing using an electrospinning process, where the prepared nanofibers were made of different weight ratios of polycaprolactone and bioactive glass that can induce the growth of new tissue. The membranes showed smooth and uniform nanofibers with an average diameter of 118 nm. FTIR and XRD results indicated no chemical interactions of polycaprolactone and bioactive glass and an increase in polycaprolactone crystallinity by the incorporation of bioactive glass nanoparticles. Nanofibers containing 5% w/w of bioactive glass were selected to be loaded with atorvastatin, considering their best mechanical properties compared to the other prepared nanofibers (3, 10, and 20% w/w bioactive glass). Atorvastatin can speed up the tissue healing process, and it was loaded into the selected nanofibers using a dip-coating technique with ethyl cellulose as a coating polymer. The study of the in vitro drug release found that atorvastatin-loaded nanofibers with a 10% coating polymer revealed gradual drug release compared to the non-coated nanofibers and nanofibers coated with 5% ethyl cellulose. Integration of atorvastatin and bioactive glass with polycaprolactone nanofibers showed superior wound closure results in the human skin fibroblast cell line. The results from this study highlight the ability of polycaprolactone-bioactive glass-based fibers loaded with atorvastatin to stimulate skin wound healing. Full article
(This article belongs to the Special Issue Nanofibrous Scaffolds Application in Biomedicine)
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39 pages, 5389 KiB  
Review
Nano- and Microemulsions in Biomedicine: From Theory to Practice
Pharmaceutics 2023, 15(7), 1989; https://doi.org/10.3390/pharmaceutics15071989 - 20 Jul 2023
Cited by 4 | Viewed by 1964
Abstract
Nano- and microemulsions are colloidal systems that are widely used in various fields of biomedicine, including wound and burn healing, cosmetology, the development of antibacterial and antiviral drugs, oncology, etc. The stability of these systems is governed by the balance of molecular interactions [...] Read more.
Nano- and microemulsions are colloidal systems that are widely used in various fields of biomedicine, including wound and burn healing, cosmetology, the development of antibacterial and antiviral drugs, oncology, etc. The stability of these systems is governed by the balance of molecular interactions between nanodomains. Microemulsions as a colloidal form play a special important role in stability. The microemulsion is the thermodynamically stable phase from oil, water, surfactant and co-surfactant which forms the surface of drops with very small surface energy. The last phenomena determines the shortage time of all fluid dispersions including nanoemulsions and emulgels. This review examines the theory and main methods of obtaining nano- and microemulsions, particularly focusing on the structure of microemulsions and methods for emulsion analysis. Additionally, we have analyzed the main preclinical and clinical studies in the field of wound healing and the use of emulsions in cancer therapy, emphasizing the prospects for further developments in this area. Full article
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15 pages, 4248 KiB  
Article
Improving Overall Survival and Quality of Life in Patients with Prostate Cancer and Neuroendocrine Tumors Using 177Lu-iPSMA and 177Lu-DOTATOC: Experience after 905 Treatment Doses
Pharmaceutics 2023, 15(7), 1988; https://doi.org/10.3390/pharmaceutics15071988 - 20 Jul 2023
Cited by 1 | Viewed by 1484
Abstract
177Lu-iPSMA is a novel radioligand developed at ININ-Mexico with a high affinity for the PSMA protein heavily expressed in cancer cells of approximately 95% of patients with metastatic castration-resistant prostate cancer (mCRPC). 177Lu-DOTATOC is a patent-free radioligand, molecularly recognized by somatostatin [...] Read more.
177Lu-iPSMA is a novel radioligand developed at ININ-Mexico with a high affinity for the PSMA protein heavily expressed in cancer cells of approximately 95% of patients with metastatic castration-resistant prostate cancer (mCRPC). 177Lu-DOTATOC is a patent-free radioligand, molecularly recognized by somatostatin receptors (SSTR-2) overexpressed in cancer cells of about 80% of patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET). This translational research aimed to determine the efficacy and safety of 177Lu-iPSMA and 177Lu-DOTATOC developed as GMP pharmaceutical formulations for treating progressive and advanced mCRPC and NET. One hundred and forty-five patients with mCRPC and one hundred and eighty-seven subjects with progressive NET (83% GEP-NET and 17% other NET), treated with 177Lu-iPSMA and 177Lu-DOTATOC, respectively, were evaluated. Patients received a mean dose of 7.4 GBq per administration of 177Lu-iPSMA (range 1–5 administrations; 394 treatment doses) or 177Lu-DOTATOC (range 2–8 administrations; 511 treatment doses) at intervals of 1.5–2.5 months. Efficacy was assessed by SPECT/CT or PET/CT. Results were stratified by primary tumor origin and number of doses administered. Patients with mCRPC showed overall survival (OS) of 21.7 months with decreased radiotracer tumor uptake (SUV) and PSA level in 80% and 73% of patients, respectively. In addition, a significant reduction in pain (numerical scale from 10–7 to 3–1) was observed in 88% of patients with bone metastases between one and two weeks after the second injection. In the GEP-NET population, the median progression-free survival was 34.7 months, with an OS of >44.2 months. The treatments were well tolerated. Only ten patients experienced grade ≥ 3 myelosuppression (3% of all patients). The observed safety profiles and favorable therapeutic responses demonstrated the potential of 177Lu-iPSMA and 177Lu-DOTATOC to improve overall survival and quality of life in patients with progressive and advanced mCRPC and NET. Full article
(This article belongs to the Special Issue Novel Anticancer Strategies (Volume III))
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24 pages, 5651 KiB  
Article
In Vitro and In Vivo Evaluation of Composite Oral Fast Disintegrating Film: An Innovative Strategy for the Codelivery of Ranitidine HCl and Flurbiprofen
Pharmaceutics 2023, 15(7), 1987; https://doi.org/10.3390/pharmaceutics15071987 - 20 Jul 2023
Cited by 1 | Viewed by 1410
Abstract
Here, we evaluate the feasibility of co-loading plain ranitidine hydrochloride (RHCl) and microencapsulated flurbiprofen (FBP) in a Lycoat® RS780-based oral fast disintegrating film (ODF). These films were developed by the solvent casting method to minimize the adverse effects of FBP and reduce [...] Read more.
Here, we evaluate the feasibility of co-loading plain ranitidine hydrochloride (RHCl) and microencapsulated flurbiprofen (FBP) in a Lycoat® RS780-based oral fast disintegrating film (ODF). These films were developed by the solvent casting method to minimize the adverse effects of FBP and reduce the dosage form burden on patients. Optimized FBP microparticles (M3) with an average size of 21.2 ± 9.2 µm were loaded alone (F1) and in combination with plain RHCl (F2) in the composite ODF. All films were evaluated physicomechanically and physicochemically. These films were resilient, flexible, and disintegrated within thirty seconds. SEM images showed intact FBP microparticles in both formulations and, moreover, did not observe an interaction between the drug and film components. Microencapsulated FBP was released in a controlled manner over 48 h from the proposed formulations, while RHCl was released within 5 min from F2. After in vitro evaluation, formulations were also tested for in vivo anti-inflammatory activity, cytokine (TNF-α and IL-6) levels, and gastroprotective effects in rats. The anti-inflammatory activity and gastroprotective effect of F2 were markedly higher than pure FBP and other synthesized formulations (M3 and F1). The average score of gastric lesions was in the order of pure FBP (15.5 ± 1.32) > M3 (8 ± 2) > F1 (1 ± 0.5) > F2 (0.5 ± 0) > control (0). Additionally, F2 showed a sustained anti-inflammatory effect up to 10 h in the rat paw edema model. Furthermore, F2 also markedly reduced TNF-α and IL-6 levels. Conclusively, the Lycoat® RS780-based composite film could be a promising carrier for the co-loading of microencapsulated FBP with RHCl. In the future, an optimized formulation (F2) could be capable of countering the issues related to multiple drug administration in geriatric patients and evading the gastric irritation associated with FBP. Full article
(This article belongs to the Special Issue Development of Orally Dispersible Dosage Forms)
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12 pages, 3226 KiB  
Article
Inherently Fluorescent Peanut-Shaped Polymersomes for Active Cargo Transportation
Pharmaceutics 2023, 15(7), 1986; https://doi.org/10.3390/pharmaceutics15071986 - 20 Jul 2023
Cited by 1 | Viewed by 1131
Abstract
Nanomotors have been extensively explored for various applications in nanomedicine, especially in cargo transportation. Motile properties enable them to deliver pharmaceutical ingredients more efficiently to the targeted site. However, it still remains a challenge to design motor systems that are therapeutically active and [...] Read more.
Nanomotors have been extensively explored for various applications in nanomedicine, especially in cargo transportation. Motile properties enable them to deliver pharmaceutical ingredients more efficiently to the targeted site. However, it still remains a challenge to design motor systems that are therapeutically active and can also be effectively traced when taken up by cells. Here, we designed a nanomotor with integrated fluorescence and therapeutic potential based on biodegradable polymersomes equipped with aggregation-induced emission (AIE) agents. The AIE segments provided the polymersomes with autofluorescence, facilitating the visualization of cell uptake. Furthermore, the membrane structure enabled the reshaping of the AIE polymersomes into asymmetric, peanut-shaped polymersomes. Upon laser irradiation, these peanut polymersomes not only displayed fluorescence, but also produced reactive oxygen species (ROS). Because of their specific shape, the ROS gradient induced motility in these particles. As ROS is also used for cancer cell treatment, the peanut polymersomes not only acted as delivery vehicles but also as therapeutic agents. As an integrated platform, these peanut polymersomes therefore represent an interesting delivery system with biomedical potential. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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27 pages, 4052 KiB  
Article
Development of Atomoxetine-Loaded NLC In Situ Gel for Nose-to-Brain Delivery: Optimization, In Vitro, and Preclinical Evaluation
Pharmaceutics 2023, 15(7), 1985; https://doi.org/10.3390/pharmaceutics15071985 - 20 Jul 2023
Cited by 6 | Viewed by 1580
Abstract
The present study investigates the brain-targeted efficiency of atomoxetine (AXT)-loaded nanostructured lipid carrier (NLC)-laden thermosensitive in situ gel after intranasal administration. AXT-NLC was prepared by the melt emulsification ultrasonication method and optimized using the Box–Behnken design (BBD). The optimized formulation (AXT-NLC) exhibited particle [...] Read more.
The present study investigates the brain-targeted efficiency of atomoxetine (AXT)-loaded nanostructured lipid carrier (NLC)-laden thermosensitive in situ gel after intranasal administration. AXT-NLC was prepared by the melt emulsification ultrasonication method and optimized using the Box–Behnken design (BBD). The optimized formulation (AXT-NLC) exhibited particle size PDI, zeta potential, and entrapment efficiency (EE) of 108 nm, 0.271, −42.3 mV, and 84.12%, respectively. The morphology of AXT-NLC was found to be spherical, as confirmed by SEM analysis. DSC results displayed that the AXT was encapsulated within the NLC matrix. Further, optimized NLC (AXT-NLC13) was incorporated into a thermosensitive in situ gel using poloxamer 407 and carbopol gelling agent and evaluated for different parameters. The optimized in situ gel (AXT-NLC13G4) formulation showed excellent viscosity (2532 ± 18 Cps) at 37 °C and formed the gel at 28–34 °C. AXT-NLC13-G4 showed a sustained release of AXT (92.89 ± 3.98% in 12 h) compared to pure AXT (95.47 ± 2.76% in 4 h). The permeation flux through goat nasal mucosa of AXT from pure AXT and AXT-NLC13-G4 was 504.37 µg/cm2·h and 232.41 µg/cm2·h, respectively. AXT-NLC13-G4 intranasally displayed significantly higher absolute bioavailability of AXT (1.59-fold higher) than intravenous administration. AXT-NLC13-G4 intranasally showed 51.91% higher BTP than pure AXT (28.64%) when administered via the same route (intranasally). AXT-NLC13-G4 showed significantly higher BTE (207.92%) than pure AXT (140.14%) when administered intranasally, confirming that a high amount of the AXT reached the brain. With the disrupted performance induced by L-methionine, the AXT-NLC13-G4 showed significantly (p < 0.05) better activity than pure AXT as well as donepezil (standard). The finding concluded that NLC in situ gel is a novel carrier of AXT for improvement of brain delivery by the intranasal route and requires further investigation for more justification. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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