Pharmaceutics

Open AccessArticle

New Lidocaine-Based Pharmaceutical Cocrystals: Preparation, Characterization, and Influence of the Racemic vs. Enantiopure Coformer on the Physico-Chemical Properties

by

Panpan Ma

,

Balthazar Toussaint

,

Enrica Angela Roberti

,

Noémie Scornet

,

Axel Santos Silva

,

Luis Castillo Henríquez

,

,

,

,

,

,

,

Maria Cristina Gamberini

,

,

,

,

and

Pharmaceutics 2023, 15(4), 1102; https://doi.org/10.3390/pharmaceutics15041102 (registering DOI) - 29 Mar 2023

Abstract

This study describes the preparation, characterization, and influence of the enantiopure vs. racemic coformer on the physico-chemical properties of a pharmaceutical cocrystal. For that purpose, two new 1:1 cocrystals, namely lidocaine:dl-menthol and lidocaine:d-menthol, were prepared. The menthol racemate-based cocrystal [...] Read more.

This study describes the preparation, characterization, and influence of the enantiopure vs. racemic coformer on the physico-chemical properties of a pharmaceutical cocrystal. For that purpose, two new 1:1 cocrystals, namely lidocaine:dl-menthol and lidocaine:d-menthol, were prepared. The menthol racemate-based cocrystal was evaluated by means of X-ray diffraction, infrared spectroscopy, Raman, thermal analysis, and solubility experiments. The results were exhaustively compared with the first menthol-based pharmaceutical cocrystal, i.e., lidocaine:l-menthol, discovered in our group 12 years ago. Furthermore, the stable lidocaine/dl-menthol phase diagram has been screened, thoroughly evaluated, and compared to the enantiopure phase diagram. Thus, it has been proven that the racemic vs. enantiopure coformer leads to increased solubility and improved dissolution of lidocaine due to the low stable form induced by menthol molecular disorder in the lidocaine:dl-menthol cocrystal. To date, the 1:1 lidocaine:dl-menthol cocrystal is the third menthol-based pharmaceutical cocrystal, after the 1:1 lidocaine:l-menthol and the 1:2 lopinavir:l-menthol cocrystals reported in 2010 and 2022, respectively. Overall, this study shows promising potential for designing new materials with both improved characteristics and functional properties in the fields of pharmaceutical sciences and crystal engineering. Full article

(This article belongs to the Special Issue Advances in Pharmaceutical Solid Forms)

► Show Figures

Figure 1

Open AccessArticle

Liposomal Forms of Fluoroquinolones and Antifibrotics Decorated with Mannosylated Chitosan for Inhalation Drug Delivery

by

,

,

,

,

,

,

and

Pharmaceutics 2023, 15(4), 1101; https://doi.org/10.3390/pharmaceutics15041101 (registering DOI) - 29 Mar 2023

Abstract

The severe course of COVID-19 leads to the long-terming pulmonary diseases, such as bacterial pneumonia and post-COVID-19 pulmonary fibrosis. Thus, the essential task of biomedicine is a design of new effective drug formulations, including those for inhalation administration. In this work, we propose [...] Read more.

The severe course of COVID-19 leads to the long-terming pulmonary diseases, such as bacterial pneumonia and post-COVID-19 pulmonary fibrosis. Thus, the essential task of biomedicine is a design of new effective drug formulations, including those for inhalation administration. In this work, we propose an approach to the creation of lipid–polymer delivery systems for fluoroquinolones and pirfenidone based on liposomes of various compositions decorated with mucoadhesive mannosylated chitosan. A generalizing study on the physicochemical patterns of the interactions of drugs with bilayers of various compositions was carried out, and the main binding sites were identified. The role of the polymer shell in the stabilization of vesicles and the delayed release of the contents has been demonstrated. For the liquid–polymer formulation of moxifloxacin, a prolonged accumulation of the drug in lung tissues was found after a single endotracheal administration to mice, significantly exceeding the control intravenous and endotracheal administration of the drug. Full article

(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)

► Show Figures

Graphical abstract

Open AccessReview

Novel Developments to Enable Treatment of CNS Diseases with Targeted Drug Delivery

by

,

,

,

,

Ramakrishna Venugopalan

and

Didier R. Lefebvre

Pharmaceutics 2023, 15(4), 1100; https://doi.org/10.3390/pharmaceutics15041100 (registering DOI) - 29 Mar 2023

Abstract

The blood-brain barrier (BBB) is a major hurdle for the development of systemically delivered drugs against diseases of the central nervous system (CNS). Because of this barrier there is still a huge unmet need for the treatment of these diseases, despite years of [...] Read more.

The blood-brain barrier (BBB) is a major hurdle for the development of systemically delivered drugs against diseases of the central nervous system (CNS). Because of this barrier there is still a huge unmet need for the treatment of these diseases, despite years of research efforts across the pharmaceutical industry. Novel therapeutic entities, such as gene therapy and degradomers, have become increasingly popular in recent years, but have not been the focus for CNS indications so far. To unfold their full potential for the treatment of CNS diseases, these therapeutic entities will most likely have to rely on innovative delivery technologies. Here we will describe and assess approaches, both invasive and non-invasive, that can enable, or at least increase, the probability of a successful drug development of such novel therapeutics for CNS indications. Full article

(This article belongs to the Special Issue Emerging Trends and Translational Challenges in Drug and Vaccine Delivery)

Open AccessArticle

Influence of Silver Nanoparticles on the Growth of Ascitic and Solid Ehrlich Adenocarcinoma: Focus on Copper Metabolism

by

Daria N. Magazenkova

,

Ekaterina A. Skomorokhova

,

,

,

,

,

,

and

Ekaterina Y. Ilyechova

Pharmaceutics 2023, 15(4), 1099; https://doi.org/10.3390/pharmaceutics15041099 (registering DOI) - 29 Mar 2023

Abstract

The link between copper metabolism and tumor progression motivated us to use copper chelators for suppression of tumor growth. We assume that silver nanoparticles (AgNPs) can be used for lowering bioavailable copper. Our assumption is based on the ability of Ag(I) ions released [...] Read more.

The link between copper metabolism and tumor progression motivated us to use copper chelators for suppression of tumor growth. We assume that silver nanoparticles (AgNPs) can be used for lowering bioavailable copper. Our assumption is based on the ability of Ag(I) ions released by AgNPs in biological media and interfere with Cu(I) transport. Intervention of Ag(I) into copper metabolism leads to the replacement of copper by silver in ceruloplasmin and the decrease in bioavailable copper in the bloodstream. To check this assumption, mice with ascitic or solid Ehrlich adenocarcinoma (EAC) were treated with AgNPs using different protocols. Copper status indexes (copper concentration, ceruloplasmin protein level, and oxidase activity) were monitored to assess copper metabolism. The expression of copper-related genes was determined by real-time PCR in the liver and tumors, and copper and silver levels were measured by FAAS. Intraperitoneal AgNPs treatment beginning on the day of tumor inoculation enhanced mice survival, reduced the proliferation of ascitic EAC cells, and suppressed the activity of HIF1α, TNF-α and VEGFa genes. Topical treatment by the AgNPs, which was started together with the implantation of EAC cells in the thigh, also enhanced mice survival, decreased tumor growth, and repressed genes responsible for neovascularization. The advantages of silver-induced copper deficiency over copper chelators are discussed. Full article

(This article belongs to the Special Issue Metal-Based Prodrugs and Nanoparticles in Cancer Therapy)

► Show Figures

Graphical abstract

Open AccessArticle

Effect of Ionic Liquid on Silver-Nanoparticle-Complexed Ganoderma applanatum and Its Topical Film Formulation

by

Pattwat Maneewattanapinyo

,

,

,

,

and

Jirapornchai Suksaeree

Pharmaceutics 2023, 15(4), 1098; https://doi.org/10.3390/pharmaceutics15041098 (registering DOI) - 29 Mar 2023

Abstract

Imidazolium-based ionic liquids have been widely utilized as versatile solvents for metal nanoparticle preparation. Silver nanoparticles and Ganoderma applanatum have displayed potent antimicrobial activities. This work aimed to study the effect of 1-butyl-3-methylimidazolium bromide-based ionic liquid on the silver-nanoparticle-complexed G. applanatum and its [...] Read more.

Imidazolium-based ionic liquids have been widely utilized as versatile solvents for metal nanoparticle preparation. Silver nanoparticles and Ganoderma applanatum have displayed potent antimicrobial activities. This work aimed to study the effect of 1-butyl-3-methylimidazolium bromide-based ionic liquid on the silver-nanoparticle-complexed G. applanatum and its topical film. The ratio and conditions for preparation were optimized by the design of the experiments. The optimal ratio was silver nanoparticles: G. applanatum extract: ionic liquid at 97:1:2, and the conditions were 80 °C for 1 h. The prediction was corrected with a low percentage error. The optimized formula was loaded into a topical film made of polyvinyl alcohol and Eudragit^®, and its properties were evaluated. The topical film was uniform, smooth, and compact and had other desired characteristics. The topical film was able to control the release of silver-nanoparticle-complexed G. applanatum from the matrix layer. Higuchi’s model was used to fit the kinetic of the release. The skin permeability of the silver-nanoparticle-complexed G. applanatum was improved by about 1.7 times by the ionic liquid, which might increase solubility. The produced film is suitable for topical applications and may be utilized in the development of potential future therapeutic agents for the treatment of diseases. Full article

(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)

► Show Figures

Figure 1

Open AccessArticle

Poly(N-Vinylcaprolactam)–Gold Nanorods–5 Fluorouracil Hydrogels: In the Quest of a Material for Topical Therapies against Melanoma Skin Cancer

by

Mirian A. González-Ayón

,

Alondra Rochin-Galaviz

,

Arturo Zizumbo-López

and

Angel Licea-Claverie

Pharmaceutics 2023, 15(4), 1097; https://doi.org/10.3390/pharmaceutics15041097 (registering DOI) - 29 Mar 2023

Abstract

Chemically crosslinked hydrogels based on poly(N-vinylcaprolactam) (PNVCL) were synthetized by a photoinitiated chemical method. A galactose-based monomer, 2-lactobionamidoethyl methacrylate (LAMA), and N-vinylpyrrolidone (NVP) were added with the aim to improve the physical and chemical properties of hydrogels. The effects of [...] Read more.

Chemically crosslinked hydrogels based on poly(N-vinylcaprolactam) (PNVCL) were synthetized by a photoinitiated chemical method. A galactose-based monomer, 2-lactobionamidoethyl methacrylate (LAMA), and N-vinylpyrrolidone (NVP) were added with the aim to improve the physical and chemical properties of hydrogels. The effects of both comonomers on the swelling ratio (Q), volume phase transition temperature (VPTT), glass transition temperature (T_g), and Young’s moduli by mechanical compression below and above the VPTT were studied. Gold nanorods (GNRDs) and 5-fluorouracil (5FU) were embedded into the hydrogels, to study the drug release profiles with and without the excitation of GNRDs by irradiation in the near-infrared region (NIR). Results showed that the addition of LAMA and NVP increased the hydrogels’ hydrophilicity, elasticity, and VPTT. The loading of GNRDs in the hydrogels changed the release rate of 5FU when irradiated intermittently with an NIR laser. The present study reports on the preparation of a hydrogel-based platform of PNVCL-GNRDs−5FU as a potential hybrid anticancer hydrogel for chemo/photothermal therapy that could be applied against skin cancer for topical 5FU delivery. Full article

(This article belongs to the Special Issue Advanced Bio-Hybrid Materials for Drug Delivery Systems - New Trends and Perspectives)

► Show Figures

Figure 1

Open AccessArticle

Neuroprotective Nanoparticles Targeting the Retina: A Polymeric Platform for Ocular Drug Delivery Applications

by

,

,

,

,

,

and

Pharmaceutics 2023, 15(4), 1096; https://doi.org/10.3390/pharmaceutics15041096 (registering DOI) - 29 Mar 2023

Abstract

Neuroprotective drug delivery to the posterior segment of the eye represents a major challenge to counteract vision loss. This work focuses on the development of a polymer-based nanocarrier, specifically designed for targeting the posterior eye. Polyacrylamide nanoparticles (ANPs) were synthesised and characterised, and [...] Read more.

Neuroprotective drug delivery to the posterior segment of the eye represents a major challenge to counteract vision loss. This work focuses on the development of a polymer-based nanocarrier, specifically designed for targeting the posterior eye. Polyacrylamide nanoparticles (ANPs) were synthesised and characterised, and their high binding efficiency was exploited to gain both ocular targeting and neuroprotective capabilities, through conjugation with peanut agglutinin (ANP:PNA) and neurotrophin nerve growth factor (ANP:PNA:NGF). The neuroprotective activity of ANP:PNA:NGF was assessed in an oxidative stress-induced retinal degeneration model using the teleost zebrafish. Upon nanoformulation, NGF improved the visual function of zebrafish larvae after the intravitreal injection of hydrogen peroxide, accompanied by a reduction in the number of apoptotic cells in the retina. Additionally, ANP:PNA:NGF counteracted the impairment of visual behaviour in zebrafish larvae exposed to cigarette smoke extract (CSE). Collectively, these data suggest that our polymeric drug delivery system represents a promising strategy for implementing targeted treatment against retinal degeneration. Full article

(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery—Volume II)

► Show Figures

Figure 1

Open AccessArticle

In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein

by

Gabriel Rodrigues Coutinho Pereira

,

Bárbara de Azevedo Abrahim-Vieira

and

Joelma Freire de Mesquita

Pharmaceutics 2023, 15(4), 1095; https://doi.org/10.3390/pharmaceutics15041095 (registering DOI) - 29 Mar 2023

Abstract

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, SOD1 binding ligand 1 (SBL-1) was shown to inhibit in vitro the oxidation of a critical residue for SOD1 aggregation, which is a central event in ALS-related neurodegeneration. In this work, we investigated the interactions between SOD1 wild-type and its most frequent variants, i.e., A4V (NP_000445.1:p.Ala5Val) and D90A (NP_000445.1:p.Asp91Val), with SBL-1 using molecular dynamics (MD) simulations. The pharmacokinetics and toxicological profile of SBL-1 were also characterized in silico. The MD results suggest that the complex SOD1-SBL-1 remains relatively stable and interacts within a close distance during the simulations. This analysis also suggests that the mechanism of action proposed by SBL-1 and its binding affinity to SOD1 may be preserved upon mutations A4V and D90A. The pharmacokinetics and toxicological assessments suggest that SBL-1 has drug-likeness characteristics with low toxicity. Our findings, therefore, suggested that SBL-1 may be a promising strategy to treat ALS based on an unprecedented mechanism, including for patients with these frequent mutations. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

► Show Figures

Figure 1

Open AccessReview

Revolutionizing Treatment for Posterior Segment Diseases with Biodegradable Nano-Based Drug Delivery System

by

,

,

and

Pharmaceutics 2023, 15(4), 1094; https://doi.org/10.3390/pharmaceutics15041094 (registering DOI) - 29 Mar 2023

Abstract

Posterior segment eye diseases present a challenge in treatment due to the complex structures in the eye that serve as robust static and dynamic barriers, limiting the penetration, residence time, and bioavailability of topical and intraocular medications. This hinders effective treatment and requires [...] Read more.

Posterior segment eye diseases present a challenge in treatment due to the complex structures in the eye that serve as robust static and dynamic barriers, limiting the penetration, residence time, and bioavailability of topical and intraocular medications. This hinders effective treatment and requires frequent dosing, such as the regular use of eye drops or visits to the ophthalmologist for intravitreal injections, to manage the disease. Moreover, the drugs must be biodegradable to minimize toxicity and adverse reactions, as well as small enough to not affect the visual axis. The development of biodegradable nano-based drug delivery systems (DDSs) can be the solution to these challenges. First, they can stay in ocular tissues for longer periods of time, reducing the frequency of drug administration. Second, they can pass through ocular barriers, offering higher bioavailability to targeted tissues that are otherwise inaccessible. Third, they can be made up of polymers that are biodegradable and nanosized. Hence, therapeutic innovations in biodegradable nanosized DDS have been widely explored for ophthalmic drug delivery applications. In this review, we will present a concise overview of DDSs utilized in the treatment of ocular diseases. We will then examine the current therapeutic challenges faced in the management of posterior segment diseases and explore how various types of biodegradable nanocarriers can enhance our therapeutic arsenal. A literature review of the pre-clinical and clinical studies published between 2017 and 2023 was conducted. Through the advances in biodegradable materials, combined with a better understanding of ocular pharmacology, the nano-based DDSs have rapidly evolved, showing great promise to overcome challenges currently encountered by clinicians. Full article

(This article belongs to the Special Issue Biodegradable Formulations for Ocular Drug Delivery)

► Show Figures

Figure 1

Open AccessArticle

Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α Axis

by

,

,

,

,

,

,

,

,

and

Pharmaceutics 2023, 15(4), 1093; https://doi.org/10.3390/pharmaceutics15041093 (registering DOI) - 29 Mar 2023

Abstract

Liver cancer, consisting mainly of hepatocellular carcinoma, is the third leading cause of cancer-related mortality worldwide. Despite advances in targeted therapies, these approaches remain insufficient in meeting the pressing clinical demands. Here, we present a novel alternative that calls for a non-apoptotic program [...] Read more.

Liver cancer, consisting mainly of hepatocellular carcinoma, is the third leading cause of cancer-related mortality worldwide. Despite advances in targeted therapies, these approaches remain insufficient in meeting the pressing clinical demands. Here, we present a novel alternative that calls for a non-apoptotic program to solve the current dilemma. Specifically, we identified that tubeimoside 2 (TBM-2) could induce methuosis in hepatocellular carcinoma cells, a recently recognized mode of cell death characterized by pronounced vacuolization, necrosis-like membrane disruption, and no response to caspase inhibitors. Further proteomic analysis revealed that TBM-2-driven methuosis is facilitated by the hyperactivation of the MKK4–p38α axis and the boosted lipid metabolism, especially cholesterol biosynthesis. Pharmacological interventions targeting either the MKK4–p38α axis or cholesterol biosynthesis effectively suppress TBM-2-induced methuosis, highlighting the pivotal role of these mechanisms in TBM-2-mediated cell death. Moreover, TBM-2 treatment effectively suppressed tumor growth by inducing methuosis in a xenograft mouse model of hepatocellular carcinoma. Taken together, our findings provide compelling evidence of TBM-2’s remarkable tumor-killing effects by inducing methuosis, both in vitro and in vivo. TBM-2 represents a promising avenue for the development of innovative and effective therapies for hepatocellular carcinoma, one that may ultimately offer significant clinical benefits for patients with this devastating disease. Full article

► Show Figures

Graphical abstract

Open AccessReview

The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure Management: The Continuing Challenge of Clinical Outcome Endpoints in Heart Failure Trials

by

Luxi Ji

,

Mudit Mishra

and

Bart De Geest

Pharmaceutics 2023, 15(4), 1092; https://doi.org/10.3390/pharmaceutics15041092 (registering DOI) - 29 Mar 2023

Abstract

The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the management of heart failure with preserved ejection fraction (HFpEF) may be regarded as the first effective treatment in these patients. However, this proposition must be evaluated from the perspective of the complexity of clinical [...] Read more.

The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the management of heart failure with preserved ejection fraction (HFpEF) may be regarded as the first effective treatment in these patients. However, this proposition must be evaluated from the perspective of the complexity of clinical outcome endpoints in heart failure. The major goals of heart failure treatment have been categorized as: (1) reduction in (cardiovascular) mortality, (2) prevention of recurrent hospitalizations due to worsening heart failure, and (3) improvement in clinical status, functional capacity, and quality of life. The use of the composite primary endpoint of cardiovascular death and hospitalization for heart failure in SGLT2 inhibitor HFpEF trials flowed from the assumption that hospitalization for heart failure is a proxy for subsequent cardiovascular death. The use of this composite endpoint was not justified since the effect of the intervention on both components was clearly distinct. Moreover, the lack of convincing and clinically meaningful effects of SGLT2 inhibitors on metrics of heart failure-related health status indicates that the effect of this class of drugs in HFpEF patients is essentially restricted to an effect on hospitalization for heart failure. In conclusion, SGLT2 inhibitors do not represent a substantial breakthrough in the management of HFpEF. Full article

Open AccessReview

Intrastromal Injections in the Management of Infectious Keratitis

by

Mihail Zemba

,

Madalina Radu

,

Sinziana Istrate

,

Otilia-Maria Dumitrescu

,

Mihai Alexandru Ionescu

,

Andrei Vatafu

and

Ileana Ramona Barac

Pharmaceutics 2023, 15(4), 1091; https://doi.org/10.3390/pharmaceutics15041091 - 29 Mar 2023

Abstract

Infectious keratitis is a major global cause of vision loss and blindness. Prompt diagnosis and targeted antibiotic treatment are crucial for managing the condition. Topical antimicrobials are the most effective therapy for bacterial keratitis, but they can lead to unsatisfactory results due to [...] Read more.

Infectious keratitis is a major global cause of vision loss and blindness. Prompt diagnosis and targeted antibiotic treatment are crucial for managing the condition. Topical antimicrobials are the most effective therapy for bacterial keratitis, but they can lead to unsatisfactory results due to ocular perforation, scarring, and melting. Intrastromal injection is a newer technique for delivering antimicrobials directly to the site of infection and has been successful in treating severe, treatment-resistant infectious keratitis, especially when surgery is not recommended. In cases where deep stromal disease is resistant to topical treatment, intrastromal antimicrobial injections may be necessary to achieve higher drug concentration at the infection site. However, the use of intrastromal antibiotics is limited, as topical antibacterial agents have better penetration than antifungal agents. Bacterial and fungal keratitis have been extensively researched for intrastromal medication injections, while there is limited evidence for viral keratitis. This review emphasizes the potential of intrastromal antimicrobial injections as an alternative for managing severe refractory infectious keratitis. The technique offers direct targeting of the infection site and faster resolution in some cases compared to topical therapy. However, further research is needed to determine the safest antimicrobials options, minimal effective doses, and concentrations for various pathogens. Intrastromal injections may serve as a non-surgical treatment option in high-risk cases, with benefits including direct drug delivery and reduced epithelial toxicity. Despite promising findings, more studies are required to confirm the safety and efficacy of this approach. Full article

(This article belongs to the Special Issue Recent Advances in Prevention and Treatment of Infectious Diseases)

Open AccessArticle

Synergistic Effect of Thermoresponsive and Photocuring Methacrylated Chitosan-Based Hybrid Hydrogels for Medical Applications

by

,

,

,

,

and

Pharmaceutics 2023, 15(4), 1090; https://doi.org/10.3390/pharmaceutics15041090 - 29 Mar 2023

Abstract

The thermoresponsive drug-loaded hydrogels have attracted widespread interest in the field of medical applications due to their ease of delivery to structurally complex tissue defects. However, drug-resistant infections remain a challenge, which has prompted the development of new non-antibiotic hydrogels. To this end, [...] Read more.

The thermoresponsive drug-loaded hydrogels have attracted widespread interest in the field of medical applications due to their ease of delivery to structurally complex tissue defects. However, drug-resistant infections remain a challenge, which has prompted the development of new non-antibiotic hydrogels. To this end, we prepared chitosan-methacrylate (CTSMA)/gelatin (GEL) thermoresponsive hydrogels and added natural phenolic compounds, including tannic acid, gallic acid, and pyrogallol, to improve the efficacy of hydrogels. This hybrid hydrogel imparted initial crosslinking at physiological temperature, followed by photocuring to further provide a mechanically robust structure. Rheological analysis, tensile strength, antibacterial activity against E. coli, S. aureus, P. gingivalis, and S. mutans, and L929 cytotoxicity were evaluated. The experimental results showed that the hybrid hydrogel with CTSMA/GEL ratio of 5/1 and tannic acid additive had a promising gelation temperature of about 37 °C. The presence of phenolic compounds not only significantly (p < 0.05) enhanced cell viability, but also increased the tensile strength of CTSMA/GEL hybrid hydrogels. Moreover, the hydrogel containing tannic acid revealed potent antibacterial efficacy against four microorganisms. It was concluded that the hybrid hydrogel containing tannic acid could be a potential composite material for medical applications. Full article

(This article belongs to the Special Issue Chitosan Nanoparticles in Drug Delivery 2022)

► Show Figures

Figure 1

Open AccessArticle

Dried Blood Spot Sampling to Assess Rifampicin Exposure and Treatment Outcomes among Native and Non-Native Tuberculosis Patients in Paraguay: An Exploratory Study

by

,

,

,

,

,

,

Jan-Willem C. Alffenaar

,

Marieke G. G. Sturkenboom

and

Cecile Magis-Escurra

Pharmaceutics 2023, 15(4), 1089; https://doi.org/10.3390/pharmaceutics15041089 - 29 Mar 2023

Abstract

The aim of this study was to evaluate the difference in drug exposure of rifampicin in native versus non-native Paraguayan populations using dried blood spots (DBS) samples collected utilizing a limited sampling strategy. This was a prospective pharmacokinetic study that enrolled hospitalized tuberculosis [...] Read more.

The aim of this study was to evaluate the difference in drug exposure of rifampicin in native versus non-native Paraguayan populations using dried blood spots (DBS) samples collected utilizing a limited sampling strategy. This was a prospective pharmacokinetic study that enrolled hospitalized tuberculosis (TB) patients from both native and non-native populations receiving oral rifampicin 10 mg/kg once-daily dosing. Steady-state DBS samples were collected at 2, 4, and 6 h after intake of rifampicin. The area under the time concentration curve 0–24 h (AUC_0–24) was calculated using a Bayesian population PK model. Rifampicin AUC_0–24 < 38.7 mg*h/L was considered as low. The probability of target attainment (PTA) was calculated using AUC_0–24/MIC > 271 as a target and estimated MIC values of 0.125 and 0.25 mg/L. In total, 50 patients were included. Native patients (n = 30) showed comparable drug exposure to the non-natives (n = 20), median AUC_0–24 24.7 (17.1–29.5 IQR) and 21.6 (15.0–35.4 IQR) mg*h/L (p = 0.66), respectively. Among total patients, only 16% (n = 8) had a rifampicin AUC_0–24 > 38.7 mg*h/L. Furthermore, PTA analysis showed that only 12 (24%) of the patients met a target AUC_0–24 /MIC ≥ 271, assuming an MIC of 0.125 mg/L, which plummeted to 0% at a wild-type MIC of 0.25 mg/L. We successfully used DBS and limited sampling for the AUC_0–24 estimation of rifampicin. Currently, our group, the EUSAT-RCS consortium, is preparing a prospective multinational, multicenter phase IIb clinical trial evaluating the safety and efficacy of high-dose rifampicin (35 mg/kg) in adult subjects using the DBS technique for AUC_0–24 estimation. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy)

► Show Figures

Figure 1

Open AccessArticle

Modulation of the Cytotoxic Properties of Pd(II) Complexes Based on Functionalized Carboxamides Featuring Labile Phosphoryl Coordination Sites

by

Diana V. Aleksanyan

,

Aleksandr V. Konovalov

,

Svetlana G. Churusova

,

Ekaterina Yu. Rybalkina

,

Alexander S. Peregudov

,

Svetlana A. Aksenova

,

Evgenii I. Gutsul

,

Zinaida S. Klemenkova

and

Vladimir A. Kozlov

Pharmaceutics 2023, 15(4), 1088; https://doi.org/10.3390/pharmaceutics15041088 - 28 Mar 2023

Abstract

Platinum-based drugs are commonly recognized as a keystone in modern cancer chemotherapy. However, intrinsic and acquired resistance as well as serious side effects often caused by the traditional Pt(II) anticancer agents prompt a continuous search for more selective and efficient alternatives. Today, significant [...] Read more.

Platinum-based drugs are commonly recognized as a keystone in modern cancer chemotherapy. However, intrinsic and acquired resistance as well as serious side effects often caused by the traditional Pt(II) anticancer agents prompt a continuous search for more selective and efficient alternatives. Today, significant attention is paid to the compounds of other transition metals, in particular those of palladium. Recently, our research group has suggested functionalized carboxamides as a useful platform for the creation of cytotoxic Pd(II) pincer complexes. In this work, a robust picolinyl- or quinoline-carboxamide core was combined with a phosphoryl ancillary donor group to achieve hemilabile coordination capable of providing the required level of thermodynamic stability and kinetic lability of the ensuing Pd(II) complexes. Several cyclopalladated derivatives featuring either a bi- or tridentate pincer-type coordination mode of the deprotonated phosphoryl-functionalized amides were selectively synthesized and fully characterized using IR and NMR spectroscopy as well as X-ray crystallography. The preliminary evaluation of the anticancer potential of the resulting palladocycles revealed a strong dependence of their cytotoxic properties on the binding mode of the deprotonated amide ligands and demonstrated certain advantages of the pincer-type ligation. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy (Volume II))

► Show Figures

Graphical abstract

Open AccessArticle

Mineralization of Bone Extracellular Matrix-like Scaffolds Fabricated as Silk Sericin-Functionalized Dense Collagen–Fibrin Hybrid Hydrogels

by

Gabriele Griffanti

,

Marc D. McKee

and

Showan N. Nazhat

Pharmaceutics 2023, 15(4), 1087; https://doi.org/10.3390/pharmaceutics15041087 - 28 Mar 2023

Abstract

The design of hydrogels that combine both the biochemical cues needed to direct seeded cellular functions and mineralization to provide the structural and mechanical properties approaching those of mineralized native bone extracellular matrix (ECM) represents a significant challenge in bone tissue engineering. While [...] Read more.

The design of hydrogels that combine both the biochemical cues needed to direct seeded cellular functions and mineralization to provide the structural and mechanical properties approaching those of mineralized native bone extracellular matrix (ECM) represents a significant challenge in bone tissue engineering. While fibrous hydrogels constituting of collagen or fibrin (and their hybrids) can be considered as scaffolds that mimic to some degree native bone ECM, their insufficient mechanical properties limit their application. In the present study, an automated gel aspiration–ejection (automated GAE) method was used to generate collagen–fibrin hybrid gel scaffolds with micro-architectures and mechanical properties approaching those of native bone ECM. Moreover, the functionalization of these hybrid scaffolds with negatively charged silk sericin accelerated their mineralization under acellular conditions in simulated body fluid and modulated the proliferation and osteoblastic differentiation of seeded MC3T3-E1 pre-osteoblastic cells. In the latter case, alkaline phosphatase activity measurements indicated that the hybrid gel scaffolds with seeded cells showed accelerated osteoblastic differentiation, which in turn led to increased matrix mineralization. In summary, the design of dense collagen–fibrin hybrid gels through an automated GAE process can provide a route to tailoring specific biochemical and mechanical properties to different types of bone ECM-like scaffolds, and can provide a model to better understand cell–matrix interactions in vitro for bioengineering purposes. Full article

(This article belongs to the Special Issue Biomolecule-Based Supramolecular Hydrogels for Biomedical Applications: The Current Trends)

► Show Figures

Figure 1

Open AccessReview

ApoE Mimetic Peptides to Improve the Vicious Cycle of Malnutrition and Enteric Infections by Targeting the Intestinal and Blood-Brain Barriers

by

Reinaldo B. Oriá

,

Raul S. Freitas

,

Cássia R. Roque

,

José Carlos R. Nascimento

,

Ana Paula P. S. Martins

,

João O. Malva

,

Richard L. Guerrant

and

Michael P. Vitek

Pharmaceutics 2023, 15(4), 1086; https://doi.org/10.3390/pharmaceutics15041086 - 28 Mar 2023

Abstract

Apolipoprotein E (apoE) mimetic peptides are engineered fragments of the native apoE protein’s LDL-receptor binding site that improve the outcomes following a brain injury and intestinal inflammation in a variety of models. The vicious cycle of enteric infections and malnutrition is closely related [...] Read more.

Apolipoprotein E (apoE) mimetic peptides are engineered fragments of the native apoE protein’s LDL-receptor binding site that improve the outcomes following a brain injury and intestinal inflammation in a variety of models. The vicious cycle of enteric infections and malnutrition is closely related to environmental-driven enteric dysfunction early in life, and such chronic inflammatory conditions may blunt the developmental trajectories of children with worrisome and often irreversible physical and cognitive faltering. This window of time for microbiota maturation and brain plasticity is key to protecting cognitive domains, brain health, and achieving optimal/full developmental potential. This review summarizes the potential role of promising apoE mimetic peptides to improve the function of the gut-brain axis, including targeting the blood-brain barrier in children afflicted with malnutrition and enteric infections. Full article

(This article belongs to the Special Issue Blood–Brain Barrier Drug Targeting: The Future of Brain Drug Development (Volume II))

► Show Figures

Figure 1

Open AccessArticle

MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis

by

,

,

,

,

,

,

,

,

,

,

and

Pharmaceutics 2023, 15(4), 1085; https://doi.org/10.3390/pharmaceutics15041085 - 28 Mar 2023

Abstract

Conventional chemotherapy for killing cancer cells using cytotoxic drugs suffers from low selectivity, significant toxicity, and a narrow therapeutic index. Hyper-specific targeted drugs achieve precise destruction of tumors by inhibiting molecular pathways that are critical to tumor growth. Myeloid cell leukemia 1 (MCL-1), [...] Read more.

Conventional chemotherapy for killing cancer cells using cytotoxic drugs suffers from low selectivity, significant toxicity, and a narrow therapeutic index. Hyper-specific targeted drugs achieve precise destruction of tumors by inhibiting molecular pathways that are critical to tumor growth. Myeloid cell leukemia 1 (MCL-1), an important pro-survival protein in the BCL-2 family, is a promising antitumor target. In this study, we chose to investigate the effects of S63845, a small-molecule inhibitor that targets MCL-1, on the normal hematopoietic system. A mouse model of hematopoietic injury was constructed, and the effects of the inhibitor on the hematopoietic system of mice were evaluated via routine blood tests and flow cytometry. The results showed that S63845 affected the hematopoiesis of various lineages in the early stage of action, causing extramedullary compensatory hematopoiesis in the myeloid and megakaryocytic lineages. The maturation of the erythroid lineage in the intramedullary and extramedullary segments was blocked to varying degrees, and both the intramedullary and extramedullary lymphoid lineages were inhibited. This study provides a complete description of the effects of MCL-1 inhibitor on the intramedullary and extramedullary hematopoietic lineages, which is important for the selection of combinations of antitumor drugs and the prevention of adverse hematopoiesis-related effects. Full article

(This article belongs to the Topic New Molecular Targets and Novel Strategies in Drug Development to Prevent Relapse in Acute Leukemia)

► Show Figures

Figure 1

Open AccessArticle

Chitosan Hydrogels Cross-Linked with Trimesic Acid for the Delivery of 5-Fluorouracil in Cancer Therapy

by

,

,

,

and

Pharmaceutics 2023, 15(4), 1084; https://doi.org/10.3390/pharmaceutics15041084 - 28 Mar 2023

Abstract

Chitosan exhibits unique properties making it a suitable material for drug delivery. Considering the rising popularity of hydrogels in this field, this work offers a comprehensive study of hydrogels constituted by chitosan and cross-linked with 1,3,5-benzene tricarboxylic acid (BTC; also known as trimesic [...] Read more.

Chitosan exhibits unique properties making it a suitable material for drug delivery. Considering the rising popularity of hydrogels in this field, this work offers a comprehensive study of hydrogels constituted by chitosan and cross-linked with 1,3,5-benzene tricarboxylic acid (BTC; also known as trimesic acid). Hydrogels were prepared by cross-linking chitosan with BTC in different concentrations. The nature of the gels was studied through oscillatory amplitude strain and frequency sweep tests within the linear viscoelastic region (LVE) limit. The flow curves of the gels revealed shear thinning behavior. High G′ values imply strong cross-linking with improved stability. The rheological tests revealed that the strength of the hydrogel network increased with the cross-linking degree. Hardness, cohesiveness, adhesiveness, compressibility, and elasticity of the gels were determined using a texture analyzer. The scanning electron microscopy (SEM) data of the cross-linked hydrogels showed distinctive pores with a pore size increasing according to increasing concentrations (pore size range between 3–18 µm). Computational analysis was performed by docking simulations between chitosan and BTC. Drug release studies employing 5-fluorouracil (5-FU) yielded a more sustained release profile with 35 to 50% release among the formulations studied in a 3 h period. Overall, this work demonstrated that the presence of BTC as cross-linker leads to satisfactory mechanical properties of the chitosan hydrogel, suggesting potential applications in the sustained release of cancer therapeutics. Full article

(This article belongs to the Special Issue Recent Advances in Long-Acting Drug Delivery and Formulations)

► Show Figures

Figure 1

Journal Description

Pharmaceutics

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI