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Pharmaceutics, Volume 14, Issue 4 (April 2022) – 202 articles

Cover Story (view full-size image): Hyaluronic acid (HA), through its interactions with the cluster of differentiation 44 (CD44), acts as a potent modulator of the tumor microenvironment, creating extracellular stimuli for tumor growth, angiogenesis, invasion, and metastasis. An innovative antitumor strategy based on the development of a nanodevice for selective release of an inhibitor of the HA-CD44 interaction is presented. Computational analysis was performed to evaluate the interaction of the designed inhibitor with a CD44 binding site. Cell viability, efficiency, and selectivity of drug release under acidic conditions together with CD44 binding capacity, migration, and apoptotic effect were evaluated. Remarkably, the nanodevice generated a reduction in the dose required to achieve a significant therapeutic effect. View this paper.
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Article
A Novel CXCR4-Targeted Diphtheria Toxin Nanoparticle Inhibits Invasion and Metastatic Dissemination in a Head and Neck Squamous Cell Carcinoma Mouse Model
Pharmaceutics 2022, 14(4), 887; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040887 - 18 Apr 2022
Viewed by 678
Abstract
Loco-regional recurrences and metastasis represent the leading causes of death in head and neck squamous cell carcinoma (HNSCC) patients, highlighting the need for novel therapies. Chemokine receptor 4 (CXCR4) has been related to loco-regional and distant recurrence and worse patient prognosis. In this [...] Read more.
Loco-regional recurrences and metastasis represent the leading causes of death in head and neck squamous cell carcinoma (HNSCC) patients, highlighting the need for novel therapies. Chemokine receptor 4 (CXCR4) has been related to loco-regional and distant recurrence and worse patient prognosis. In this regard, we developed a novel protein nanoparticle, T22-DITOX-H6, aiming to selectively deliver the diphtheria toxin cytotoxic domain to CXCR4+ HNSCC cells. The antimetastatic effect of T22-DITOX-H6 was evaluated in vivo in an orthotopic mouse model. IVIS imaging system was utilized to assess the metastatic dissemination in the mouse model. Immunohistochemistry and histopathological analyses were used to study the CXCR4 expression in the cancer cells, to evaluate the effect of the nanotoxin treatment, and its potential off-target toxicity. In this study, we report that CXCR4+ cancer cells were present in the invasive tumor front in an orthotopic mouse model. Upon repeated T22-DITOX-H6 administration, the number of CXCR4+ cancer cells was significantly reduced. Similarly, nanotoxin treatment effectively blocked regional and distant metastatic dissemination in the absence of systemic toxicity in the metastatic HNSCC mouse model. The repeated administration of T22-DITOX-H6 clearly abrogates tumor invasiveness and metastatic dissemination without inducing any off-target toxicity. Thus, T22-DITOX-H6 holds great promise for the treatment of CXCR4+ HNSCC patients presenting worse prognosis. Full article
(This article belongs to the Special Issue Novel Strategies for Cancer Targeted Delivery)
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Review
An Overview of Cell Membrane Perforation and Resealing Mechanisms for Localized Drug Delivery
Pharmaceutics 2022, 14(4), 886; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040886 - 18 Apr 2022
Viewed by 642
Abstract
Localized and reversible plasma membrane disruption is a promising technique employed for the targeted deposition of exogenous therapeutic compounds for the treatment of disease. Indeed, the plasma membrane represents a significant barrier to successful delivery, and various physical methods using light, sound, and [...] Read more.
Localized and reversible plasma membrane disruption is a promising technique employed for the targeted deposition of exogenous therapeutic compounds for the treatment of disease. Indeed, the plasma membrane represents a significant barrier to successful delivery, and various physical methods using light, sound, and electrical energy have been developed to generate cell membrane perforations to circumvent this issue. To restore homeostasis and preserve viability, localized cellular repair mechanisms are subsequently triggered to initiate a rapid restoration of plasma membrane integrity. Here, we summarize the known emergency membrane repair responses, detailing the salient membrane sealing proteins as well as the underlying cytoskeletal remodeling that follows the physical induction of a localized plasma membrane pore, and we present an overview of potential modulation strategies that may improve targeted drug delivery approaches. Full article
(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)
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Article
Anti-Psoriasis Effect of Diclofenac and Celecoxib Using the Tail Model for Psoriasis
Pharmaceutics 2022, 14(4), 885; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040885 - 18 Apr 2022
Viewed by 518
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) showed effects in some hyperproliferative dermatologic pathologies. The aim of the study is the assessment of anti-psoriasis effect of diclofenac and celecoxib using a mice tail model. The topical application of substances on the proximal mice tails was performed [...] Read more.
Non-steroidal anti-inflammatory drugs (NSAIDs) showed effects in some hyperproliferative dermatologic pathologies. The aim of the study is the assessment of anti-psoriasis effect of diclofenac and celecoxib using a mice tail model. The topical application of substances on the proximal mice tails was performed for two weeks. The effects on the epidermal granular layer and mean epidermal thickness (excluding the stratum corneum) were evaluated using hematoxylin–eosin staining. Orthokeratosis degree and percentual drug activity were calculated. A positive control group treated with tretinoin and two negative controls (white soft paraffin and untreated mice) were used. Orthokeratosis degree significantly increased in all the NSAIDs groups (celecoxib 1%, 2% and diclofenac 1%, 2%) and in the tretinoin 0.05% group, versus negative controls. Celecoxib 1% and 2%, tretinoin 0.05% and white soft paraffin significantly increased mean epidermal thickness, versus untreated mice. The values obtained in the case of celecoxib 2% ointment regarding the orthokeratosis degree and percentual drug activity are providing premises for further investigations regarding this effect and the mechanisms of action involved. Celecoxib 2% had the greatest percentual drug activity and is a promising substance for the anti-psoriasis topical treatment. Along with the COX-2 inhibition, celecoxib might have an anti-psoriasis effect by other independent mechanisms. Full article
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Article
β-Lactoglobulin-Modified Mesoporous Silica Nanoparticles: A Promising Carrier for the Targeted Delivery of Fenbendazole into Prostate Cancer Cells
Pharmaceutics 2022, 14(4), 884; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040884 - 18 Apr 2022
Cited by 1 | Viewed by 611
Abstract
The clinical utilization of fenbendazole (FBZ) as a potential anticancer drug has been limited due to its low water solubility, which causes its low bioavailability. The development of a drug nanoformulation that includes the solubilizing agent as a drug carrier can improve solubility [...] Read more.
The clinical utilization of fenbendazole (FBZ) as a potential anticancer drug has been limited due to its low water solubility, which causes its low bioavailability. The development of a drug nanoformulation that includes the solubilizing agent as a drug carrier can improve solubility and bioavailability. In this study, Mobil Composition of Matter Number 48 (MCM-48) nanoparticles were synthesized and functionalized with succinylated β-lactoglobulin (BLG) to prevent early-burst drug release. The BLG-modified amine-functionalized MCM-48 (MCM-BLG) nanoparticles were loaded with FBZ to produce the drug nanoformulation (FBZ-MCM-BLG) and improved the water solubility and, consequently, its anticancer effects against human prostate cancer PC-3 cells. The prepared FBZ-MCM-BLG was characterized in terms of size, zeta potential, drug loading capacity, morphology, thermal and chemical analyses, drug release, cellular uptake, cell viability, cell proliferation, production of reactive oxygen species (ROS), and cell migration. The results demonstrated that the FBZ-MCM-BLG nanoparticles have a spherical morphology with a size and zeta potential of 369 ± 28 nm and 28 ± 0.4 mV, respectively. The drug loading efficiency of the new nanoformulation was 19%. The release of FBZ was pH-dependent; a maximum cumulative release of about 76 and 62% in 12 h and a burst release of 53 and 38% in the first 0.5 h was observed at pH 1.2 and 6.8, respectively. The prepared FBZ-MCM-BLG formulation demonstrated higher cytotoxicity effects against PC-3 cells by 5.6- and 1.8-fold, respectively, when compared to FBZ and FBZ-MCM nanoparticles. The new formulation also increased the production of ROS by 1.6- and 1.2-fold and inhibited the migration of PC-3 cells when compared to the FBZ and FBZ-MCM nanoparticles, respectively. Overall, FBZ-MCM-BLG nanoparticles improved FBZ delivery to PC-3 cells and have the potential to be evaluated for the treatment of prostate cancer following a comprehensive in vivo study. Full article
(This article belongs to the Special Issue Smart Drug Delivery Strategies Based on Porous Materials)
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Review
Nanocarrier Drug Delivery Systems: Characterization, Limitations, Future Perspectives and Implementation of Artificial Intelligence
Pharmaceutics 2022, 14(4), 883; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040883 - 18 Apr 2022
Cited by 1 | Viewed by 833
Abstract
There has been an increasing demand for the development of nanocarriers targeting multiple diseases with a broad range of properties. Due to their tiny size, giant surface area and feasible targetability, nanocarriers have optimized efficacy, decreased side effects and improved stability over conventional [...] Read more.
There has been an increasing demand for the development of nanocarriers targeting multiple diseases with a broad range of properties. Due to their tiny size, giant surface area and feasible targetability, nanocarriers have optimized efficacy, decreased side effects and improved stability over conventional drug dosage forms. There are diverse types of nanocarriers that have been synthesized for drug delivery, including dendrimers, liposomes, solid lipid nanoparticles, polymersomes, polymer–drug conjugates, polymeric nanoparticles, peptide nanoparticles, micelles, nanoemulsions, nanospheres, nanocapsules, nanoshells, carbon nanotubes and gold nanoparticles, etc. Several characterization techniques have been proposed and used over the past few decades to control and predict the behavior of nanocarriers both in vitro and in vivo. In this review, we describe some fundamental in vitro, ex vivo, in situ and in vivo characterization methods for most nanocarriers, emphasizing their advantages and limitations, as well as the safety, regulatory and manufacturing aspects that hinder the transfer of nanocarriers from the laboratory to the clinic. Moreover, integration of artificial intelligence with nanotechnology, as well as the advantages and problems of artificial intelligence in the development and optimization of nanocarriers, are also discussed, along with future perspectives. Full article
(This article belongs to the Special Issue Novel Nanoparticle-Based Treatment and Imaging Modalities)
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Correction
Correction: Kazmi et al. Formulation and Evaluation of Kaempferol Loaded Nanoparticles against Experimentally Induced Hepatocellular Carcinoma: In Vitro and In Vivo Studies. Pharmaceutics 2021, 13, 2086
Pharmaceutics 2022, 14(4), 882; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040882 - 18 Apr 2022
Viewed by 399
Abstract
In the original publication [...] Full article
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Article
Oleyl Conjugated Histidine-Arginine Cell-Penetrating Peptides as Promising Agents for siRNA Delivery
Pharmaceutics 2022, 14(4), 881; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040881 - 18 Apr 2022
Viewed by 742
Abstract
Recent approvals of siRNA-based products motivated the scientific community to explore siRNA as a treatment option for several intractable ailments, especially cancer. The success of approved siRNA therapy requires a suitable and safer drug delivery agent. Herein, we report a series of oleyl [...] Read more.
Recent approvals of siRNA-based products motivated the scientific community to explore siRNA as a treatment option for several intractable ailments, especially cancer. The success of approved siRNA therapy requires a suitable and safer drug delivery agent. Herein, we report a series of oleyl conjugated histidine–arginine peptides as a promising nonviral siRNA delivery tool. The conjugated peptides were found to bind with the siRNA at N/P ratio ≥ 2 and demonstrated complete protection for the siRNA from early enzymatic degradation at N/P ratio ≥ 20. Oleyl-conjugated peptide -siRNA complexes were found to be noncytotoxic in breast cancer cells (MCF-7 and MDA-MB-231) and normal breast epithelial cells (MCF 10A) at N/P ratio of ~40. The oleyl-R3-(HR)4 and oleyl-R4-(HR)4 showed ~80-fold increased cellular uptake in MDA-MB-231 cells at N/P 40. Moreover, the conjugated peptides-siRNA complexes form nanocomplexes (~115 nm in size) and have an appropriate surface charge to interact with the cell membrane and cause cellular internalization. Furthermore, this study provides a proof-of-concept that oleyl-R5-(HR)4 can efficiently silence STAT-3 gene (~80% inhibition) in MDA-MB-231 cells with similar effectiveness to Lipofectamine. Further exploration of this approach holds a great promise in discovering a successful in vivo siRNA delivery agent with a favorable pharmacokinetic profile. Full article
(This article belongs to the Special Issue Peptide-Based Drug Delivery Systems)
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Article
Tolmetin Sodium Fast Dissolving Tablets for Rheumatoid Arthritis Treatment: Preparation and Optimization Using Box-Behnken Design and Response Surface Methodology
Pharmaceutics 2022, 14(4), 880; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040880 - 18 Apr 2022
Cited by 1 | Viewed by 768
Abstract
Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a [...] Read more.
Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a rather protracted start to the effect, according to pharmacokinetic studies. The aim of this study was to create a combination for TLM fast dissolving tablets (TLM-FDT) that would boost the drug’s bioavailability by increasing pre-gastric absorption. The TLM-FDTs were developed using a Box-Behnken experimental design with varied doses of crospovidone (CP), croscarmellose sodium (CCS) as super-disintegrants, and camphor as a sublimating agent. In addition, the current study used response surface approach to explore the influence of various formulation and process factors on tablet qualities in order to verify an optimized TLM-FDTs formulation. The optimized TLM-FDTs formula was subsequently evaluated for its in vivo anti-inflammatory activity. TLM-FDTs have good friability, disintegration time, drug release, and wetting time, as well as fast disintegration and dissolution behavior. Significant increase in drug bioavailability and reliable anti-inflammatory efficacy were also observed, as evidenced by considerable reductions in paw thickness in rats following carrageenan-induced rat paw edema. For optimizing and analyzing the effect of super-disintegrants and sublimating agents in the TLM-FDTs formula, the three-factor, three-level full factorial design is a suitable tool. TLM-FDTs are a possible drug delivery system for enhancing TLM bioavailability and could be used to treat rheumatoid arthritis. Full article
(This article belongs to the Special Issue Development of Orally Dispersible Dosage Forms)
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Article
Transdermal Delivery of Metformin Using Dissolving Microneedles and Iontophoresis Patches for Browning Subcutaneous Adipose Tissue
Pharmaceutics 2022, 14(4), 879; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040879 - 17 Apr 2022
Viewed by 591
Abstract
Obesity is a serious public health problem that is strongly associated with increased multiple comorbidities such as diabetes, cardiovascular disease, and some types of cancer. While current anti-obesity treatments have various issues, locally transforming energy-storing white adipose tissue (WAT) into energy-burning brown-like/beige adipose [...] Read more.
Obesity is a serious public health problem that is strongly associated with increased multiple comorbidities such as diabetes, cardiovascular disease, and some types of cancer. While current anti-obesity treatments have various issues, locally transforming energy-storing white adipose tissue (WAT) into energy-burning brown-like/beige adipose tissue, the so-called browning of WAT, has been suggested to enhance obesity treatment efficiency with minimized side effects. Metformin is a first-line antidiabetes drug and a potent activator of AMP-activated protein kinase. Emerging evidence has suggested that metformin might enhance energy expenditure via the browning of WAT and hence reduce body weight. Subcutaneous WAT is easier to access and has a stronger browning potential than other WAT depots. In this study, we used dissolvable poly (lactic-co-glycolic acid) microneedles (MN) to deliver metformin to the subcutaneous WAT in obese C57BL/6J mice with the assistance of iontophoresis (INT), and then investigated metformin-induced WAT browning and its subsequent thermogenesis effects. Compared with MN alone or INT alone, MN + INT had better anti-obesity activity, as indicated by decreasing body weight and fat gain, increased energy expenditure, decreased fat pad size, and improved energy metabolism through the browning of WAT. Browning subcutaneous WAT by delivering metformin and other browning agents using this MN + INT approach might combat obesity in an effective, easy, and safe regimen. Full article
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Systematic Review
Systematic Review of Pharmacogenetics of ABC and SLC Transporter Genes in Acute Myeloid Leukemia
Pharmaceutics 2022, 14(4), 878; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040878 - 17 Apr 2022
Viewed by 668
Abstract
Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic [...] Read more.
Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic review was performed to evaluate the influence of SLC and ABC polymorphisms and their combinations on efficacy and safety in AML cohorts. Anthracycline intake was especially influenced by SLCO1B1 polymorphisms, associated with lower hepatic uptake, showing higher survival rates and toxicity in AML studies. The variant alleles of ABCB1 were related to anthracycline intracellular accumulation, increasing complete remission, survival and toxicity. Similar findings have been suggested with ABCC1 and ABCG2 polymorphisms. Polymorphisms of SLC29A1, responsible for cytarabine uptake, demonstrated significant associations with survival and response in Asian populations. Promising results were observed with SLC and ABC combinations regarding anthracycline toxicities. Knowledge of the role of transporter pharmacogenetics could explain the differences observed in drug disposition in the blast. Further studies including novel targeted therapies should be performed to determine the influence of genetic variability to individualize chemotherapy schemes. Full article
(This article belongs to the Special Issue The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery)
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Article
Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2
Pharmaceutics 2022, 14(4), 877; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040877 - 17 Apr 2022
Viewed by 676
Abstract
The development of effective antiviral drugs against SARS-CoV-2 is urgently needed and a global health priority. In light of the initial data regarding the repurposing of hydroxychloroquine (HCQ) to tackle this coronavirus, herein we present a quantitative synthesis and spectroscopic and thermal characterization [...] Read more.
The development of effective antiviral drugs against SARS-CoV-2 is urgently needed and a global health priority. In light of the initial data regarding the repurposing of hydroxychloroquine (HCQ) to tackle this coronavirus, herein we present a quantitative synthesis and spectroscopic and thermal characterization of seven HCQ room temperature ionic liquids (HCQ-ILs) obtained by direct protonation of the base with two equivalents of organic sulfonic, sulfuric and carboxylic acids of different polarities. Two non-toxic and hydrophilic HCQ-ILs, in particular, [HCQH2][C1SO3]2 and [HCQH2][GlcCOO]2, decreased the virus-induced cytopathic effect by two-fold in comparison with the original drug, [HCQH2][SO4]. Despite there being no significant differences in viral RNA production between the three compounds, progeny virus production was significantly affected (p < 0.05) by [HCQH2][GlcCOO]2. Overall, the data suggest that the in vitro antiviral activities of the HCQ-ILs are most likely the result of specific intra- and intermolecular interactions and not so much related with their hydrophilic or lipophilic character. This work paves the way for the development of future novel ionic formulations of hydroxychloroquine with enhanced physicochemical properties. Full article
(This article belongs to the Special Issue Therapeutic Formulations of Repurposed Drugs against COVID-19)
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Article
Influence of Formulation Factors, Process Parameters, and Selected Quality Attributes on Carvedilol Release from Roller-Compacted Hypromellose-Based Matrix Tablets
Pharmaceutics 2022, 14(4), 876; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040876 - 16 Apr 2022
Cited by 1 | Viewed by 464
Abstract
The importance of roller compaction is recently increasing. This study evaluates the combined effects of formulation factors, process parameters, and selected quality attributes on drug release from roller-compacted hypromellose-based matrix tablets containing carvedilol as a model drug. The influence of selected factors was [...] Read more.
The importance of roller compaction is recently increasing. This study evaluates the combined effects of formulation factors, process parameters, and selected quality attributes on drug release from roller-compacted hypromellose-based matrix tablets containing carvedilol as a model drug. The influence of selected factors was statistically assessed and good predictive models were developed for various time points of the release profile. The results show that the release profile is mostly affected by the particle size distribution of granules and roll speed. This indicates that the roller compaction process has a major impact on drug release, which is also formulation dependent. A higher d50 and lower d90 value of spatial filtering technique-based particle size distribution results, a lower roll speed, increased hypromellose content, using microcrystalline cellulose as a filler, and higher tablet hardness, resulted in a decrease in the drug release rate. On the other hand, the effect of the roll pressure, size of screen apertures, and d10 values on drug release was insignificant. The significance of the factors was further explained by granule shape, their porosity, and friability evaluation, and by compressibility and compactibility studies of compression mixtures. Additionally, the spatial filtering technique demonstrated to be a promising tool in controlling the roller compaction process. Full article
(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)
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Article
Tailoring of Selenium-Plated Novasomes for Fine-Tuning Pharmacokinetic and Tumor Uptake of Quercetin: In Vitro Optimization and In Vivo Radiobiodistribution Assessment in Ehrlich Tumor-Bearing Mice
Pharmaceutics 2022, 14(4), 875; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040875 - 16 Apr 2022
Viewed by 548
Abstract
Quercetin (QRC) is a bioflavonoid with anti-inflammatory, antioxidant, and anticancer activities, yet QRC poor bioavailability has hampered its clinical implementation. The aim of the current work was to harness novasomes (NOVs), free fatty acid enriched vesicles, as a novel nano-cargo for felicitous QRC [...] Read more.
Quercetin (QRC) is a bioflavonoid with anti-inflammatory, antioxidant, and anticancer activities, yet QRC poor bioavailability has hampered its clinical implementation. The aim of the current work was to harness novasomes (NOVs), free fatty acid enriched vesicles, as a novel nano-cargo for felicitous QRC delivery with subsequent functionalization with selenium (SeNOVs), to extend the systemic bio-fate of NOVs and potentiate QRC anticancer efficacy through the synergy with selenium. QRC-NOVs were primed embedding oleic acid, Brij 35, and cholesterol adopting thin-film hydration technique according to Box–Behnken design. Employing Design-Expert® software, the impact of formulation variables on NOVs physicochemical characteristics besides the optimum formulation election were explored. Based on the optimal NOVs formulation, QRC-SeNOVs were assembled via electrostatic complexation/in situ reduction method. The MTT cytotoxicity assay of the uncoated, and coated nanovectors versus crude QRC was investigated in human rhabdomyosarcoma (RD) cells. The in vivo pharmacokinetic and biodistribution studies after intravenous administrations of technetium-99m (99mTc)-labeled QRC-NOVs, QRC-SeNOVs, and QRC-solution were scrutinized in Ehrlich tumor-bearing mice. QRC-NOVs and QRC-SeNOVs disclosed entrapment efficiency of 67.21 and 70.85%, vesicle size of 107.29 and 129.16 nm, ζ potential of −34.71 and −43.25 mV, and accumulatively released 43.26 and 31.30% QRC within 24 h, respectively. Additionally, QRC-SeNOVs manifested a far lower IC50 of 5.56 μg/mL on RD cells than that of QRC-NOVs (17.63 μg/mL) and crude QRC (38.71 μg/mL). Moreover, the biodistribution study elicited higher preferential uptake of 99mTc-QRC-SeNOVs within the tumorous tissues by 1.73- and 5.67-fold as compared to 99mTc-QRC-NOVs and 99mTc-QRC-solution, respectively. Furthermore, the relative uptake efficiency of 99mTc-QRC-SeNOVs was 5.78, the concentration efficiency was 4.74 and the drug-targeting efficiency was 3.21. Hence, the engineered QRC-SeNOVs could confer an auspicious hybrid nanoparadigm for QRC delivery with fine-tuned pharmacokinetics, and synergized antitumor traits. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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Review
Reptiles as Promising Sources of Medicinal Natural Products for Cancer Therapeutic Drugs
Pharmaceutics 2022, 14(4), 874; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040874 - 16 Apr 2022
Viewed by 477
Abstract
Natural products have historically played an important role as a source of therapeutic drugs for various diseases, and the development of medicinal natural products is still a field with high potential. Although diverse drugs have been developed for incurable diseases for several decades, [...] Read more.
Natural products have historically played an important role as a source of therapeutic drugs for various diseases, and the development of medicinal natural products is still a field with high potential. Although diverse drugs have been developed for incurable diseases for several decades, discovering safe and efficient anticancer drugs remains a formidable challenge. Reptiles, as one source of Asian traditional medicines, are known to possess anticancer properties and have been used for a long time without a clarified scientific background. Recently, it has been reported that extracts, crude peptides, sera, and venom isolated from reptiles could effectively inhibit the survival and proliferation of various cancer cells. In this article, we summarize recent studies applying ingredients derived from reptiles in cancer therapy and discuss the difficulties and prospective development of natural product research. Full article
(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)
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Article
Polymeric Nanocapsules Containing Fennel Essential Oil: Their Preparation, Physicochemical Characterization, Stability over Time and in Simulated Gastrointestinal Conditions
Pharmaceutics 2022, 14(4), 873; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040873 - 16 Apr 2022
Viewed by 546
Abstract
Plant essential oils, a source of biologically active compounds, represent a promising segment in the pharmaceutical market. However, their volatility, hydrophobicity, poor stability, and low toxicity limit direct use in pharmaceutical-related applications. Nanoencapsulation is a technique that allows overcoming these obstacles by improving [...] Read more.
Plant essential oils, a source of biologically active compounds, represent a promising segment in the pharmaceutical market. However, their volatility, hydrophobicity, poor stability, and low toxicity limit direct use in pharmaceutical-related applications. Nanoencapsulation is a technique that allows overcoming these obstacles by improving bioaccessibility and bioavailability. Nanocapsules (NCs) based on biodegradable and biocompatible poly(ɛ-caprolactone) containing Foeniculum vulgare Mill. essential oil (FEO), known for its biological activities, were successfully prepared by interfacial deposition of the preformed polymer method. The composition of FEO (trans-anethole chemotype) was determined by gas chromatography analyses. The FEO presence inside the NCs was confirmed by nuclear magnetic resonance experiments. The FEO-NCs showed nanometer size (210 nm), low polydispersity index (0.10), negative zeta potential (−15 mV), non-Newtonian rheological behavior, and high efficiency of encapsulation (93%). Moreover, parameters such as FEO-NC particle size, bioactive compound retention, and FEO composition were monitored for 30 days at storage temperatures of 4 and 40 °C, confirming the robustness of the nanosystem. Finally, FEO-NCs were resistant to the simulated gastric digestion and showed an effective bioaccessibility of 29% in simulated intestinal digestion. Based on the results obtained, this FEO-NC nanosystem could find interesting applications in the nutraceutical and pharmaceutical sectors. Full article
(This article belongs to the Special Issue Essential Oils in Pharmaceutical Products)
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Review
Recent Fabrication Methods to Produce Polymer-Based Drug Delivery Matrices (Experimental and In Silico Approaches)
Pharmaceutics 2022, 14(4), 872; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040872 - 15 Apr 2022
Viewed by 607
Abstract
The study of novel drug delivery systems represents one of the frontiers of the biomedical research area. Multi-disciplinary scientific approaches combining traditional or engineered technologies are used to provide major advances in improving drug bioavailability, rate of release, cell/tissue specificity and therapeutic index. [...] Read more.
The study of novel drug delivery systems represents one of the frontiers of the biomedical research area. Multi-disciplinary scientific approaches combining traditional or engineered technologies are used to provide major advances in improving drug bioavailability, rate of release, cell/tissue specificity and therapeutic index. Biodegradable and bio-absorbable polymers are usually the building blocks of these systems, and their copolymers are employed to create delivery components. For example, poly (lactic acid) or poly (glycolic acid) are often used as bricks for the production drug-based delivery systems as polymeric microparticles (MPs) or micron-scale needles. To avoid time-consuming empirical approaches for the optimization of these formulations, in silico-supported models have been developed. These methods can predict and tune the release of different drugs starting from designed combinations. Starting from these considerations, this review has the aim of investigating recent approaches to the production of polymeric carriers and the combination of in silico and experimental methods as promising platforms in the biomedical field. Full article
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Article
Assessment of the Extrusion Process and Printability of Suspension-Type Drug-Loaded AffinisolTM Filaments for 3D Printing
Pharmaceutics 2022, 14(4), 871; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040871 - 15 Apr 2022
Viewed by 597
Abstract
Three-dimensional (3D) printing technology enables the design of new drug delivery systems for personalised medicine. Polymers that can be molten are needed to obtain extruded filaments for Fused Deposition Modelling (FDM), one of the most frequently employed techniques for 3D printing. The aim [...] Read more.
Three-dimensional (3D) printing technology enables the design of new drug delivery systems for personalised medicine. Polymers that can be molten are needed to obtain extruded filaments for Fused Deposition Modelling (FDM), one of the most frequently employed techniques for 3D printing. The aim of this work was to evaluate the extrusion process and the physical appearance of filaments made of a hydrophilic polymer and a non-molten model drug. Metformin was used as model drug and Affinisol™ 15LV as the main carrier. Drug-loaded filaments were obtained by using a single-screw extruder and, subsequently, their printability was tested. Blends containing up to a 60% and 50% drug load with 5% and 7.5% of auxiliary excipients, respectively, were successfully extruded. Between the obtained filaments, those containing up to 50% of the drug were suitable for use in FDM 3D printing. The studied parameters, including residence time, flow speed, brittleness, and fractal dimension, reflect a critical point in the extrusion process at between 30–40% drug load. This finding could be essential for understanding the behaviour of filaments containing a non-molten component. Full article
(This article belongs to the Special Issue Additive Manufacturing Approaches to Produce Drug Delivery Systems)
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Article
Effect of Solvents, Stabilizers and the Concentration of Stabilizers on the Physical Properties of Poly(d,l-lactide-co-glycolide) Nanoparticles: Encapsulation, In Vitro Release of Indomethacin and Cytotoxicity against HepG2-Cell
Pharmaceutics 2022, 14(4), 870; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040870 - 15 Apr 2022
Cited by 2 | Viewed by 515
Abstract
A biocompatible, biodegradable and FDA-approved polymer [Poly lactic-co-glycolic acid (PLGA)] was used to prepare the nanoparticles (NPs) to observe the effect of solvents, stabilizers and their concentrations on the physical properties of the PLGA-NPs, following the encapsulation and in vitro release [...] Read more.
A biocompatible, biodegradable and FDA-approved polymer [Poly lactic-co-glycolic acid (PLGA)] was used to prepare the nanoparticles (NPs) to observe the effect of solvents, stabilizers and their concentrations on the physical properties of the PLGA-NPs, following the encapsulation and in vitro release of Indomethacin (IND). PLGA-NPs were prepared by the single-emulsion solvent evaporation technique using dichloromethane (DCM)/chloroform as the organic phase with Polyvinyl-alcohol (PVA)/Polyvinylpyrrolidone (PVP) as stabilizers to encapsulate IND. The effects of different proportions of PVA/PVP with DCM/chloroform on the physiochemical properties (particle size, the polydispersity index, the zeta potential by Malvern Zetasizer and morphology by SEM) of the NPs were investigated. DSC was used to check the physical state, the possible complexation of PLGA with stabilizer(s) and the crystallinity of the encapsulated drug. Stabilizers at all concentrations produced spherical, regular-shaped, smooth-surfaced discrete NPs. Average size of 273.2–563.9 nm was obtained when PVA (stabilizer) with DCM, whereas it ranged from 317.6 to 588.1 nm with chloroform. The particle size was 273.2–563.9 nm when PVP was the stabilizer with DCM, while it was 381.4–466.6 nm with chloroform. The zeta potentials of PVA-stabilized NPs were low and negative (−0.62 mV) while they were comparatively higher and positive for PVP-stabilized NPs (+17.73 mV). Finally, drug-loaded optimal NPs were composed of PLGA (40 mg) and IND (4 mg) in 1 mL DCM/chloroform with PVA/PVP (1–3%), which resulted in sufficient encapsulation (54.94–74.86%) and drug loading (4.99–6.81%). No endothermic peak of PVA/PVP appeared in the optimized formulation, which indicated the amorphous state of IND in the core of the PLGA-NPs. The in vitro release study indicated a sustained release of IND (32.83–52.16%) from the PLGA-NPs till 72 h and primarily followed the Higuchi matrix release kinetics followed by Korsmeyer–Peppas models. The cell proliferation assay clearly established that the organic solvents used to prepare PLGA-NPs had evaporated. The PLGA-NPs did not show any particular toxicity in the HepG2 cells within the dose range of IND (250–500 µg/mL) and at an equivalent concentration of PLGA-NPs (3571.4–7142.7 µg/mL). The cytotoxicity of the hepatotoxic drug (IND) was reduced by its encapsulation into PLGA-NPs. The outcomes of this investigation could be implemented to prepare PLGA-NPs of acceptable properties for the encapsulation of low/high molecular weight drugs. It would be useful for further in vitro and in vivo applications to use this delivery system. Full article
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Article
Ovarian Follicular Growth through Intermittent Vaginal Gonadotropin Administration in Diminished Ovarian Reserve Women
Pharmaceutics 2022, 14(4), 869; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040869 - 15 Apr 2022
Cited by 1 | Viewed by 462
Abstract
It is a challenge to obtain enough oocytes during in vitro fertilization (IVF) in women who have a poor ovarian response (POR) in achieving conception. We have adopted the characteristics of the first uterine pass effect, which we pioneered in employing the vaginal [...] Read more.
It is a challenge to obtain enough oocytes during in vitro fertilization (IVF) in women who have a poor ovarian response (POR) in achieving conception. We have adopted the characteristics of the first uterine pass effect, which we pioneered in employing the vaginal administration of gonadotropins in women receiving IVF treatments. In our previous study employing vaginal administration, faster absorption and slower elimination of gonadotropins were demonstrated, and, female subjects presented proper ovarian follicle growth and pregnancy rates. In this study, during 2016–2020, 300 to 675 IU of gonadotropins were administered vaginally every three days in 266 POR women for their controlled ovarian hyperstimulation (COH). The injections were performed with needles angled at 15–30° towards the middle-upper portions of the bilateral vaginal wall, with an injection depth of 1–2 mm. For the COH results, these women, on average, received 3.0 ± 0.9 vaginal injections and a total dose of 1318.4 ± 634.4 IU gonadotropins, resulting in 2.2 ± 1.9 mature oocytes and 1.0 ± 1.2 good embryos. Among these embryos, 0.9 ± 1.0 were transferred to reach a clinical pregnancy rate of 18.1% and a live birth rate of 16.7%. In conclusion, the intermittent vaginal administration of gonadotropins proved to be effective in POR women for their IVF treatments. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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Article
Evaluation of CTB-sLip for Targeting Lung Metastasis of Colorectal Cancer
Pharmaceutics 2022, 14(4), 868; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040868 - 15 Apr 2022
Viewed by 538
Abstract
Lung metastasis of colorectal cancer is common in the clinic; however, precise targeting for the diagnosis and therapy purposes of those lung metastases remains challenging. Herein, cholera toxin subunit b (CTB) protein was chemically conjugated on the surface of PEGylated liposomes (CTB-sLip). Both [...] Read more.
Lung metastasis of colorectal cancer is common in the clinic; however, precise targeting for the diagnosis and therapy purposes of those lung metastases remains challenging. Herein, cholera toxin subunit b (CTB) protein was chemically conjugated on the surface of PEGylated liposomes (CTB-sLip). Both human-derived colorectal cancer cell lines, HCT116 and HT-29, demonstrated high binding affinity and cellular uptake with CTB-sLip. In vivo, CTB-sLip exhibited elevated targeting capability to the lung metastasis of colorectal cancer in the model nude mice in comparison to PEGylated liposomes (sLip) without CTB modification. CTB conjugation induced ignorable effects on the interaction between liposomes and plasma proteins but significantly enhanced the uptake of liposomes by numerous blood cells and splenic cells, leading to relatively rapid blood clearance in BALB/c mice. Even though repeated injections of CTB-sLip induced the production of anti-CTB antibodies, our results suggested CTB-sLip as promising nanocarriers for the diagnosis of lung metastasis of colorectal cancer. Full article
(This article belongs to the Special Issue Strategies to Enhance Drug Permeability across Biological Barriers)
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Review
Therapeutic Vaccines Targeting Neoantigens to Induce T-Cell Immunity against Cancers
Pharmaceutics 2022, 14(4), 867; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040867 - 15 Apr 2022
Viewed by 635
Abstract
Cancer immunotherapy has achieved multiple clinical benefits and has become an indispensable component of cancer treatment. Targeting tumor-specific antigens, also known as neoantigens, plays a crucial role in cancer immunotherapy. T cells of adaptive immunity that recognize neoantigens, but do not induce unwanted [...] Read more.
Cancer immunotherapy has achieved multiple clinical benefits and has become an indispensable component of cancer treatment. Targeting tumor-specific antigens, also known as neoantigens, plays a crucial role in cancer immunotherapy. T cells of adaptive immunity that recognize neoantigens, but do not induce unwanted off-target effects, have demonstrated high efficacy and low side effects in cancer immunotherapy. Tumor neoantigens derived from accumulated genetic instability can be characterized using emerging technologies, such as high-throughput sequencing, bioinformatics, predictive algorithms, mass-spectrometry analyses, and immunogenicity validation. Neoepitopes with a higher affinity for major histocompatibility complexes can be identified and further applied to the field of cancer vaccines. Therapeutic vaccines composed of tumor lysates or cells and DNA, mRNA, or peptides of neoantigens have revoked adaptive immunity to kill cancer cells in clinical trials. Broad clinical applicability of these therapeutic cancer vaccines has emerged. In this review, we discuss recent progress in neoantigen identification and applications for cancer vaccines and the results of ongoing trials. Full article
(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))
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Review
Emerging Nanotherapeutic Approaches to Overcome Drug Resistance in Cancers with Update on Clinical Trials
Pharmaceutics 2022, 14(4), 866; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040866 - 15 Apr 2022
Cited by 1 | Viewed by 626
Abstract
A key issue with modern cancer treatments is the emergence of resistance to conventional chemotherapy and molecularly targeted medicines. Cancer nanotherapeutics were created in order to overcome the inherent limitations of traditional chemotherapeutics. Over the last few decades, cancer nanotherapeutics provided unparalleled opportunities [...] Read more.
A key issue with modern cancer treatments is the emergence of resistance to conventional chemotherapy and molecularly targeted medicines. Cancer nanotherapeutics were created in order to overcome the inherent limitations of traditional chemotherapeutics. Over the last few decades, cancer nanotherapeutics provided unparalleled opportunities to understand and overcome drug resistance through clinical assessment of rationally designed nanoparticulate delivery systems. In this context, various design strategies such as passive targeting, active targeting, nano-drug, and multimodal nano-drug combination therapy provided effective cancer treatment. Even though cancer nanotherapy has made great technological progress, tumor biology complexity and heterogeneity and a lack of comprehensive knowledge of nano-bio interactions remain important roadblocks to future clinical translation and commercialization. The current developments and advancements in cancer nanotherapeutics employing a wide variety of nanomaterial-based platforms to overcome cancer treatment resistance are discussed in this article. There is also a review of various nanotherapeutics-based approaches to cancer therapy, including targeting strategies for the tumor microenvironment and its components, advanced delivery systems for specific targeting of cancer stem cells (CSC), as well as exosomes for delivery strategies, and an update on clinical trials. Finally, challenges and the future perspective of the cancer nanotherapeutics to reverse cancer drug resistance are discussed. Full article
(This article belongs to the Special Issue Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy)
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Article
Bio-Responsive Carriers for Controlled Delivery of Doxorubicin to Cancer Cells
Pharmaceutics 2022, 14(4), 865; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040865 - 15 Apr 2022
Cited by 1 | Viewed by 497
Abstract
The cellular internalization of drug carriers occurs via different endocytic pathways that ultimately involve the endosomes and the lysosomes, organelles where the pH value drops to 6.0 and 5.0, respectively. We aimed to design and characterize pH/temperature-responsive carriers for the effective delivery of [...] Read more.
The cellular internalization of drug carriers occurs via different endocytic pathways that ultimately involve the endosomes and the lysosomes, organelles where the pH value drops to 6.0 and 5.0, respectively. We aimed to design and characterize pH/temperature-responsive carriers for the effective delivery of the anti-tumoral drug doxorubicin. To this purpose, poly(N-isopropylacrylamide-co-vinylimidazole) was synthesized as an attractive pH/temperature-sensitive copolymer. Microspheres made of this copolymer, loaded with doxorubicin (MS-DXR), disintegrate in monodisperse nanospheres (NS-DXR) under conditions similar to that found in the bloodstream (pH = 7.4, temperature of 36 °C) releasing a small amount of payload. However, in environments that simulate the endosomal and lysosomal conditions, nanospheres solubilize, releasing the entire amount of drug. We followed the NS-DXR internalization using two cancer cell lines, hepatic carcinoma HepG2 cells and lung adenocarcinoma A549 cells. The data showed that NS-DXR are internalized to a greater extent by HepG2 cells than A549 cells, and this correlated with increased cytotoxicity induced by NS-DXR in HepG2 cells compared with A549 cells. Moreover, NS-DXR particles do not cause hemolysis and erythrocytes aggregation. Administered in vivo, NS-DXR localized in the liver and kidneys of mice, and the loading of DXR into NS resulted in the reduced renal clearance of DXR. In conclusion, the newly developed poly(N-isopropylacrylamide-co-vinyl imidazole) particles are biocompatible and may be introduced as carriers for doxorubicin to hepatic tumors. Full article
(This article belongs to the Special Issue Controlled Release of Nanostructured Drug Systems (Volume II))
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Article
Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay
Pharmaceutics 2022, 14(4), 864; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040864 - 15 Apr 2022
Viewed by 384
Abstract
Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-β-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were [...] Read more.
Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-β-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were carried out at 4 temperatures in 0–0.05 M CD concentration range for pH 2.0 and pH 7.4. AL- and AL-type phase-solubility profiles were obtained for both compounds in pH 2.0 and pH 7.4. The racemic formed more stable complexes with CD as compared to R-isomer. Disclosing of chiral discrimination was facilitated using the approach based on the complex consideration of the derived complexation/solubilization/inherent dissolution thermodynamic functions, including the differential parameters between the racemic compound and R-enantiomer. The differences in the thermodynamic parameters determined by the chirality were discussed in terms of the driving forces of the processes and the main interactions of the compounds with CD in solution. The membrane permeability of both samples in the presence of CD was accessed in order to evaluate the specificity of enantioselective transport through the lipophilic membrane. The solubility/permeability interrelation was disclosed. The investigated compounds were classified as medium permeable in pure buffers and low permeable in the presence of 0.01 M CD. The obtained results can be useful for the design of pharmaceutical products in the form of liquid formulations based on the investigated substances. Full article
(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)
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Article
Fabrication and In Vitro/In Vivo Appraisal of Metronidazole Intra-Gastric Buoyant Sustained-Release Tablets in Healthy Volunteers
Pharmaceutics 2022, 14(4), 863; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040863 - 14 Apr 2022
Cited by 1 | Viewed by 484
Abstract
Helicobacter pylori is thought to be the most common cause of peptic and duodenal ulcers. Eradication of this organism is now considered one of the lines of treatment of gastric and duodenal ulcers. This can be achieved via local delivery of antibacterial agents [...] Read more.
Helicobacter pylori is thought to be the most common cause of peptic and duodenal ulcers. Eradication of this organism is now considered one of the lines of treatment of gastric and duodenal ulcers. This can be achieved via local delivery of antibacterial agents in high concentrations. Accordingly, our objective was to fabricate and evaluate sustained release floating tablets for metronidazole to extend the gastric residence period and control the release rate of metronidazole. Floating tablets containing cellulose derivatives and Avicel were prepared using direct compression. The rate of metronidazole release from the floating tablets (K = 6.278 mg min−1/2) was significantly lower than that from conventional tablets (K = 10.666 mg min−1/2), indicating sustained drug release, according to the Higuchi model, for more than 6 h in an acidic medium of 0.1 N HCl. In vivo study in healthy volunteers revealed significantly improved bioavailability; increased Tmax, AUC, and MRT; and significantly lower absorption rate constant after a single oral dose of 150 mg metronidazole as floating tablets. In addition, the significant increase in MRT indicated an in vivo sustained drug release. The floating tablets provided several benefits, including ease of preparation, absence of effervescent ingredients, and reliance on a pH-independent gel-forming agent to deliver metronidazole in a sustained manner. In conclusion, the prepared tablets could be promising for enhancing both local and systemic metronidazole efficacy. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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Article
Squalene-Based Nano-Assemblies Improve the Pro-Autophagic Activity of Trehalose
Pharmaceutics 2022, 14(4), 862; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040862 - 14 Apr 2022
Viewed by 483
Abstract
The disaccharide trehalose is a well-established autophagy inducer, but its therapeutic application is severely hampered by its low potency and poor pharmacokinetic profile. Thus, we targeted the rational design and synthesis of trehalose-based small molecules and nano objects to overcome such issues. Among [...] Read more.
The disaccharide trehalose is a well-established autophagy inducer, but its therapeutic application is severely hampered by its low potency and poor pharmacokinetic profile. Thus, we targeted the rational design and synthesis of trehalose-based small molecules and nano objects to overcome such issues. Among several rationally designed trehalose-centered putative autophagy inducers, we coupled trehalose via suitable spacers with known self-assembly inducer squalene to yield two nanolipid-trehalose conjugates. Squalene is known for its propensity, once linked to a bioactive compound, to assemble in aqueous media in controlled conditions, internalizing its payload and forming nanoassemblies with better pharmacokinetics. We assembled squalene conjugates to produce the corresponding nanoassemblies, characterized by a hydrodynamic diameter of 188 and 184 nm and a high stability in aqueous media as demonstrated by the measured Z-potential. Moreover, the nanoassemblies were characterized for their toxicity and capability to induce autophagy in vitro. Full article
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Article
Using a State-Bounding Observer to Predict the Guaranteed Limits of Drug Amounts in Rats after Oral Administration Based on an Uncertain Pharmacokinetic Model
Pharmaceutics 2022, 14(4), 861; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040861 - 14 Apr 2022
Viewed by 326
Abstract
In the first part of this paper, the problem of using an uncertain pharmacokinetic model is resolved to determine drug concentrations in rats after the oral administration of drug suspensions with and without added tenside. To this end, a generalized pharmacokinetic model determining [...] Read more.
In the first part of this paper, the problem of using an uncertain pharmacokinetic model is resolved to determine drug concentrations in rats after the oral administration of drug suspensions with and without added tenside. To this end, a generalized pharmacokinetic model determining the guaranteed limits of drug concentrations was designed. Based on this, the design of the so-called state-bounding observer is described in the second part. Rather than being driven by the output of the pharmacokinetic model, the observer can be driven exclusively by a concentration collected from a suitable part of the body and predict the possible risk of the drug concentration not remaining within the therapeutic range for a sufficiently long time. Specifically, the observer determines the upper and lower limits of the concentrations in all the compartments, especially those that are inaccessible for the collection of samples. The proposed approaches are demonstrated by examples. Full article
(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)
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Article
Pharmacokinetics of Tildipirosin in Plasma, Milk, and Somatic Cells Following Intravenous, Intramuscular, and Subcutaneous Administration in Dairy Goats
Pharmaceutics 2022, 14(4), 860; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040860 - 13 Apr 2022
Viewed by 422
Abstract
Tildipirosin is a macrolide currently authorized for treating respiratory diseases in cattle and swine. The disposition kinetics of tildipirosin in plasma, milk, and somatic cells were investigated in dairy goats. Tildipirosin was administered at a single dose of 2 mg/kg by intravenous (IV) [...] Read more.
Tildipirosin is a macrolide currently authorized for treating respiratory diseases in cattle and swine. The disposition kinetics of tildipirosin in plasma, milk, and somatic cells were investigated in dairy goats. Tildipirosin was administered at a single dose of 2 mg/kg by intravenous (IV) and 4 mg/kg by intramuscular (IM) and subcutaneous (SC) routes. Concentrations of tildipirosin were determined by an HPLC method with UV detection. Pharmacokinetic parameters were estimated by non-compartmental analysis. Muscle damage, cardiotoxicity, and inflammation were evaluated. After IV administration, the apparent volume of distribution in the steady state was 7.2 L/kg and clearance 0.64 L/h/kg. Plasma and milk half-lives were 6.2 and 58.3 h, respectively, indicating nine times longer persistence of tildipirosin in milk than in plasma. Moreover, if somatic cells are considered, persistence and exposure measured by the area under concentration–time curve (AUC) significantly exceeded those obtained in plasma. Similarly, longer half-lives in whole milk and somatic cells compared to plasma were observed after IM and SC administration. No adverse effects were observed. In brief, tildipirosin should be reserved for cases where other suitable antibiotics have been unsuccessful, discarding milk production of treated animals for at least 45 days or treating goats at the dry-off period. Full article
(This article belongs to the Special Issue Specific Drug Disposition in Veterinary Medicine)
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Article
Puzzle out Machine Learning Model-Explaining Disintegration Process in ODTs
Pharmaceutics 2022, 14(4), 859; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040859 - 13 Apr 2022
Viewed by 538
Abstract
Tablets are the most common dosage form of pharmaceutical products. While tablets represent the majority of marketed pharmaceutical products, there remain a significant number of patients who find it difficult to swallow conventional tablets. Such difficulties lead to reduced patient compliance. Orally disintegrating [...] Read more.
Tablets are the most common dosage form of pharmaceutical products. While tablets represent the majority of marketed pharmaceutical products, there remain a significant number of patients who find it difficult to swallow conventional tablets. Such difficulties lead to reduced patient compliance. Orally disintegrating tablets (ODT), sometimes called oral dispersible tablets, are the dosage form of choice for patients with swallowing difficulties. ODTs are defined as a solid dosage form for rapid disintegration prior to swallowing. The disintegration time, therefore, is one of the most important and optimizable critical quality attributes (CQAs) for ODTs. Current strategies to optimize ODT disintegration times are based on a conventional trial-and-error method whereby a small number of samples are used as proxies for the compliance of whole batches. We present an alternative machine learning approach to optimize the disintegration time based on a wide variety of machine learning (ML) models through the H2O AutoML platform. ML models are presented with inputs from a database originally presented by Han et al., which was enhanced and curated to include chemical descriptors representing active pharmaceutical ingredient (API) characteristics. A deep learning model with a 10-fold cross-validation NRMSE of 8.1% and an R2 of 0.84 was obtained. The critical parameters influencing the disintegration of the directly compressed ODTs were ascertained using the SHAP method to explain ML model predictions. A reusable, open-source tool, the ODT calculator, is now available at Heroku platform. Full article
(This article belongs to the Special Issue Computational Intelligence (CI) Tools in Drug Discovery and Design)
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Article
Dual Stimuli-Responsive Multifunctional Silicon Nanocarriers for Specifically Targeting Mitochondria in Human Cancer Cells
Pharmaceutics 2022, 14(4), 858; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040858 - 13 Apr 2022
Viewed by 680
Abstract
Specific targeting, selective stimuli-responsiveness, and controlled release of anticancer agents are requested for high therapeutic efficiency with a minimal adverse effect. Herein, we report the sophisticated synthesis and functionalization of fluorescent mesoporous silicon (FMPSi) nanoparticles decorated with graphene oxide (GO) nanosheets. GO-wrapped FMPSi [...] Read more.
Specific targeting, selective stimuli-responsiveness, and controlled release of anticancer agents are requested for high therapeutic efficiency with a minimal adverse effect. Herein, we report the sophisticated synthesis and functionalization of fluorescent mesoporous silicon (FMPSi) nanoparticles decorated with graphene oxide (GO) nanosheets. GO-wrapped FMPSi ([email protected]) was loaded with a cisplatin (Cis) anticancer agent, and Cis-loaded [email protected] ([email protected]) exhibited the dual stimuli (pH and NIR)-responsiveness of controlled drug release, i.e., the drug release rate was distinctly enhanced at acidic pH 5.5 than at neutral pH 7.0 and further enhanced under NIR irradiation at acidic pH condition. Notably, dequalinium-conjugated [email protected] ([email protected]@DQA) demonstrated an excellent specificity for mitochondrial targeting in cancer cells without noticeable toxicity to normal human cells. Our novel silicon nanocarriers demonstrated not only stimuli (pH and NIR)-responsive controlled drug release, but also selective accumulation in the mitochondria of cancer cells and destroying them. Full article
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