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Pharmaceutics, Volume 15, Issue 11 (November 2023) – 128 articles

Cover Story (view full-size image): The lymphatic system is essential for the uptake of lipophilic drugs, particularly their transport via the chylomicrons, lipoproteins formed within the intestinal cells. In this study, an in vitro model that mimics drug movement from the intestinal lumen into the intestinal cells and their interaction with chylomicrons was developed. Through this model, we were able to predict the lymphatic drug absorption of a number of model drugs. It also evaluated agents that can enhance or inhibit this process, replicating what happens in the body. This innovative in vitro model serves as a promising physiologically inspired biopharmaceutical tool for assessing drug delivery through intestinal lymphatics via chylomicrons, advancing our understanding of this delivery route. View this paper
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18 pages, 1557 KiB  
Article
Quantitative Analysis of a Pilot Transwell Barrier Model with Automated Sampling and Mathematical Modeling
Pharmaceutics 2023, 15(11), 2646; https://doi.org/10.3390/pharmaceutics15112646 - 20 Nov 2023
Viewed by 702
Abstract
In the preclinical phase of drug development, it is necessary to determine how the active compound can pass through the biological barriers surrounding the target tissue. In vitro barrier models provide a reliable, low-cost, high-throughput solution for screening substances early in the drug [...] Read more.
In the preclinical phase of drug development, it is necessary to determine how the active compound can pass through the biological barriers surrounding the target tissue. In vitro barrier models provide a reliable, low-cost, high-throughput solution for screening substances early in the drug candidate development process, thus reducing more complex and costly animal studies. In this pilot study, the transport properties of TB501, an antimycobacterial drug candidate, were characterized using an in vitro barrier model of VERO E6 kidney cells. The compound was delivered into the apical chamber of the transwell insert, and its concentration passing through the barrier layer was measured through the automated sampling of the basolateral compartment, where media were replaced every 30 min for 6 h, and the collected samples were stored for further spectroscopic analysis. The kinetics of TB501 concentration obtained from VERO E6 transwell cultures and transwell membranes saturated with serum proteins reveal the extent to which the cell layer functions as a diffusion barrier. The large number of samples collected allows us to fit a detailed mathematical model of the passive diffusive currents to the measured concentration profiles. This approach enables the determination of the diffusive permeability, the diffusivity of the compound in the cell layer, the affinity of the compound binding to the cell membrane as well as the rate by which the cells metabolize the compound. The proposed approach goes beyond the determination of the permeability coefficient and offers a more detailed pharmacokinetic characterization of the transwell barrier model. We expect the presented method to be fruitful in evaluating other compounds with different chemical features on simple in vitro barrier models. The proposed mathematical model can also be extended to include various forms of active transport. Full article
(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)
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15 pages, 3183 KiB  
Article
Influence of Dose, Particle Size and Concentration on Dermal Penetration Efficacy of Curcumin
Pharmaceutics 2023, 15(11), 2645; https://doi.org/10.3390/pharmaceutics15112645 - 20 Nov 2023
Viewed by 663
Abstract
The influence of size, particle concentration and applied dose (finite vs. infinite dose) on the dermal penetration efficacy of curcumin was investigated in this study. For this, curcumin suspensions with different particle sizes (approx. 20 µm and approx. 250 nm) were produced in [...] Read more.
The influence of size, particle concentration and applied dose (finite vs. infinite dose) on the dermal penetration efficacy of curcumin was investigated in this study. For this, curcumin suspensions with different particle sizes (approx. 20 µm and approx. 250 nm) were produced in different concentrations (0.625–5% (w/w)). The dermal penetration efficacy was determined semi-quantitatively on the ex vivo porcine ear model. The results demonstrated that the presence of particles increases the dermal penetration efficacy of the active compounds being dissolved in the water phase of the formulation. The reason for this is the formation of an aqueous meniscus that develops between particles and skin due to the partial evaporation of water from the vehicle after topical application. The aqueous meniscus contains dissolved active ingredients, and therefore creates a small local spot with a locally high concentration gradient that leads to improved dermal penetration. The increase in penetration efficacy depends on the number of particles in the vehicle, i.e., higher numbers of particles and longer contact times lead to higher penetration efficacy. Therefore, nanocrystals with a high particle concentration were found to be the most suitable formulation principle for efficient and deep dermal penetration of poorly water-soluble active ingredients. Full article
(This article belongs to the Special Issue Nanoparticles and Microparticles in Drug Delivery)
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20 pages, 7246 KiB  
Article
In Vitro/In Vivo Preparation and Evaluation of cRGDyK Peptide-Modified Polydopamine-Bridged Paclitaxel-Loaded Nanoparticles
Pharmaceutics 2023, 15(11), 2644; https://doi.org/10.3390/pharmaceutics15112644 - 20 Nov 2023
Viewed by 839
Abstract
Cancer remains a disease with one of the highest mortality rates worldwide. The poor water solubility and tissue selectivity of commonly used chemotherapeutic agents contribute to their poor efficacy and serious adverse effects. This study proposes an alternative to the traditional physicochemically combined [...] Read more.
Cancer remains a disease with one of the highest mortality rates worldwide. The poor water solubility and tissue selectivity of commonly used chemotherapeutic agents contribute to their poor efficacy and serious adverse effects. This study proposes an alternative to the traditional physicochemically combined modifications used to develop targeted drug delivery systems, involving a simpler surface modification strategy. cRGDyK peptide (RGD)-modified PLGA nanoparticles (NPs) loaded with paclitaxel were constructed by coating the NP surfaces with polydopamine (PD). The average particle size of the produced NPs was 137.6 ± 2.9 nm, with an encapsulation rate of over 80%. In vitro release tests showed that the NPs had pH-responsive drug release properties. Cellular uptake experiments showed that the uptake of modified NPs by tumor cells was significantly better than that of unmodified NPs. A tumor cytotoxicity assay demonstrated that the modified NPs had a lower IC50 and greater cytotoxicity than those of unmodified NPs and commercially available paclitaxel formulations. An in vitro cytotoxicity study indicated good biosafety. A tumor model in female BALB/c rats was established using murine-derived breast cancer 4T1 cells. RGD-modified NPs had the highest tumor-weight suppression rate, which was higher than that of the commercially available formulation. PTX-PD-RGD-NPs can overcome the limitations of antitumor drugs, reduce drug toxicity, and increase efficacy, showing promising potential in cancer therapy. Full article
(This article belongs to the Special Issue Nanosystems and Antibody/Peptide Modified Drugs for Cancer Treatment)
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31 pages, 5090 KiB  
Article
Transferrin-Bearing, Zein-Based Hybrid Lipid Nanoparticles for Drug and Gene Delivery to Prostate Cancer Cells
Pharmaceutics 2023, 15(11), 2643; https://doi.org/10.3390/pharmaceutics15112643 - 20 Nov 2023
Viewed by 903
Abstract
Gene therapy holds great promise for treating prostate cancer unresponsive to conventional therapies. However, the lack of delivery systems that can transport therapeutic DNA and drugs while targeting tumors without harming healthy tissues presents a significant challenge. This study aimed to explore the [...] Read more.
Gene therapy holds great promise for treating prostate cancer unresponsive to conventional therapies. However, the lack of delivery systems that can transport therapeutic DNA and drugs while targeting tumors without harming healthy tissues presents a significant challenge. This study aimed to explore the potential of novel hybrid lipid nanoparticles, composed of biocompatible zein and conjugated to the cancer-targeting ligand transferrin. These nanoparticles were designed to entrap the anti-cancer drug docetaxel and carry plasmid DNA, with the objective of improving the delivery of therapeutic payloads to prostate cancer cells, thereby enhancing their anti-proliferative efficacy and gene expression levels. These transferrin-bearing, zein-based hybrid lipid nanoparticles efficiently entrapped docetaxel, leading to increased uptake by PC-3 and LNCaP cancer cells and significantly enhancing anti-proliferative efficacy at docetaxel concentrations exceeding 1 µg/mL. Furthermore, they demonstrated proficient DNA condensation, exceeding 80% at polymer–DNA weight ratios of 1500:1 and 2000:1. This resulted in increased gene expression across all tested cell lines, with the highest transfection levels up to 11-fold higher than those observed with controls, in LNCaP cells. These novel transferrin-bearing, zein-based hybrid lipid nanoparticles therefore exhibit promising potential as drug and gene delivery systems for prostate cancer therapy. Full article
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16 pages, 3696 KiB  
Article
Analysis of the Physical Characteristics of an Anhydrous Vehicle for Compounded Pediatric Oral Liquids
Pharmaceutics 2023, 15(11), 2642; https://doi.org/10.3390/pharmaceutics15112642 - 20 Nov 2023
Viewed by 789
Abstract
The paucity of suitable drug formulations for pediatric patients generates a need for customized, compounded medications. This research study was set out to comprehensively analyze the physical properties of the new, proprietary anhydrous oral vehicle SuspendIt® Anhydrous, which was designed for compounding [...] Read more.
The paucity of suitable drug formulations for pediatric patients generates a need for customized, compounded medications. This research study was set out to comprehensively analyze the physical properties of the new, proprietary anhydrous oral vehicle SuspendIt® Anhydrous, which was designed for compounding pediatric oral liquids. A wide range of tests was used, including sedimentation volume, viscosity, droplet size after dispersion in simulated gastric fluid, microscopic examination and content uniformity measurements to evaluate the properties of the anhydrous vehicle. The results showed that the vehicle exhibited consistent physical properties under varying conditions and maintained stability over time. This can be attributed to the unique blend of excipients in its formulation, which not only maintain its viscosity but also confer thixotropic behavior. The unique combination of viscous, thixotropic and self-emulsifying properties allows for rapid redispersibility, sedimentation stability, accurate dosing, potential drug solubility, dispersion and promotion of enhanced gastrointestinal distribution and absorption. Furthermore, the vehicle demonstrated long-term sedimentation stability and content uniformity for a list of 13 anhydrous suspensions. These results suggest that the anhydrous oral vehicle could serve as a versatile base for pediatric formulation, potentially filling an important gap in pediatric drug delivery. Future studies can further investigate its compatibility, stability and performance with other drugs and in different clinical scenarios. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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85 pages, 8256 KiB  
Review
Polypeptide-Based Systems: From Synthesis to Application in Drug Delivery
Pharmaceutics 2023, 15(11), 2641; https://doi.org/10.3390/pharmaceutics15112641 - 20 Nov 2023
Cited by 2 | Viewed by 1179
Abstract
Synthetic polypeptides are biocompatible and biodegradable macromolecules whose composition and architecture can vary over a wide range. Their unique ability to form secondary structures, as well as different pathways of modification and biofunctionalization due to the diversity of amino acids, provide variation in [...] Read more.
Synthetic polypeptides are biocompatible and biodegradable macromolecules whose composition and architecture can vary over a wide range. Their unique ability to form secondary structures, as well as different pathways of modification and biofunctionalization due to the diversity of amino acids, provide variation in the physicochemical and biological properties of polypeptide-containing materials. In this review article, we summarize the advances in the synthesis of polypeptides and their copolymers and the application of these systems for drug delivery in the form of (nano)particles or hydrogels. The issues, such as the diversity of polypeptide-containing (nano)particle types, the methods for their preparation and drug loading, as well as the influence of physicochemical characteristics on stability, degradability, cellular uptake, cytotoxicity, hemolysis, and immunogenicity of polypeptide-containing nanoparticles and their drug formulations, are comprehensively discussed. Finally, recent advances in the development of certain drug nanoformulations for peptides, proteins, gene delivery, cancer therapy, and antimicrobial and anti-inflammatory systems are summarized. Full article
(This article belongs to the Special Issue Polymer-Based Delivery System)
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15 pages, 2357 KiB  
Article
Enhancing Pharmacokinetics and Pharmacodynamics of Rosuvastatin Calcium through the Development and Optimization of Fast-Dissolving Films
Pharmaceutics 2023, 15(11), 2640; https://doi.org/10.3390/pharmaceutics15112640 - 19 Nov 2023
Viewed by 928
Abstract
Rosuvastatin (RSV) is a widely used cholesterol-lowering medication, but its limited bioavailability due to its susceptibility to stomach pH and extensive first-pass metabolism poses a significant challenge. A fast-dissolving film (FDF) formulation of RSV was developed, characterized, and compared to the conventional marketed [...] Read more.
Rosuvastatin (RSV) is a widely used cholesterol-lowering medication, but its limited bioavailability due to its susceptibility to stomach pH and extensive first-pass metabolism poses a significant challenge. A fast-dissolving film (FDF) formulation of RSV was developed, characterized, and compared to the conventional marketed tablet to address this issue. The formulation process involved optimizing the thickness, disintegration time, and folding durability. All formulations were assessed for in vitro disintegration, thickness, folding endurance, in vitro dissolution, weight, and content uniformity. The study’s results revealed that the optimized RSV-FDF displayed a significantly faster time to maximum plasma concentration (tmax) of 2 h, compared to 4 h for the marketed tablet. The maximum plasma concentration (Cmax) for the RSV-FDF (1.540 µg/mL ± 0.044) was notably higher than that of the marketed tablet (0.940 µg/mL ± 0.017). Additionally, the pharmacodynamic assessment in male Wistar rats demonstrated that the optimized RSV-FDF exhibited an improved lipid profile, including reduced levels of low-density lipoproteins (LDLs), elevated high-density lipoproteins (HDLs), decreased triglycerides (TGs), and lower very-low-density lipoproteins (VLDLs) compared to the conventional tablet. These findings underscore the potential of RSV-FDFs as a promising alternative to enhance the bioavailability and therapeutic efficacy of rosuvastatin in treating dyslipidemia. The faster onset of action and improved lipid-lowering effects make RSV-FDFs an attractive option for patients requiring efficient cholesterol management. Full article
(This article belongs to the Special Issue Dosage Form Formulation Technologies for Improving Bioavailability)
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31 pages, 9165 KiB  
Review
Aerogels as Carriers for Oral Administration of Drugs: An Approach towards Colonic Delivery
Pharmaceutics 2023, 15(11), 2639; https://doi.org/10.3390/pharmaceutics15112639 - 17 Nov 2023
Viewed by 1029
Abstract
Polysaccharide aerogels have emerged as a highly promising technology in the field of oral drug delivery. These nanoporous, ultralight materials, derived from natural polysaccharides such as cellulose, starch, or chitin, have significant potential in colonic drug delivery due to their unique properties. The [...] Read more.
Polysaccharide aerogels have emerged as a highly promising technology in the field of oral drug delivery. These nanoporous, ultralight materials, derived from natural polysaccharides such as cellulose, starch, or chitin, have significant potential in colonic drug delivery due to their unique properties. The particular degradability of polysaccharide-based materials by the colonic microbiota makes them attractive to produce systems to load, protect, and release drugs in a controlled manner, with the capability to precisely target the colon. This would allow the local treatment of gastrointestinal pathologies such as colon cancer or inflammatory bowel diseases. Despite their great potential, these applications of polysaccharide aerogels have not been widely explored. This review aims to consolidate the available knowledge on the use of polysaccharides for oral drug delivery and their performance, the production methods for polysaccharide-based aerogels, the drug loading possibilities, and the capacity of these nanostructured systems to target colonic regions. Full article
(This article belongs to the Special Issue Supercritical Techniques for Pharmaceutical Applications)
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14 pages, 1795 KiB  
Article
N-Succinylaspartic-Acid-Conjugated Riluzole Is a Safe and Potent Colon-Targeted Prodrug of Riluzole against DNBS-Induced Rat Colitis
Pharmaceutics 2023, 15(11), 2638; https://doi.org/10.3390/pharmaceutics15112638 - 16 Nov 2023
Cited by 1 | Viewed by 697
Abstract
In our previous study, riluzole azo-linked to salicylic acid (RAS) was prepared as a colon-targeted prodrug of riluzole (RLZ) to facilitate the repositioning of RLZ as an anticolitic drug. RAS is more effective against rat colitis than RLZ and sulfasalazine, currently used as [...] Read more.
In our previous study, riluzole azo-linked to salicylic acid (RAS) was prepared as a colon-targeted prodrug of riluzole (RLZ) to facilitate the repositioning of RLZ as an anticolitic drug. RAS is more effective against rat colitis than RLZ and sulfasalazine, currently used as an anti-inflammatory bowel disease drug. The aim of this study is to further improve colon specificity, anticolitic potency, and safety of RAS. N-succinylaspart-1-ylRLZ (SAR) and N-succinylglutam-1-ylRLZ (SGR) were synthesized and evaluated as a “me-better” colon-targeted prodrug of RLZ against rat colitis. SAR but not SGR was converted to RLZ in the cecal contents, whereas both conjugates remained intact in the small intestine. When comparing the colon specificity of SAR with that of RAS, the distribution coefficient and cell permeability of SAR were lower than those of RAS. In parallel, oral SAR delivered a greater amount of RLZ to the cecum of rats than oral RAS. In a DNBS-induced rat model of colitis, oral SAR mitigated colonic damage and inflammation and was more potent than oral RAS. Moreover, upon oral administration, SAR had a greater ability to limit the systemic absorption of RLZ than RAS, indicating a reduced risk of systemic side effects of SAR. Taken together, SAR may be a “me-better” colon-targeted prodrug of RLZ to improve the safety and anticolitic potency of RAS, an azo-type colon-targeted prodrug of RLZ. Full article
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23 pages, 1191 KiB  
Review
Advanced Progress in the Role of Adipose-Derived Mesenchymal Stromal/Stem Cells in the Application of Central Nervous System Disorders
Pharmaceutics 2023, 15(11), 2637; https://doi.org/10.3390/pharmaceutics15112637 - 16 Nov 2023
Cited by 1 | Viewed by 779
Abstract
Currently, adipose-derived mesenchymal stromal/stem cells (ADMSCs) are recognized as a highly promising material for stem cell therapy due to their accessibility and safety. Given the frequently irreversible damage to neural cells associated with CNS disorders, ADMSC-related therapy, which primarily encompasses ADMSC transplantation and [...] Read more.
Currently, adipose-derived mesenchymal stromal/stem cells (ADMSCs) are recognized as a highly promising material for stem cell therapy due to their accessibility and safety. Given the frequently irreversible damage to neural cells associated with CNS disorders, ADMSC-related therapy, which primarily encompasses ADMSC transplantation and injection with exosomes derived from ADMSCs or secretome, has the capability to inhibit inflammatory response and neuronal apoptosis, promote neural regeneration, as well as modulate immune responses, holding potential as a comprehensive approach to treat CNS disorders and improve prognosis. Empirical evidence from both experiments and clinical trials convincingly demonstrates the satisfactory safety and efficacy of ADMSC-related therapies. This review provides a systematic summary of the role of ADMSCs in the treatment of central nervous system (CNS) disorders and explores their therapeutic potential for clinical application. ADMSC-related therapy offers a promising avenue to mitigate damage and enhance neurological function in central nervous system (CNS) disorders. However, further research is necessary to establish the safety and efficacy of clinical ADMSC-based therapy, optimize targeting accuracy, and refine delivery approaches for practical applications. Full article
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17 pages, 3489 KiB  
Article
Exploring Environmental Settings to Improve the Printability of Paroxetine-Loaded Filaments by Fused Deposition Modelling
Pharmaceutics 2023, 15(11), 2636; https://doi.org/10.3390/pharmaceutics15112636 - 16 Nov 2023
Cited by 1 | Viewed by 645
Abstract
The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions on the printability of formulations, since they significantly affect the properties of the raw materials, whose control is crucial to [...] Read more.
The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions on the printability of formulations, since they significantly affect the properties of the raw materials, whose control is crucial to enable three-dimensional printing (3DP). Hence, the objective of this work was to investigate the correlation between the environmental settings and the properties of paroxetine (PRX)-loaded filaments, previously produced by HME, which affect printability by FDM. The influence of different drying methods of the physical mixtures (PMs) and HME-filaments (FILs) on the quality and printability of these products was also assessed. The printability of FILs was evaluated in terms of the water content, and the mechanical and thermal properties of the products. Stability studies and physicochemical, thermal, and in vitro dissolution tests were carried out on the 3D-printed tablets. Stability studies demonstrated the high ductility of the PRX loaded FILs, especially under high humidity conditions. Under low humidity storage conditions (11% RH), the FILs became stiffer and were successfully used to feed the FDM printer. Water removal was slow when carried out passively in a controlled atmosphere (desiccator) or accelerated by using active drying methods (heat or microwave). Pre-drying of the PRX/excipients and/or PMs did not show any positive effect on the printability of the FIL. On the contrary, dry heat and, preferably, microwave mediated drying processes were shown to reduce the holding time required for successful FDM printing, enabling on-demand production at the point of care. Full article
(This article belongs to the Special Issue 3D Printing Technology for Pharmaceutical and Biomedical Application)
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42 pages, 3332 KiB  
Review
Anti-Obesity Drug Delivery Systems: Recent Progress and Challenges
Pharmaceutics 2023, 15(11), 2635; https://doi.org/10.3390/pharmaceutics15112635 - 16 Nov 2023
Viewed by 1034
Abstract
Obesity has reached an epidemic proportion in the last thirty years, and it is recognized as a major health issue in modern society now with the possibility of serious social and economic consequences. By the year 2030, nearly 60% of the global population [...] Read more.
Obesity has reached an epidemic proportion in the last thirty years, and it is recognized as a major health issue in modern society now with the possibility of serious social and economic consequences. By the year 2030, nearly 60% of the global population may be obese or overweight, which emphasizes a need for novel obesity treatments. Various traditional approaches, such as pharmacotherapy and bariatric surgery, have been utilized in clinical settings to treat obesity. However, these methods frequently show the possibility of side effects while remaining ineffective. There is, therefore, an urgent need for alternative obesity treatments with improved efficacy and specificity. Polymeric materials and chemical strategies are employed in emerging drug delivery systems (DDSs) to enhance therapy effectiveness and specificity by stabilizing and controlling the release of active molecules such as natural ingredients. Designing DDSs is currently a top priority research objective with an eye towards creating obesity treatment approaches. In reality, the most recent trends in the literature demonstrate that there are not enough in-depth reviews that emphasize the current knowledge based on the creation and design of DDSs for obesity treatment. It is also observed in the existing literature that a complex interplay of different physical and chemical parameters must be considered carefully to determine the effectiveness of the DDSs, including microneedles, for obesity treatment. Additionally, it is observed that these properties depend on how the DDS is synthesized. Although many studies are at the animal-study stage, the use of more advanced DDS techniques would significantly enhance the development of safe and efficient treatment approaches for obese people in the future. Considering these, this review provides an overview of the current anti-obesity treatment approaches as well as the conventional anti-obesity therapeutics. The article aims to conduct an in-depth discussion on the current trends in obesity treatment approaches. Filling in this knowledge gap will lead to a greater understanding of the safest ways to manage obesity. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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22 pages, 4043 KiB  
Review
Bioactive ZnO Nanoparticles: Biosynthesis, Characterization and Potential Antimicrobial Applications
Pharmaceutics 2023, 15(11), 2634; https://doi.org/10.3390/pharmaceutics15112634 - 16 Nov 2023
Cited by 1 | Viewed by 1466
Abstract
In recent years, biosynthesized zinc oxide nanoparticles (ZnONPs) have gained tremendous attention because of their safe and non-toxic nature and distinctive biomedical applications. A diverse range of microbes (bacteria, fungi and yeast) and various parts (leaf, root, fruit, flower, peel, stem, etc.) of [...] Read more.
In recent years, biosynthesized zinc oxide nanoparticles (ZnONPs) have gained tremendous attention because of their safe and non-toxic nature and distinctive biomedical applications. A diverse range of microbes (bacteria, fungi and yeast) and various parts (leaf, root, fruit, flower, peel, stem, etc.) of plants have been exploited for the facile, rapid, cost-effective and non-toxic synthesis of ZnONPs. Plant extracts, microbial biomass or culture supernatant contain various biomolecules including enzymes, amino acids, proteins, vitamins, alkaloids, flavonoids, etc., which serve as reducing, capping and stabilizing agents during the biosynthesis of ZnONPs. The biosynthesized ZnONPs are generally characterized using UV-VIS spectroscopy, TEM, SEM, EDX, XRD, FTIR, etc. Antibiotic resistance is a serious problem for global public health. Due to mutation, shifting environmental circumstances and excessive drug use, the number of multidrug-resistant pathogenic microbes is continuously rising. To solve this issue, novel, safe and effective antimicrobial agents are needed urgently. Biosynthesized ZnONPs could be novel and effective antimicrobial agents because of their safe and non-toxic nature and powerful antimicrobial characteristics. It is proven that biosynthesized ZnONPs have strong antimicrobial activity against various pathogenic microorganisms including multidrug-resistant bacteria. The possible antimicrobial mechanisms of ZnONPs are the generation of reactive oxygen species, physical interactions, disruption of the cell walls and cell membranes, damage to DNA, enzyme inactivation, protein denaturation, ribosomal destabilization and mitochondrial dysfunction. In this review, the biosynthesis of ZnONPs using microbes and plants and their characterization have been reviewed comprehensively. Also, the antimicrobial applications and mechanisms of biosynthesized ZnONPs against various pathogenic microorganisms have been highlighted. Full article
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19 pages, 4878 KiB  
Article
Carbohydrate Core–Shell Electrosprayed Microcapsules for Enhanced Oxidative Stability of Vitamin A Palmitate
Pharmaceutics 2023, 15(11), 2633; https://doi.org/10.3390/pharmaceutics15112633 - 16 Nov 2023
Cited by 1 | Viewed by 705
Abstract
Vitamin A is an essential micronutrient that is readily oxidized. In this study, the encapsulation of vitamin A palmitate (AP) within a core–shell carbohydrate matrix by co-axial electrospray and its oxidative stability was evaluated. The electrosprayed core–shell microcapsules consisted of a shell of [...] Read more.
Vitamin A is an essential micronutrient that is readily oxidized. In this study, the encapsulation of vitamin A palmitate (AP) within a core–shell carbohydrate matrix by co-axial electrospray and its oxidative stability was evaluated. The electrosprayed core–shell microcapsules consisted of a shell of octenyl succinic anhydride (OSA) modified corn starch, maltose (Hi-Cap), and a core of ethyl cellulose–AP (average diameter of about 3.7 µm). The effect of different compounds (digestion-resistant maltodextrin, soy protein hydrolysate, casein protein hydrolysate, and lecithin) added to the base core–shell matrix formulation on the oxidative stability of AP was investigated. The oxidative stability of AP was evaluated using isothermal and non-isothermal differential scanning calorimetry (DSC), and Raman and Attenuated Total Reflectance–Fourier Transform Infrared (ATR-FTIR) spectroscopy methods. The core–shell carbohydrate matrix minimizes the amount of AP present at the microparticle surface, thus protecting AP from oxidation. Furthermore, the most effective oxidation protection was achieved when casein protein hydrolysate was added to the core of the microcapsule due to hydrophobic and hydrogen bond interactions with AP and by the resistant maltodextrin in the shell, which acted as a filler. The utilization of ethanol as a solvent for the dispersion of the core compounds increased the hydrophobicity of the hydrolyzed proteins and contributed to the enhancement of their antioxidant ability. Both the carbohydrate core–shell microcapsule prepared by co-axial electrospray and the addition of oxidation protection compounds enhance the oxidative stability of the encapsulated AP. Full article
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14 pages, 1702 KiB  
Article
Efficient Delivery of Antimicrobial Peptides in an Innovative, Slow-Release Pharmacological Formulation
Pharmaceutics 2023, 15(11), 2632; https://doi.org/10.3390/pharmaceutics15112632 - 16 Nov 2023
Cited by 1 | Viewed by 821
Abstract
Both nanostructure and multivalency enhance the biological activities of antimicrobial peptides (AMPs), whose mechanism of action is cooperative. In addition, the efficacy of a particular AMP should benefit from a steady concentration at the local place of action and, therefore, from a slow [...] Read more.
Both nanostructure and multivalency enhance the biological activities of antimicrobial peptides (AMPs), whose mechanism of action is cooperative. In addition, the efficacy of a particular AMP should benefit from a steady concentration at the local place of action and, therefore, from a slow release after a dynamic repository. In the context of emerging multi-resistant bacterial infections and the urgent need for novel and effective antimicrobial drugs, we tested these concepts through the engineering of four AMPs into supramolecular complexes as pharmacological entities. For that purpose, GWH1, T22, Pt5, and PaD, produced as GFP or human nidogen-based His-tagged fusion proteins, were engineered as self-assembling oligomeric nanoparticles ranging from 10 to 70 nm and further packaged into nanoparticle-leaking submicron granules. Since these materials slowly release functional nanoparticles during their time-sustained unpacking, they are suitable for use as drug depots in vivo. In this context, a particular AMP version (GWH1-NIDO-H6) was selected for in vivo validation in a zebrafish model of a complex bacterial infection. The GWH1-NIDO-H6-secreting protein granules are protective in zebrafish against infection by the multi-resistant bacterium Stenotrophomonas maltophilia, proving the potential of innovative formulations based on nanostructured and slowly released recombinant AMPs in the fight against bacterial infections. Full article
(This article belongs to the Special Issue Long-Acting Drug Delivery Strategies for Precision Nanomedicine)
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19 pages, 3129 KiB  
Article
Nanoemulsion-Based Orodispersible Film Formulation of Guava Leaf Oil for Inhibition of Oral Cancer Cells
Pharmaceutics 2023, 15(11), 2631; https://doi.org/10.3390/pharmaceutics15112631 - 16 Nov 2023
Viewed by 750
Abstract
Among natural sources, guava leaf oil (GLO) has emerged as a potential anticancer agent. However, its limited water solubility poses a significant challenge for its use. Oil-in-water nanoemulsions are used to address the limitation of water solubility of GLO prior to its incorporation [...] Read more.
Among natural sources, guava leaf oil (GLO) has emerged as a potential anticancer agent. However, its limited water solubility poses a significant challenge for its use. Oil-in-water nanoemulsions are used to address the limitation of water solubility of GLO prior to its incorporation into orodipersible films. Nanoemulsions containing GLO:virgin coconut oil (VCO) at a ratio of 50:50 to 70:30 presented a small droplet size of approximately 50 nm and a relatively low zeta potential. GLO:VCO at a ratio of 70:30 was selected for incorporation into sodium alginate film at various concentrations ranging from 1% to 30% w/w. Tensile strength and elongation at break relied on the concentration of nanoemulsions as well as the internal structure of films. Fourier transform infrared spectroscopy revealed that GLO was compatible with sodium alginate. Film containing 2% w/w of nanoemulsions (2G_ODF) exhibited effective in vitro antioral cancer activity, with an IC50 of 62.49 ± 6.22 mg/mL; furthermore, its anticancer activity showed no significant difference after storage at 25 °C for 1 year. Moreover, 2G_ODF at IC60 arrested colony formation and cell invasion. There is also evidence that cell death occurred via apoptosis, as indicated by nuclear fragmentation and positive Annexin-V staining. These findings highlight the potential of orodispersible films containing GLO nanoemulsions as a prospective oral anticancer agent. Full article
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23 pages, 9762 KiB  
Article
Virtually Possible: Enhancing Quality Control of 3D-Printed Medicines with Machine Vision Trained on Photorealistic Images
Pharmaceutics 2023, 15(11), 2630; https://doi.org/10.3390/pharmaceutics15112630 - 16 Nov 2023
Viewed by 922
Abstract
Three-dimensional (3D) printing is an advanced pharmaceutical manufacturing technology, and concerted efforts are underway to establish its applicability to various industries. However, for any technology to achieve widespread adoption, robustness and reliability are critical factors. Machine vision (MV), a subset of artificial intelligence [...] Read more.
Three-dimensional (3D) printing is an advanced pharmaceutical manufacturing technology, and concerted efforts are underway to establish its applicability to various industries. However, for any technology to achieve widespread adoption, robustness and reliability are critical factors. Machine vision (MV), a subset of artificial intelligence (AI), has emerged as a powerful tool to replace human inspection with unprecedented speed and accuracy. Previous studies have demonstrated the potential of MV in pharmaceutical processes. However, training models using real images proves to be both costly and time consuming. In this study, we present an alternative approach, where synthetic images were used to train models to classify the quality of dosage forms. We generated 200 photorealistic virtual images that replicated 3D-printed dosage forms, where seven machine learning techniques (MLTs) were used to perform image classification. By exploring various MV pipelines, including image resizing and transformation, we achieved remarkable classification accuracies of 80.8%, 74.3%, and 75.5% for capsules, tablets, and films, respectively, for classifying stereolithography (SLA)-printed dosage forms. Additionally, we subjected the MLTs to rigorous stress tests, evaluating their scalability to classify over 3000 images and their ability to handle irrelevant images, where accuracies of 66.5% (capsules), 72.0% (tablets), and 70.9% (films) were obtained. Moreover, model confidence was also measured, and Brier scores ranged from 0.20 to 0.40. Our results demonstrate promising proof of concept that virtual images exhibit great potential for image classification of SLA-printed dosage forms. By using photorealistic virtual images, which are faster and cheaper to generate, we pave the way for accelerated, reliable, and sustainable AI model development to enhance the quality control of 3D-printed medicines. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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15 pages, 3027 KiB  
Article
Methods for Developing a Process Design Space Using Retrospective Data
Pharmaceutics 2023, 15(11), 2629; https://doi.org/10.3390/pharmaceutics15112629 - 16 Nov 2023
Viewed by 650
Abstract
Prospectively planned designs of experiments (DoEs) offer a valuable approach to preventing collinearity issues that can result in statistical confusion, leading to misinterpretation and reducing the predictability of statistical models. However, it is also possible to develop models using historical data, provided that [...] Read more.
Prospectively planned designs of experiments (DoEs) offer a valuable approach to preventing collinearity issues that can result in statistical confusion, leading to misinterpretation and reducing the predictability of statistical models. However, it is also possible to develop models using historical data, provided that certain guidelines are followed to enhance and ensure proper statistical modeling. This article presents a methodology for constructing a design space using process data, while avoiding the common pitfalls associated with retrospective data analysis. For this study, data from a real wet granulation process were collected to pragmatically illustrate all the concepts and methods developed in this article. Full article
(This article belongs to the Special Issue Understanding Pharmaceutical Quality by Design)
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13 pages, 10661 KiB  
Article
In Vitro Assessment of SWEEPS and Antimicrobial Photodynamic Therapy Alone or in Combination for Eradicating Enterococcus faecalis Biofilm in Root Canals
Pharmaceutics 2023, 15(11), 2628; https://doi.org/10.3390/pharmaceutics15112628 - 15 Nov 2023
Viewed by 658
Abstract
Objectives: This study investigates the efficacy of antimicrobial photodynamic therapy (aPDT) using riboflavin and a blue diode laser (BDL), combined with shock wave-enhanced emission photoacoustic streaming (SWEEPS), against Enterococcus faecalis. Materials and Methods: A total of 48 extracted single-rooted human teeth were [...] Read more.
Objectives: This study investigates the efficacy of antimicrobial photodynamic therapy (aPDT) using riboflavin and a blue diode laser (BDL), combined with shock wave-enhanced emission photoacoustic streaming (SWEEPS), against Enterococcus faecalis. Materials and Methods: A total of 48 extracted single-rooted human teeth were used. The root canals were instrumented, sealed at their apices, had the smear layer removed, and then underwent autoclave sterilization. Subsequently, each canal was inoculated with E. faecalis bacterial suspension and allowed to incubate for ten days. After confirming the presence of biofilms through scanning electron microscopy (SEM) in three teeth, the remaining teeth were randomly allocated into nine groups, each containing five teeth: control, 5.25% sodium hypochlorite (NaOCl), BDL, SWEEPS + normal saline, SWEEPS + NaOCl, riboflavin, riboflavin + SWEEPS, riboflavin + BDL, and riboflavin + BDL + SWEEPS. After the treatment, the numbers of colony-forming units (CFUs)/mL were calculated. The data were analysed using one-way ANOVA followed by Tukey’s test for comparisons. Results: All groups, with the exception of the BDL group, exhibited a significant reduction in E. faecalis CFU/mL when compared to the control group (p < 0.001). The difference in CFU/mL value between riboflavin + BDL + SWEEPS and riboflavin + SWEEPS was significant (p = 0.029), whereas there was no significant difference between riboflavin + BDL + SWEEPS and riboflavin + BDL (p = 0.397). Moreover, there was no statistically significant difference between the riboflavin + SWEEPS group and the riboflavin + BDL group (p = 0.893). Conclusions: The results demonstrated that combining the SWEEPS technique with riboflavin as a photosensitizer activated by BDL in aPDT effectively reduced the presence of E. faecalis in root canals. Full article
(This article belongs to the Special Issue Photodynamic Therapy: Recent Progress and Development)
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15 pages, 3737 KiB  
Article
Curcumin Disrupts a Positive Feedback Loop between ADMSCs and Cancer Cells in the Breast Tumor Microenvironment via the CXCL12/CXCR4 Axis
Pharmaceutics 2023, 15(11), 2627; https://doi.org/10.3390/pharmaceutics15112627 - 15 Nov 2023
Cited by 2 | Viewed by 954
Abstract
Adipose tissue has a significant impact on breast cancer initiation and progression owing to its substantial proportion in the breast. Adipose-derived mesenchymal stem cells (ADMSCs) are major players in the breast tumor microenvironment (TME) as they interact with cancer cells. The intricate interaction [...] Read more.
Adipose tissue has a significant impact on breast cancer initiation and progression owing to its substantial proportion in the breast. Adipose-derived mesenchymal stem cells (ADMSCs) are major players in the breast tumor microenvironment (TME) as they interact with cancer cells. The intricate interaction between ADMSCs and cancer cells not only drives the differentiation of ADMSCs into cancer-associated fibroblasts (CAFs) but also the metastasis of cancer cells, which is attributed to the CXCL12/CXCR4 axis. We investigated the effects of curcumin, a flavonoid known for CXCL12/CXCR4 axis inhibition, on breast TME by analyzing whether it can disrupt the ADMSC-cancer positive loop. Using MCF7 breast cancer cell-derived conditioned medium (MCF7-CM), we induced ADMSC transformation and verified that curcumin diminished the phenotypic change, inhibiting CAF marker expression. Additionally, curcumin suppressed the CXCL12/CXCR4 axis and its downstream signaling both in ADMSCs and MCF7 cells. The CM from ADMSCs, whose ADMSC-to-CAF transformation was repressed by the curcumin treatment, inhibited the positive feedback loop between ADMSCs and MCF7 as well as epithelial–mesenchymal transition in MCF7. Our study showed that curcumin is a potent anti-cancer agent that can remodel the breast TME, thereby restricting the ADMSC-cancer positive feedback loop associated with the CXCL12/CXCR4 axis. Full article
(This article belongs to the Section Biologics and Biosimilars)
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11 pages, 772 KiB  
Article
Synthesis and Preclinical Evaluation of Radiolabeled [103Ru]BOLD-100
Pharmaceutics 2023, 15(11), 2626; https://doi.org/10.3390/pharmaceutics15112626 - 15 Nov 2023
Viewed by 819
Abstract
The first-in-class ruthenium-based chemotherapeutic agent BOLD-100 (formerly IT-139, NKP-1339, KP1339) is currently the subject of clinical evaluation for the treatment of gastric, pancreatic, colorectal and bile duct cancer. A radiolabeled version of the compound could present a helpful diagnostic tool. Thus, this study [...] Read more.
The first-in-class ruthenium-based chemotherapeutic agent BOLD-100 (formerly IT-139, NKP-1339, KP1339) is currently the subject of clinical evaluation for the treatment of gastric, pancreatic, colorectal and bile duct cancer. A radiolabeled version of the compound could present a helpful diagnostic tool. Thus, this study investigated the pharmacokinetics of BOLD-100 in more detail to facilitate the stratification of patients for the therapy. The synthesis of [103Ru]BOLD-100, radiolabeled with carrier added (c.a.) ruthenium-103, was established and the product was characterized by HPLC and UV/Vis spectroscopy. In order to compare the radiolabeled and non-radioactive versions of BOLD-100, both complexes were fully evaluated in vitro and in vivo. The cytotoxicity of the compounds was determined in two colon carcinoma cell lines (HCT116 and CT26) and biodistribution studies were performed in Balb/c mice bearing CT26 allografts over a time period of 72 h post injection (p.i.). We report herein preclinical cytotoxicity and pharmacokinetic data for BOLD-100, which were found to be identical to those of its radiolabeled analog [103Ru]BOLD-100. Full article
(This article belongs to the Special Issue Application of Metal-Based Complexes in Cancer Treatment)
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12 pages, 3788 KiB  
Article
A Rapid Screening Platform for Simultaneous Evaluation of Biodegradation and Therapeutic Release of an Ocular Hydrogel
Pharmaceutics 2023, 15(11), 2625; https://doi.org/10.3390/pharmaceutics15112625 - 15 Nov 2023
Viewed by 1077
Abstract
This study attempts to address the challenge of accurately measuring the degradation of biodegradable hydrogels, which are frequently employed in drug delivery for controlled and sustained release. The traditional method utilizes a mass-loss approach, which is cumbersome and time consuming. The aim of [...] Read more.
This study attempts to address the challenge of accurately measuring the degradation of biodegradable hydrogels, which are frequently employed in drug delivery for controlled and sustained release. The traditional method utilizes a mass-loss approach, which is cumbersome and time consuming. The aim of this study was to develop an innovative screening platform using a millifluidic device coupled with automated image analysis to measure the degradation of Gelatin methacrylate (GelMA) and the subsequent release of an entrapped wetting agent, polyvinyl alcohol (PVA). Gel samples were placed within circular wells on a custom millifluidic chip and stained with a red dye for enhanced visualization. A camera module captured time-lapse images of the gels throughout their degradation. An image-analysis algorithm was used to translate the image data into degradation rates. Simultaneously, the eluate from the chip was collected to quantify the amount of GelMA degraded and PVA released at various time points. The visual method was validated by comparing it with the mass-loss approach (R = 0.91), as well as the amount of GelMA eluted (R = 0.97). The degradation of the GelMA gels was also facilitated with matrix metalloproteinases 9. Notably, as the gels degraded, there was an increase in the amount of PVA released. Overall, these results support the use of the screening platform to assess hydrogel degradation and the subsequent release of entrapped therapeutic compounds. Full article
(This article belongs to the Topic New Challenges in Ocular Drug Delivery)
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22 pages, 1251 KiB  
Review
A Literature Review of Changes in Phase II Drug-Metabolizing Enzyme and Drug Transporter Expression during Pregnancy
Pharmaceutics 2023, 15(11), 2624; https://doi.org/10.3390/pharmaceutics15112624 - 15 Nov 2023
Cited by 1 | Viewed by 1796
Abstract
The purpose of this literature review is to comprehensively summarize changes in the expression of phase II drug-metabolizing enzymes and drug transporters in both the pregnant woman and the placenta. Using PubMed®, a systematic search was conducted to identify literature relevant [...] Read more.
The purpose of this literature review is to comprehensively summarize changes in the expression of phase II drug-metabolizing enzymes and drug transporters in both the pregnant woman and the placenta. Using PubMed®, a systematic search was conducted to identify literature relevant to drug metabolism and transport in pregnancy. PubMed was searched with pre-specified terms during the period of 26 May 2023 to 10 July 2023. The final dataset of 142 manuscripts was evaluated for evidence regarding the effect of gestational age and hormonal regulation on the expression of phase II enzymes (n = 16) and drug transporters (n = 38) in the pregnant woman and in the placenta. This comprehensive review exposes gaps in current knowledge of phase II enzyme and drug transporter localization, expression, and regulation during pregnancy, which emphasizes the need for further research. Moreover, the information collected in this review regarding phase II drug-metabolizing enzyme and drug transporter changes will aid in optimizing pregnancy physiologically based pharmacokinetic (PBPK) models to inform dose selection in the pregnant population. Full article
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33 pages, 1908 KiB  
Review
Translational Challenges and Prospective Solutions in the Implementation of Biomimetic Delivery Systems
Pharmaceutics 2023, 15(11), 2623; https://doi.org/10.3390/pharmaceutics15112623 - 14 Nov 2023
Cited by 1 | Viewed by 830
Abstract
Biomimetic delivery systems (BDSs), inspired by the intricate designs of biological systems, have emerged as a groundbreaking paradigm in nanomedicine, offering unparalleled advantages in therapeutic delivery. These systems, encompassing platforms such as liposomes, protein-based nanoparticles, extracellular vesicles, and polysaccharides, are lauded for their [...] Read more.
Biomimetic delivery systems (BDSs), inspired by the intricate designs of biological systems, have emerged as a groundbreaking paradigm in nanomedicine, offering unparalleled advantages in therapeutic delivery. These systems, encompassing platforms such as liposomes, protein-based nanoparticles, extracellular vesicles, and polysaccharides, are lauded for their targeted delivery, minimized side effects, and enhanced therapeutic outcomes. However, the translation of BDSs from research settings to clinical applications is fraught with challenges, including reproducibility concerns, physiological stability, and rigorous efficacy and safety evaluations. Furthermore, the innovative nature of BDSs demands the reevaluation and evolution of existing regulatory and ethical frameworks. This review provides an overview of BDSs and delves into the multifaceted translational challenges and present emerging solutions, underscored by real-world case studies. Emphasizing the potential of BDSs to redefine healthcare, we advocate for sustained interdisciplinary collaboration and research. As our understanding of biological systems deepens, the future of BDSs in clinical translation appears promising, with a focus on personalized medicine and refined patient-specific delivery systems. Full article
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21 pages, 1867 KiB  
Review
Advances in Polymeric Micelles: Responsive and Targeting Approaches for Cancer Immunotherapy in the Tumor Microenvironment
Pharmaceutics 2023, 15(11), 2622; https://doi.org/10.3390/pharmaceutics15112622 - 13 Nov 2023
Viewed by 911
Abstract
In recent years, to treat a diverse array of cancer forms, considerable advancements have been achieved in the field of cancer immunotherapies. However, these therapies encounter multiple challenges in clinical practice, such as high immune-mediated toxicity, insufficient accumulation in cancer tissues, and undesired [...] Read more.
In recent years, to treat a diverse array of cancer forms, considerable advancements have been achieved in the field of cancer immunotherapies. However, these therapies encounter multiple challenges in clinical practice, such as high immune-mediated toxicity, insufficient accumulation in cancer tissues, and undesired off-target reactions. To tackle these limitations and enhance bioavailability, polymer micelles present potential solutions by enabling precise drug delivery to the target site, thus amplifying the effectiveness of immunotherapy. This review article offers an extensive survey of recent progress in cancer immunotherapy strategies utilizing micelles. These strategies include responsive and remodeling approaches to the tumor microenvironment (TME), modulation of immunosuppressive cells within the TME, enhancement of immune checkpoint inhibitors, utilization of cancer vaccine platforms, modulation of antigen presentation, manipulation of engineered T cells, and targeting other components of the TME. Subsequently, we delve into the present state and constraints linked to the clinical utilization of polymeric micelles. Collectively, polymer micelles demonstrate excellent prospects in tumor immunotherapy by effectively addressing the challenges associated with conventional cancer immunotherapies. Full article
(This article belongs to the Special Issue Smart Nanomedicine for Cancer Diagnosis and Therapy)
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15 pages, 4769 KiB  
Article
Effect of E. cava and C. indicum Complex Extract on Phorbol 12-Myristate 13-Acetate (PMA)-Stimulated Inflammatory Response in Human Pulmonary Epithelial Cells and Particulate Matter (PM)2.5-Induced Pulmonary Inflammation in Mice
Pharmaceutics 2023, 15(11), 2621; https://doi.org/10.3390/pharmaceutics15112621 - 13 Nov 2023
Cited by 1 | Viewed by 803
Abstract
This study explores the potential of a natural composite formulation known as ED, consisting of Ecklonia cava (E. cava, family: Lessoniaceae) and Chrysanthemum indicum Linne (C. indicum, family: Asteraceae), in alleviating lung inflammation induced by fine particulate matter (PM2.5 [...] Read more.
This study explores the potential of a natural composite formulation known as ED, consisting of Ecklonia cava (E. cava, family: Lessoniaceae) and Chrysanthemum indicum Linne (C. indicum, family: Asteraceae), in alleviating lung inflammation induced by fine particulate matter (PM2.5). Initial assessments confirmed that neither ED nor one of its components, dieckol, exhibited cytotoxic effects on A549 cells. Subsequently, the impact of ED and dieckol on MUC5AC gene expression in A549 cells stimulated by phorbol 12-myristate 13-acetate (PMA) was investigated, revealing promising results that demonstrated a dose-dependent inhibition of MUC5AC gene expression. The study also delves into the underlying mechanisms, demonstrating that ED and dieckol effectively suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including JNK, ERK, and p38, which are known to be involved in the regulation of MUC5AC gene expression. In in vivo experiments using a PM2.5-induced pulmonary inflammation mouse model, the research findings showed that ED mitigated cellular accumulation in the airways, leading to a significant reduction in the total cell count in bronchoalveolar lavage fluid (BALF). Moreover, ED exhibited protective effects against PM2.5-induced pulmonary damage, characterized by reduced inflammatory cell infiltration and decreased mucus secretion in pulmonary tissues. Additionally, ED’s anti-inflammatory properties were evident in its ability to decrease the levels of key inflammatory cytokines, TNF-α and IL-6, both in the serum and lung tissue of the PM2.5-induced pulmonary inflammation mouse model. These findings suggest the potential of ED as a therapeutic agent for inflammatory respiratory diseases. Full article
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29 pages, 5612 KiB  
Review
Colorectal Cancer: Disease Process, Current Treatment Options, and Future Perspectives
Pharmaceutics 2023, 15(11), 2620; https://doi.org/10.3390/pharmaceutics15112620 - 12 Nov 2023
Cited by 2 | Viewed by 1759
Abstract
Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It continues to be a menace, and the incidence has been projected to more than double by 2035, especially [...] Read more.
Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It continues to be a menace, and the incidence has been projected to more than double by 2035, especially in underdeveloped countries. This review seeks to provide some insights into the disease progression, currently available treatment options and their challenges, and future perspectives. Searches were conducted in the PubMed search engine in the university’s online library. The keywords were “Colorectal Cancer” AND “disease process” OR “disease mechanisms” OR “Current Treatment” OR “Prospects”. Selection criteria were original articles published primarily during the period of 2013 through 2023. Abstracts, books and documents, and reviews/systematic reviews were filtered out. Of over 490 thousand articles returned, only about 800 met preliminary selection criteria, 200 were reviewed in detail, but 191 met final selection criteria. Fifty-one other articles were used due to cross-referencing. Although recently considered a disease of lifestyle, CRC incidence appears to be rising in countries with low, low–medium, and medium social demographic indices. CRC can affect all parts of the colon and rectum but is more fatal with poor disease outcomes when it is right-sided. The disease progression usually takes between 7–10 years and can be asymptomatic, making early detection and diagnosis difficult. The CRC tumor microenvironment is made up of different types of cells interacting with each other to promote the growth and proliferation of the tumor cells. Significant advancement has been made in the treatment of colorectal cancer. Notable approaches include surgery, chemotherapy, radiation therapy, and cryotherapy. Chemotherapy, including 5-fluorouracil, irinotecan, oxaliplatin, and leucovorin, plays a significant role in the management of CRC that has been diagnosed at advanced stages. Two classes of monoclonal antibody therapies have been approved by the FDA for the treatment of colorectal cancer: the vascular endothelial growth factor (VEGF) inhibitor, e.g., bevacizumab (Avastin®), and the epidermal growth factor receptor (EGFR) inhibitor, e.g., cetuximab (Erbitux®) and panitumumab (Verbitix®). However, many significant problems are still being experienced with these treatments, mainly off-target effects, toxic side effects, and the associated therapeutic failures of small molecular drugs and the rapid loss of efficacy of mAb therapies. Other novel delivery strategies continue to be investigated, including ligand-based targeting of CRC cells. Full article
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30 pages, 654 KiB  
Review
The Trends and Future Prospective of In Silico Models from the Viewpoint of ADME Evaluation in Drug Discovery
Pharmaceutics 2023, 15(11), 2619; https://doi.org/10.3390/pharmaceutics15112619 - 12 Nov 2023
Viewed by 1261
Abstract
Drug discovery and development are aimed at identifying new chemical molecular entities (NCEs) with desirable pharmacokinetic profiles for high therapeutic efficacy. The plasma concentrations of NCEs are a biomarker of their efficacy and are governed by pharmacokinetic processes such as absorption, distribution, metabolism, [...] Read more.
Drug discovery and development are aimed at identifying new chemical molecular entities (NCEs) with desirable pharmacokinetic profiles for high therapeutic efficacy. The plasma concentrations of NCEs are a biomarker of their efficacy and are governed by pharmacokinetic processes such as absorption, distribution, metabolism, and excretion (ADME). Poor ADME properties of NCEs are a major cause of attrition in drug development. ADME screening is used to identify and optimize lead compounds in the drug discovery process. Computational models predicting ADME properties have been developed with evolving model-building technologies from a simplified relationship between ADME endpoints and physicochemical properties to machine learning, including support vector machines, random forests, and convolution neural networks. Recently, in the field of in silico ADME research, there has been a shift toward evaluating the in vivo parameters or plasma concentrations of NCEs instead of using predictive results to guide chemical structure design. Another research hotspot is the establishment of a computational prediction platform to strengthen academic drug discovery. Bioinformatics projects have produced a series of in silico ADME models using free software and open-access databases. In this review, we introduce prediction models for various ADME parameters and discuss the currently available academic drug discovery platforms. Full article
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14 pages, 489 KiB  
Review
Challenges Related to Acquisition of Physiological Data for Physiologically Based Pharmacokinetic (PBPK) Models in Postpartum, Lactating Women and Breastfed Infants—A Contribution from the ConcePTION Project
Pharmaceutics 2023, 15(11), 2618; https://doi.org/10.3390/pharmaceutics15112618 - 12 Nov 2023
Cited by 1 | Viewed by 1223
Abstract
Physiologically based pharmacokinetic (PBPK) modelling is a bottom-up approach to predict pharmacokinetics in specific populations based on population-specific and medicine-specific data. Using an illustrative approach, this review aims to highlight the challenges of incorporating physiological data to develop postpartum, lactating women and breastfed [...] Read more.
Physiologically based pharmacokinetic (PBPK) modelling is a bottom-up approach to predict pharmacokinetics in specific populations based on population-specific and medicine-specific data. Using an illustrative approach, this review aims to highlight the challenges of incorporating physiological data to develop postpartum, lactating women and breastfed infant PBPK models. For instance, most women retain pregnancy weight during the postpartum period, especially after excessive gestational weight gain, while breastfeeding might be associated with lower postpartum weight retention and long-term weight control. Based on a structured search, an equation for human milk intake reported the maximum intake of 153 mL/kg/day in exclusively breastfed infants at 20 days, which correlates with a high risk for medicine reactions at 2–4 weeks in breastfed infants. Furthermore, the changing composition of human milk and its enzymatic activities could affect pharmacokinetics in breastfed infants. Growth in breastfed infants is slower and gastric emptying faster than in formula-fed infants, while a slower maturation of specific metabolizing enzymes in breastfed infants has been described. The currently available PBPK models for these populations lack structured systematic acquisition of population-specific data. Future directions include systematic searches to fully identify physiological data. Following data integration as mathematical equations, this holds the promise to improve postpartum, lactation and infant PBPK models. Full article
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27 pages, 5672 KiB  
Review
Photodynamic Therapy-Induced Anti-Tumor Immunity: Influence Factors and Synergistic Enhancement Strategies
Pharmaceutics 2023, 15(11), 2617; https://doi.org/10.3390/pharmaceutics15112617 - 11 Nov 2023
Viewed by 1099
Abstract
Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity towards tumor cells by activating photosensitizers (PSs) with light exposure to produce reactive oxygen species (ROS). Compared to traditional treatment strategies such as surgery, chemotherapy, and radiation therapy, PDT not only [...] Read more.
Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity towards tumor cells by activating photosensitizers (PSs) with light exposure to produce reactive oxygen species (ROS). Compared to traditional treatment strategies such as surgery, chemotherapy, and radiation therapy, PDT not only kills the primary tumors, but also effectively suppresses metastatic tumors by activating the immune response. However, the anti-tumor immune effects induced by PDT are influenced by several factors, including the localization of PSs in cells, PSs concentration, fluence rate of light, oxygen concentration, and the integrity of immune function. In this review, we systematically summarize the influence factors of anti-tumor immune effects mediated by PDT. Furthermore, an update on the combination of PDT and other immunotherapy strategies are provided. Finally, the future directions and challenges of anti-tumor immunity induced by PDT are discussed. Full article
(This article belongs to the Special Issue Photodynamic Therapy: Rising Star in Pharmaceutical Applications)
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