Editor’s Choice Articles

This study focuses on how to define an Analytical Target Profile (ATP) which is intended for use in practice and on facilitating the selection of in vitro release test (IVRT) technology for diclofenac sodium topical hydrogel and cream. The implementation involves incorporating the new draft guidelines of the International Council for Harmonisation (ICH Q14) and USP (United States Pharmacopeia) Chapter 1220. Four IVRT apparatuses were compared (USP Apparatus II with immersion cell, USP Apparatus IV with semisolid adapter, static vertical diffusion cell, and a new, in-house-developed flow-through diffusion cell) with the help of the ATP. Performance characteristics such as accuracy, precision, cumulative amount released at the end of the IVRT experiment, and robustness were investigated. We found that the best apparatus for developing IVRT quality control (QC) tests in both cases was USP II with an immersion cell. All four different IVRT apparatuses were compared with each other and with the data found in the literature. Full article

The ranibizumab (RBZ) port delivery system (PDS) is a device designed to continuously deliver RBZ in the vitreous chamber for the treatment of neovascular age-related macular degeneration (nAMD). It is implanted during a surgical procedure and can provide sustained release of the medication for several months. This review, updated to January 2024, focuses on past clinical studies as well as current and forthcoming trials looking into a PDS with RBZ. In the phase 2 LADDER trial, the mean time to first refill of a PDS with RBZ 100 mg/mL was 15.8 months, with the pharmacokinetic (PK) profile showing a sustained concentration of RBZ in the blood and aqueous humor. More recently, a PDS with RBZ (100 mg/mL) refilled every 24 weeks was shown to be non-inferior to a monthly intravitreal injection (IVI) with RBZ (0.5 mg) over 40 and 92 weeks in the phase 3 ARCHWAY trial. The refill every 24 weeks allowed for a RBZ vitreous exposure within the concentration range of monthly intravitreal injections (IVIs), and the expected half-life (106 days) was comparable with the in vitro results. Nonetheless, vitreous hemorrhage and endophthalmitis were more common side effects in PDS patients. In conclusion, a PDS continuously delivering RBZ has a clinical effectiveness level comparable with IVI treatment. However, a greater frequency of unfavorable occurrences highlights the need for procedure optimization for a wider adoption. Ongoing trials and possible future approaches need to be addressed. Full article

Small Extracellular Vesicles (sEVs) are typically 30–150 nm in diameter, produced inside cells, and released into the extracellular space. These vesicles carry RNA, DNA, proteins, and lipids that reflect the characteristics of their parent cells, enabling communication between cells and the alteration of functions or differentiation of target cells. Owing to these properties, sEVs have recently gained attention as potential carriers for functional molecules and drug delivery tools. However, their use as a therapeutic platform faces limitations, such as challenges in mass production, purity issues, and the absence of established protocols and characterization methods. To overcome these, researchers are exploring the characterization and engineering of sEVs for various applications. This review discusses the origins of sEVs and their engineering for therapeutic effects, proposing areas needing intensive study. It covers the use of cell-derived sEVs in their natural state and in engineered forms for specific purposes. Additionally, the review details the sources of sEVs and their subsequent purification methods. It also outlines the potential of therapeutic sEVs and the requirements for successful clinical trials, including methods for large-scale production and purification. Finally, we discuss the progress of ongoing clinical trials and the implications for future healthcare, offering a comprehensive overview of the latest research in sEV applications. Full article

In recent years, the rapid emergence of antibiotic-resistant bacteria has become a significant concern in the healthcare field, and although bactericidal dressings loaded with various classes of antibiotics have been used in clinics, in addition to other anti-infective strategies, this alarming issue necessitates the development of innovative strategies to combat bacterial infections and promote wound healing. Electrospinning technology has gained significant attention as a versatile method for fabricating advanced wound dressings with enhanced functionalities. This work is based on the generation of polyvinylpyrrolidone (PVP)-based dressings through electrospinning, using a DomoBIO4A bioprinter, and incorporating graphene oxide (GO)/zinc oxide (ZnO) nanocomposites as a potent antibacterial agent. GO and ZnO nanoparticles offer unique properties, including broad-spectrum antibacterial activity for improved wound healing capabilities. The synthesis process was performed in an inexpensive one-pot reaction, and the nanocomposites were thoroughly characterized using XRD, TEM, EDX, SEM, EDS, and TGA. The antibacterial activity of the dispersions was demonstrated against E. coli and B. subtilis, Gram-negative and Gram-positive bacteria, respectively, using the well diffusion method and the spread plate method. Bactericidal mats were synthesized in a rapid and cost-effective manner, and the fiber-based structure of the electrospun dressings was studied by SEM. Evaluations of their antibacterial efficacy against E. coli and B. subtilis were explored by the disk-diffusion method, revealing an outstanding antibacterial capacity, especially against the Gram-positive strain. Overall, the findings of this research contribute to the development of next-generation wound dressings that effectively combat bacterial infections and pave the way for advanced therapeutic interventions in the field of wound care. Full article

Genistein (GEN) is an active pharmaceutical ingredient that presents the challenges of poor water solubility and low oral bioavailability. To tackle these challenges, a GEN solid dispersion was prepared by solvent rotary evaporation using polyvinylpyrrolidone K30 (PVP K30) as a carrier. The optimal formulation was determined by drug loading efficiency and in vitro release. The physical state of the solid dispersion was characterized by DSC, XRD, SEM and FT-IR. And the results of the in vitro release study indicate that the drug release of SD (1:7) increased 482-fold that of pure GEN at 60 min. Following oral administration to rats, the C_max and AUC_0–24 of SD (1:7) was increased 6.86- and 2.06-fold to that of pure GEN. The adipose fat index and body weight of the SD (1:7) group were significantly lower than those of the GEN group (p < 0.05). Meanwhile, the levels of TC and TG in the serum were significantly decreased in the SD (1:7) group compared with the GEN group (p < 0.05). All experiments revealed that solid dispersion could be a promising formulation approach to improve the dissolution rate, oral bioavailability, and effect on the reduction of lipid accumulation in high-fat diet-induced obesity mice. Full article

The treatment of peri-implantitis is challenging in the clinical practice of implant dentistry. With limited therapeutic options and drug resistance, there is a need for alternative methods, such as photodynamic therapy (PDT), which is a minimally invasive procedure used to treat peri-implantitis. This study evaluated whether the type of photosensitizer used influences the results of inflammatory control, reduction in peri-implant pocket depth, bleeding during probing, and reduction in bone loss in the dental implant region. We registered the study in the PROSPERO (International Prospective Register of Systematic Review) database. We searched three main databases and gray literature in English without date restrictions. In vivo randomized clinical studies involving individuals with peri-implantitis, smokers, patients with diabetes, and healthy controls were included. PDT was used as the primary intervention. Comparators considered mechanical debridement with a reduction in pocket depth as the primary outcome and clinical attachment level, bleeding on probing, gingival index, plaque index, and microbiological analysis as secondary outcomes. After reviewing the eligibility criteria, we included seven articles out of 266. A great variety of photosensitizers were observed, and it was concluded that the selection of the most appropriate type of photosensitizer must consider the patient’s characteristics and peri-implantitis conditions. The effectiveness of PDT, its effects on the oral microbiome, and the clinical patterns of peri-implantitis may vary depending on the photosensitizer chosen, which is a crucial factor in personalizing peri-implantitis treatment. Full article

Lurasidone, an antipsychotic medication for schizophrenia, is administered daily via oral intake. Adherence is a critical challenge, given that many schizophrenia patients deny their condition, thus making alternative delivery methods desirable. This study aimed to deliver lurasidone by the transdermal route and provide therapeutic effects for three days. Passive diffusion was found to be insufficient for lurasidone delivery. The addition of chemical enhancers increased permeation, but it was still insufficient to reach the designed target dose from a patch, so a microneedle patch array was fabricated by using biodegradable polymers. For prolonged and effective delivery, the drug was encapsulated in Poly (lactic-co-glycolic acid) (PLGA) nanoparticles which were made using the solvent evaporation method and incorporated in microneedles. Effervescent technology was also employed in the preparation of the microneedle patch to facilitate the separation of the needle tip from the patch. Once separated, only the needle tip remains embedded in the skin, thus preventing premature removal by the patient. The microneedles demonstrated robust preformation in a characterization test evaluating their insertion capacity, mechanical strength, and the uniformity of microneedle arrays, and were able to deliver a dose equivalent to 20 mg oral administration. Therefore, the potential of a transdermal delivery system for lurasidone using microneedles with nanoparticles was demonstrated. Full article

Acute respiratory distress syndrome (ARDS) is a potential life-threatening, heterogenous, inflammatory lung disease. There are no data available on potential drug–drug interactions (pDDIs) in critically ill patients with ARDS. This study analyzed pDDIs in this specific cohort and aimed to investigate possible associations of coronavirus disease 2019 (COVID-19) as an underlying cause of ARDS and treatment with extracorporeal membrane oxygenation (ECMO) with the occurrence of pDDIs. This retrospective study included patients ≥18 years of age diagnosed with ARDS between January 2010 and September 2021. The Janusmed database was used for the identification of pDDIs. A total of 2694 pDDIs were identified in 189 patients with a median treatment duration of 22 days. These included 323 (12%) clinically relevant drug combinations that are best avoided, corresponding to a median rate of 0.05 per day. There was no difference in the number of pDDIs between COVID-19- and non-COVID-19-associated ARDS. In patients treated with ECMO, the rate of the most severely graded pDDIs per day was significantly higher compared with those who did not require ECMO. PDDIs occur frequently in patients with ARDS. On average, each patient may encounter at least one clinically relevant drug combination that should be avoided during their intensive care unit stay. Full article

In this study, protein-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared via supercritical fluid extraction of emulsion (SFEE) technology. To understand the correlation between process parameters and the main quality characteristics of PLGA microspheres, a comprehensive prior study on the influence of process variables on encapsulation efficiency (EE), initial drug burst release (IBR), morphology, surface property, and particle size distribution (PSD) was conducted within a wide process condition range of each unit process step, from the double-emulsion preparation step to the extraction step. Bovine serum albumin (BSA), a high-molecular weight-protein that is difficult to control the IBR and EE of PLGA microspheres with, was used as a model material. As double-emulsion manufacturing process parameters, the primary (W/O) and secondary emulsion (W/O/W) homogenization speed and secondary emulsification time were evaluated. In addition, the effect of the SFEE process parameters, including the pressure (70–160 bar), temperature (35–65 °C), stirring rate (50–1000 rpm), and flow rate of supercritical carbon dioxide, SC-CO₂ (1–40 mL/min), on PLGA microsphere quality properties were also evaluated. An increase in the homogenization speed of the primary emulsion resulted in an increase in EE and a decrease in IBR. In contrast, increasing the secondary emulsification speed resulted in a decrease in EE and an increase in IBR along with a decrease in microsphere size. The insufficient secondary emulsification time resulted in excessive increases in particle size, and excessive durations resulted in decreased EE and increased IBR. Increasing the temperature and pressure of SFEE resulted in an overall increase in particle size, a decrease in EE, and an increase in IBR. It was observed that, at low stirring rates or SC-CO₂ flow rates, there was an increase in particle size and SPAN value, while the EE decreased. Overall, when the EE of the prepared microspheres is low, a higher proportion of drugs is distributed on the external surface of the microspheres, resulting in a larger IBR. In conclusion, this study contributes to the scientific understanding of the influence of SFEE process variables on PLGA microspheres. Full article

Interindividual variability in drug response is a major problem in the prescription of pharmacological treatments. The therapeutic effect of drugs can be influenced by human genes. Pharmacogenomic guidelines for individualization of treatment have been validated and used for conventional dosage forms. However, drugs can often target non-specific areas and produce both desired and undesired pharmacological effects. The use of nanoparticles, liposomes, or other available forms for drug formulation could help to overcome the latter problem. Virus-like particles based on retroviruses could be a potential envelope for safe and efficient drug formulations. Human endogenous retroviruses would make it possible to overcome the host immune response and deliver drugs to the desired target. PEG10 is a promising candidate that can bind to mRNA because it is secreted like an enveloped virus-like extracellular vesicle. PEG10 is a retrotransposon-derived gene that has been domesticated. Therefore, formulations with PEG10 may have a lower immunogenicity. The use of existing knowledge can lead to the development of suitable drug formulations for the precise treatment of individual diseases. Full article

Bone defects represent an everyday challenge for clinicians who work in the fields of orthopedic surgery, maxillofacial and oral surgery, otorhinolaryngology, and dental implantology. Various bone substitutes have been developed and utilized, according to the needs of bone reconstructive surgery. Carbonate apatite has gained popularity in recent years, due to its excellent tissue behavior and osteoconductive potential. This systematic review aims to evaluate the role of carbonate apatite in bone reconstructive surgery and tissue engineering, analyze its advantages and limitations, and suggest further directions for research and development. The Web of Science, PubMed, and Scopus electronic databases were searched for relevant review articles, published from January 2014 to 21 July 2023. The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eighteen studies were included in the present review. The biological properties and medical applications of carbonate apatite (CO₃Ap) are discussed and evaluated. The majority of articles demonstrated that CO₃Ap has excellent biocompatibility, resorbability, and osteoconductivity. Furthermore, it resembles bone tissue and causes minimal immunological reactions. Therefore, it may be successfully utilized in various medical applications, such as bone substitution, scaffolding, implant coating, drug delivery, and tissue engineering. Full article

Ischemic stroke-induced neuronal cell death leads to the permanent impairment of brain function. The Fas-mediating extrinsic apoptosis pathway and the cytochrome c-mediating intrinsic apoptosis pathway are two major molecular mechanisms contributing to neuronal injury in ischemic stroke. In this study, we employed a Fas-blocking peptide (FBP) coupled with a positively charged nona-arginine peptide (9R) to form a complex with negatively charged siRNA targeting Bax (FBP9R/siBax). This complex is specifically designed to deliver siRNA to Fas-expressing ischemic brain cells. This complex enables the targeted inhibition of Fas-mediating extrinsic apoptosis pathways and cytochrome c-mediating intrinsic apoptosis pathways. Specifically, the FBP targets the Fas/Fas ligand signaling, while siBax targets Bax involved in mitochondria disruption in the intrinsic pathway. The FBP9R carrier system enables the delivery of functional siRNA to hypoxic cells expressing the Fas receptor on their surface—a finding validated through qPCR and confocal microscopy analyses. Through intranasal (IN) administration of FBP9R/siCy5 to middle cerebral artery occlusion (MCAO) ischemic rat models, brain imaging revealed the complex specifically localized to the Fas-expressing infarcted region but did not localize in the non-infarcted region of the brain. A single IN administration of FBP9R/siBax demonstrated a significant reduction in neuronal cell death by effectively inhibiting Fas signaling and preventing the release of cytochrome c. The targeted delivery of FBP9R/siBax represents a promising alternative strategy for the treatment of brain ischemia. Full article

Gene therapeutics are promising for treating diseases at the genetic level, with some already validated for clinical use. Recently, nanostructures have emerged for the targeted delivery of genetic material. Nanomaterials, exhibiting advantageous properties such as a high surface-to-volume ratio, biocompatibility, facile functionalization, substantial loading capacity, and tunable physicochemical characteristics, are recognized as non-viral vectors in gene therapy applications. Despite progress, current non-viral vectors exhibit notably low gene delivery efficiency. Progress in nanotechnology is essential to overcome extracellular and intracellular barriers in gene delivery. Specific nanostructures such as carbon nanotubes (CNTs), carbon quantum dots (CQDs), nanodiamonds (NDs), and similar carbon-based structures can accommodate diverse genetic materials such as plasmid DNA (pDNA), messenger RNA (mRNA), small interference RNA (siRNA), micro RNA (miRNA), and antisense oligonucleotides (AONs). To address challenges such as high toxicity and low transfection efficiency, advancements in the features of carbon-based nanostructures (CBNs) are imperative. This overview delves into three types of CBNs employed as vectors in drug/gene delivery systems, encompassing their synthesis methods, properties, and biomedical applications. Ultimately, we present insights into the opportunities and challenges within the captivating realm of gene delivery using CBNs. Full article

Transdermal drug delivery systems are rapidly gaining prominence and have found widespread application in the treatment of numerous diseases. However, they encounter the challenge of a low transdermal absorption rate. Microneedles can overcome the stratum corneum barrier to enhance the transdermal absorption rate. Among various types of microneedles, nanoparticle-loaded dissolving microneedles (DMNs) present a unique combination of advantages, leveraging the strengths of DMNs (high payload, good mechanical properties, and easy fabrication) and nanocarriers (satisfactory solubilization capacity and a controlled release profile). Consequently, they hold considerable clinical application potential in the precision medicine era. Despite this promise, no nanoparticle-loaded DMN products have been approved thus far. The lack of understanding regarding their in vivo fate represents a critical bottleneck impeding the clinical translation of relevant products. This review aims to elucidate the current research status of the in vivo fate of nanoparticle-loaded DMNs and elaborate the necessity to investigate the in vivo fate of nanoparticle-loaded DMNs from diverse aspects. Furthermore, it offers insights into potential entry points for research into the in vivo fate of nanoparticle-loaded DMNs, aiming to foster further advancements in this field. Full article

Alzheimer’s disease (AD) is the most common form of dementia with no cure so far, probably due to the complexity of this multifactorial disease with diverse processes associated with its origin and progress. Several neuropathological hallmarks have been identified that encourage the search for new multitarget drugs. Therefore, following a multitarget approach, nine rivastigmine–indole (RIV-IND) hybrids (5a1-3, 5b1-3, 5c1-3) were designed, synthesized and evaluated for their multiple biological properties and free radical scavenging activity, as potential multitarget anti-AD drugs. The molecular docking studies of these hybrids on the active center of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) suggest their capacity to act as dual enzyme inhibitors with probable greater disease-modifying impact relative to AChE-selective FDA-approved drugs. Compounds 5a3 (IC₅₀ = 10.9 µM) and 5c3 (IC₅₀ = 26.8 µM) revealed higher AChE inhibition than the parent RIV drug. Radical scavenging assays demonstrated that all the hybrids containing a hydroxyl substituent in the IND moiety (5a2-3, 5b2-3, 5c2-3) have good antioxidant activity (EC₅₀ 7.8–20.7 µM). The most effective inhibitors of Aβ₄₂ self-aggregation are 5a3, 5b3 and 5c3 (47.8–55.5%), and compounds 5b2 and 5c2 can prevent the toxicity induced by Aβ_1-42 to cells. The in silico evaluation of the drug-likeness of the hybrids also showed that all the compounds seem to have potential oral availability. Overall, within this class of RIV-IND hybrids, 5a3 and 5c3 appear as lead compounds for anti-AD drug candidates, deserving further investigation. Full article

Cataract surgery interventions are constantly increasing, particularly among adult and elderly patients. This type of surgery can lead to inflammatory states of the ocular anterior segment (AS), usually healed via postoperative treatment with dexamethasone (DEX)-containing eye drops. The application of eye drops is challenging due to the high number of daily administrations. In this study, mucoadhesive nanoparticles (NPs) were formulated to improve the residence time of DEX on the corneal mucosa, enhancing the drug’s solubility and bioavailability. The NPs were generated using an ionotropic gelation technique, exploiting the interaction between the cationic group of chitosan (CS) and the anionic group of sulfobutylether-β-cyclodextrin (SBE-β-CD). The formation of the inclusion complex and its stoichiometry were studied through phase solubility studies, Job’s plot method, and Bi-directional transport studies on MDCKII-MDR1. The obtained NPs showed good chemical and physical characteristics suitable for drug loading and subsequent testing on animal mucosa. The DEX-loaded CS/SBE-β-CD NPs exhibited a prolonged residence time on animal mucosa and demonstrated enhanced drug permeability through the corneal membrane, showing a sustained release profile. The developed NPs posed no irritation or toxicity concerns upon local administration, making them an optimal and innovative drug delivery system for inflammatory AS diseases treatment. Full article

Phototherapies, such as photothermal therapy (PTT) and photodynamic therapy (PDT), combined with novel all-in-one light-responsive nanocomposites have recently emerged as new therapeutic modalities for the treatment of cancer. Herein, we developed novel all-in-one triphenylphosphonium-functionalized gold nanorod/zinc oxide core–shell nanocomposites (CTPP-GNR@ZnO) for mitochondrial-targeted PTT/PDT owing to their good biocompatibility, tunable and high optical absorption, photothermal conversion efficiency, highest reactive oxygen species (ROS) generation, and high mitochondrial-targeting capability. Under laser irradiation of 780 nm, the CTPP-GNR@ZnO core–shell nanocomposites effectively produced heat in addition to generating ROS to induce cell death, implying a synergistic effect of mild PTT and PDT in combating cancer. Notably, the in vitro PTT/PDT effect of CTPP-GNR@ZnO core–shell nanocomposites exhibited effective cell ablation (95%) and induced significant intracellular ROS after the 780 nm laser irradiation for 50 min, indicating that CTPP in CTPP-GNR@ZnO core–shell nanocomposites can specifically target the mitochondria of CT-26 cells, as well as generate heat and ROS to completely kill cancer cells. Overall, this light-responsive nanocomposite-based phototherapy provides a new approach for cancer synergistic therapy. Full article

Glaucoma encompasses a group of optic neuropathies characterized by complex and often elusive etiopathology, involvihttng neurodegeneration of the optic nerve in conjunction with abnormal intraocular pressure (IOP). Currently, there is no cure for glaucoma, and treatment strategies primarily aim to halt disease progression by managing IOP. This review delves into the etiopathology, diagnostic methods, and treatment approaches for glaucoma, with a special focus on IOP management. We discuss a range of active pharmaceutical ingredients used in glaucoma therapy, emphasizing their chemical structure, pharmacological action, therapeutic effectiveness, and safety/tolerability profiles. Notably, most of these therapeutic agents are administered as topical formulations, a critical aspect considering patient compliance and drug delivery efficiency. The classes of glaucoma therapeutics covered in this review include prostaglandin analogs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and miotic (cholinergic) agents. This comprehensive overview highlights the importance of topical administration in glaucoma treatment, offering insights into the current state and future directions of pharmacological management in glaucoma. Full article

This research aimed to develop miconazole-based microemulsions using oleic acid as a natural lipophilic phase and a stabilizer mixture comprising Tween 20 and PEG 400 to solubilize miconazole as an antifungal agent known for its activity in oral candidiasis and to improve its bioavailability. The formulation and preparation process was combined with a mathematical approach using a 2³-full factorial plan. Fluid and gel-like microemulsions were obtained and analyzed considering pH, conductivity, and refractive index, followed by extensive analyses focused on droplet size, zeta potential, rheological behavior, and goniometry. In vitro release tests were performed to assess their biopharmaceutical characteristics. Independent variables coded X₁-Oleic acid (%, w/w), X₂-Tween 20 (%, w/w), and X₃-PEG 400 (%, w/w) were analyzed in relationship with three main outputs like mean droplet size, work of adhesion, and diffusion coefficient by combining statistical tools with response surface methodology. The microemulsion containing miconazole base–2%, oleic acid–5%, Tween 20–40%, PEG 400–20%, and water–33% exhibited a mean droplet size of 119.6 nm, a work of adhesion of 71.98 mN/m, a diffusion coefficient of 2.11·10⁻⁵ cm²/s, and together with remarked attributes of two gel-like systems formulated with higher oil concentrations, modeled the final optimization step of microemulsions as potential systems for buccal delivery. Full article

This review focuses on nanovesicular carriers for enhanced delivery of molecules into and across the skin, from their design to recent emerging technologies. During the last four decades, several approaches have been used aiming to design new nanovesicles, some of them by altering the properties of the classic phospholipid vesicle, the liposome. Phospholipid nanovesicular systems, including the phospholipid soft vesicles as well as the non-phospholipid vesicular carries, are reviewed. The altered nanovesicles have served in the manufacture of various cosmetic products and have been investigated and used for the treatment of a wide variety of skin conditions. The evolution and recent advances of these nanovesicular technologies are highlighted in this review. Full article

The material library is an emerging, new data-driven approach for developing pharmaceutical process models. How many materials or samples should be involved in a particular application scenario is unclear, and the impact of sample size on process modeling is worth discussing. In this work, the direct compression process was taken as the research object, and the effects of different sample sizes of material libraries on partial least squares (PLS) modeling in the prediction of tablet tensile strength were investigated. A primary material library comprising 45 materials was built. Then, material subsets containing 5 × i (i = 1, 2, 3, …, 8) materials were sampled from the primary material library. Each subset underwent sampling 1000 times to analyze variations in model fitting performance. Both hierarchical sampling and random sampling were employed and compared, with hierarchical sampling implemented with the help of the tabletability classification index d. For each subset, modeling data were organized, incorporating 18 physical properties and tableting pressure as the independent variables and tablet tensile strength as the dependent variable. A series of chemometric indicators was used to assess model performance and find important materials for model training. It was found that the minimum R² and RMSE values reached their maximum, and the corresponding values were kept almost unchanged when the sample sizes varied from 20 to 45. When the sample size was smaller than 15, the hierarchical sampling method was more reliable in avoiding low-quality few-shot PLS models than the random sampling method. Two important materials were identified as useful for building an initial material library. Overall, this work demonstrated that as the number of materials increased, the model’s reliability improved. It also highlighted the potential for effective few-shot modeling on a small material library by controlling its information richness. Full article

Traditional tumor treatments have the drawback of harming both tumor cells and normal cells, leading to significant systemic toxic side effects. As a result, there is a pressing need for targeted drug delivery methods that can specifically target cells or tissues. Currently, researchers have made significant progress in developing targeted drug delivery systems for tumor therapy using various targeting ligands. This review aims to summarize recent advancements in targeted drug delivery systems for tumor therapy, focusing on different targeting ligands such as folic acid, carbohydrates, peptides, aptamers, and antibodies. The review also discusses the advantages, challenges, and future prospects of these targeted drug delivery systems. Full article

Effective drug delivery is essential for cancer treatment. Drug delivery systems, which can be tailored to targeted transport and integrated tumor therapy, are vital in improving the efficiency of cancer treatment. Peptides play a significant role in various biological and physiological functions and offer high design flexibility, excellent biocompatibility, adjustable morphology, and biodegradability, making them promising candidates for drug delivery. This paper reviews peptide-mediated drug delivery systems, focusing on self-assembled peptides and peptide–drug conjugates. It discusses the mechanisms and structural control of self-assembled peptides, the varieties and roles of peptide–drug conjugates, and strategies to augment peptide stability. The review concludes by addressing challenges and future directions. Full article

Microneedle (MN) technology is an optimal choice for the delivery of drugs via the transdermal route, with a minimally invasive procedure. MN applications are varied from drug delivery, cosmetics, tissue engineering, vaccine delivery, and disease diagnostics. The MN is a biomedical device that offers many advantages including but not limited to a painless experience, being time-effective, and real-time sensing. This research implements additive manufacturing (AM) technology to fabricate MN arrays for advanced therapeutic applications. Stereolithography (SLA) was used to fabricate six MN designs with three aspect ratios. The MN array included conical-shaped 100 needles (10 × 10 needle) in each array. The microneedles were characterized using optical and scanning electron microscopy to evaluate the dimensional accuracy. Further, mechanical and insertion tests were performed to analyze the mechanical strength and skin penetration capabilities of the polymeric MN. MNs with higher aspect ratios had higher deformation characteristics suitable for penetration to deeper levels beyond the stratum corneum. MNs with both 0.3 mm and 0.4 mm base diameters displayed consistent force–displacement behavior during a skin-equivalent penetration test. This research establishes guidelines for fabricating polymeric MN for high-accuracy and low-cost 3D printing. Full article

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on the development of oral therapies with improved efficacy and safety compared with available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate to severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways such as AhR, PDE-4, and Jak-STAT. Tapinarof (an AhR modulator) and roflumilast (a PDE-4 inhibitor) have exhibited favorable efficacy and safety outcomes and have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis, especially those that are currently under evaluation and development for the treatment of psoriasis. Full article

Ocular pathologies present significant challenges to achieving effective therapeutic results due to various anatomical and physiological barriers. Natural products such as flavonoids, alone or in association with allopathic drugs, present many therapeutic actions including anticancer, anti-inflammatory, and antibacterial action. However, their clinical employment is challenging for scientists due to their low water solubility. In this study, we designed a liquid formulation based on rutin/sulfobutylether-β-cyclodextrin (RTN/SBE-β-CD) inclusion complex for treating ocular infections. The correct stoichiometry and the accurate binding constant were determined by employing SupraFit software (2.5.120) in the UV-vis titration experiment. A deep physical–chemical characterization of the RTN/SBE-β-CD inclusion complex was also performed; it confirmed the predominant formation of a stable complex (K_c, 9660 M⁻¹) in a 1:1 molar ratio, with high water solubility that was 20 times (2.5 mg/mL) higher than the free molecule (0.125 mg/mL), permitting the dissolution of the solid complex within 30 min. NMR studies revealed the involvement of the bicyclic flavonoid moiety in the complexation, which was also confirmed by molecular modeling studies. In vitro, the antibacterial and antibiofilm activity of the formulation was assayed against Staphylococcus aureus and Pseudomonas aeruginosa strains. The results demonstrated a significant activity of the formulation than that of the free molecules. Full article

Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. Six prodrugs (enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. Parameters such as organ blood flows, plasma-binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate (GFR) and gastrointestinal transit rate were integrated into the simulation. The pharmacokinetic profiles of these drugs and their active metabolites were simulated for 1000 virtual individuals. The developed semi-PBPK model, after validation in healthy individuals, was extrapolated to LC patients. Most of the observations fell within the 5th and 95th percentiles of simulations from 1000 virtual patients. The estimated AUC and C_max were within 0.5–2-fold of the observed values. The sensitivity analysis showed that the decreased plasma exposure of active metabolites due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model successfully predicted the pharmacokinetics of CES1 substrates and their metabolites in healthy individuals and LC patients, facilitating tailored dosing of CES1 substrates in LC patients. Full article

Inflammation is a physiological response to a damaging stimulus but sometimes can be the cause of the onset of neurodegenerative diseases, atherosclerosis, and cancer. These pathologies are characterized by the overexpression of inflammatory markers like endothelial adhesion molecules, such as Vascular Cell Adhesion Molecule-1 (VCAM-1). In the present work, the development of liposomes for therapeutic targeted delivery to inflamed endothelia is described. The idea is to exploit a three-step pretargeting system based on the biotin–avidin high-affinity interaction: the first step involves a previously described biotin derivative bearing a VCAM-1 binding peptide; in the second step, the avidin derivative NeutrAvidin^TM, which strongly binds to the biotin moiety, is injected; the final step is the administration of biotinylated liposomes that would bind to Neutravidin^TM immobilized onto VCAM-1 overexpressing endothelium. Stealth biotinylated liposomes, prepared via the thin film hydration method followed by extrusion and purification via size exclusion chromatography, have been thoroughly characterized for their chemico-physical and morphological features and loaded with metformin hydrochloride, a potential anti-inflammatory agent. The three-step system, tested in vitro on different cell lines via confocal microscopy, FACS analysis and metformin uptake, has proved its suitability for therapeutic applications. Full article

In diverse biomedical and other applications of polylactide (PLA), its bacterial contamination and colonization are unwanted. For this reason, this biodegradable polymer is often combined with antibacterial agents or fillers. Here, we present a new solution of this kind. Through the process of simple solvent casting, we developed homogeneous composite films from 28 ± 5 nm oleic-acid-capped gallium nanoparticles (Ga NPs) and poly(L-lactide) and characterized their detailed morphology, crystallinity, aqueous wettability, optical and thermal properties. The addition of Ga NPs decreased the ultraviolet transparency of the films, increased their hydrophobicity, and enhanced the PLA structural ordering during solvent casting. Albeit, above the glass transition, there is an interplay of heterogeneous nucleation and retarded chain mobility through interfacial interactions. The gallium content varied from 0.08 to 2.4 weight %, and films with at least 0.8% Ga inhibited the growth of Pseudomonas aeruginosa PAO1 in contact, while 2.4% Ga enhanced the effect of the films to be bactericidal. This contact action was a result of unwrapping the top film layer under biological conditions and the consequent bacterial contact with the exposed Ga NPs on the surface. All the tested films showed good cytocompatibility with human HaCaT keratinocytes and enabled the adhesion and growth of these skin cells on their surfaces when coated with poly(L-lysine). These properties make the nanogallium-polyl(L-lactide) composite a promising new polymer-based material worthy of further investigation and development for biomedical and pharmaceutical applications. Full article

Niosomes are vesicular nanocarriers, biodegradable, relatively non-toxic, stable, and inexpensive, that provide an alternative for lipid-solid carriers (e.g., liposomes). Niosomes may resolve issues related to the instability, fast degradation, bioavailability, and insolubility of different drugs or natural compounds. Niosomes can be very efficient potential systems for the specific delivery of anticancer, antioxidant, anti-inflammatory, antimicrobial, and antibacterial molecules. This review aims to present an overview of their composition, the most common formulation techniques, as well as of recent utilizations as delivery systems in cancer therapy. Full article

Surgical site infections (SSI) occur very frequently during post-operative procedures and are often treated with oral antibiotics, which may cause some side effects. This type of infection could be avoided by encapsulating antimicrobial/anti-inflammatory drugs within the surgical suture materials so that they can more efficiently act on the site of action during wound closure, avoiding post-operative bacterial infection and spreading. This work was aimed at developing novel electrospun bio-based anti-infective fibre-based yarns as novel suture materials for preventing surgical site infections. For this, yarns based on flying intertwined microfibres (1.95 ± 0.22 µm) were fabricated in situ during the electrospinning process using a specially designed yarn collector. The electrospun yarn sutures (diameter 300–500 µm) were made of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with different contents of 3HV units and contained ciprofloxacin hydrochloride (CPX) as the antimicrobial active pharmaceutical ingredient (API). The yarns were then analysed by scanning electron microscopy, Fourier transform infrared spectroscopy, wide-angle X-ray scattering, differential scanning calorimetry, and in vitro drug release. The yarns were also analysed in terms of antimicrobial and mechanical properties. The material characterization indicated that the varying polymer molecular architecture affected the attained polymer crystallinity, which was correlated with the different drug-eluting profiles. Moreover, the materials exhibited the inherent stiff behaviour of PHBV, which was further enhanced by the API. Lastly, all the yarn sutures presented antimicrobial properties for a time release of 5 days against both Gram-positive and Gram-negative pathogenic bacteria. The results highlight the potential of the developed antimicrobial electrospun yarns in this study as potential innovative suture materials to prevent surgical infections. Full article

Antibody–drug conjugate (ADC) therapy, an advanced therapeutic technology comprising antibodies, chemical linkers, and cytotoxic payloads, addresses the limitations of traditional chemotherapy. This study explores key elements of ADC therapy, focusing on antibody development, linker design, and cytotoxic payload delivery. The global rise in cancer incidence has driven increased investment in anticancer agents, resulting in significant growth in the ADC therapy market. Over the past two decades, notable progress has been made, with approvals for 14 ADC treatments targeting various cancers by 2022. Diverse ADC therapies for hematologic malignancies and solid tumors have emerged, with numerous candidates currently undergoing clinical trials. Recent years have seen a noteworthy increase in ADC therapy clinical trials, marked by the initiation of numerous new therapies in 2022. Research and development, coupled with patent applications, have intensified, notably from major companies like Pfizer Inc. (New York, NY, USA), AbbVie Pharmaceuticals Inc. (USA), Regeneron Pharmaceuticals Inc. (Tarrytown, NY, USA), and Seagen Inc. (Bothell, WA, USA). While ADC therapy holds great promise in anticancer treatment, challenges persist, including premature payload release and immune-related side effects. Ongoing research and innovation are crucial for advancing ADC therapy. Future developments may include novel conjugation methods, stable linker designs, efficient payload delivery technologies, and integration with nanotechnology, driving the evolution of ADC therapy in anticancer treatment. Full article

Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, injection, and oral drug delivery are the three main delivery strategies for COL. This article elaborates on the research progress of different delivery strategies in terms of toxicity reduction and efficacy enhancement, depicting that the transdermal drug delivery route can avoid the first-pass effect and the traumatic pain associated with the oral and injection routes, respectively. Therefore, such a dosage form holds a significant promise that requires the development of further research to investigate effective COL delivery formulations. In addition, the permeation-promoting technologies utilized for transdermal drug delivery systems are briefly discussed. This article is expected to provide scientific ideas and theoretical guidance for future research and the exploration of COL delivery strategies. Full article

Photodynamic therapy (PDT) has become an important therapeutic strategy because it is highly controllable, effective, and does not cause drug resistance. Moreover, precise delivery of photosensitizers to tumor lesions can greatly reduce the amount of drug administered and optimize therapeutic outcomes. As alternatives to protein antibodies, peptides have been applied as useful targeting ligands for targeted biomedical imaging, drug delivery and PDT. In addition, other functionalities of peptides such as stimuli responsiveness, self-assembly, and therapeutic activity can be integrated with photosensitizers to yield versatile peptide-based nanosystems for PDT. In this article, we start with a brief introduction to PDT and peptide-based nanosystems, followed by more detailed descriptions about the structure, property, and architecture of peptides as background information. Finally, the most recent advances in peptide-based nanosystems for PDT are emphasized and summarized according to the functionalities of peptide in the system to reveal the design and development principle in different therapeutic circumstances. We hope this review could provide useful insights and valuable reference for the development of peptide-based nanosystems for PDT. Full article

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is Paxlovid^TM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (M^pro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed. Full article

Previously obtained amphiphilic graft copolymers based on [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA) ionic liquid were used as the matrices of three types of nanocarriers, i.e., conjugates with ionic piperacillin (PIP) and micelles with tazobactam (TAZ), which represented single systems, and dual systems bearing PIP anions and encapsulated TAZ for co-delivery. The exchange of Cl anions in TMAMA units with PIP ones resulted in a yield of 45.6–72.7 mol.%. The self-assembling properties were confirmed by the critical micelle concentration (CMC), which, after ion exchange, increased significantly (from 0.011–0.020 mg/mL to 0.041–0.073 mg/mL). The amphiphilic properties were beneficial for TAZ encapsulation to reach drug loading contents (DLCs) in the ranges of 37.2–69.5 mol.% and 50.4–80.4 mol.% and to form particles with sizes of 97–319 nm and 24–192 nm in the single and dual systems, respectively. In vitro studies indicated that the ionically conjugated drug (PIP) was released in quantities of 66–81% (7.8–15.0 μg/mL) from single-drug systems and 21–25% (2.6–3.9 μg/mL) from dual-drug systems. The release of encapsulated TAZ was more efficient, achieving 47–98% (7.5–9.0 μg/mL) release from the single systems and 47–69% (9.6–10.4 μg/mL) release from the dual ones. Basic cytotoxicity studies showed non-toxicity of the polymer matrices, while the introduction of the selected drugs induced cytotoxicity against normal human bronchial epithelial cells (BEAS-2B) with the increase in concentration. Full article

Amino acid transporters are abundant amongst the solute carrier family and have an important role in facilitating the transfer of amino acids across cell membranes. Because of their impact on cell nutrient distribution, they also appear to have an important role in the growth and development of cancer. Naturally, this has made amino acid transporters a novel target of interest for the development of new anticancer drugs. Many attempts have been made to develop inhibitors of amino acid transporters to slow down cancer cell growth, and some have even reached clinical trials. The purpose of this review is to help organize the available information on the efforts to discover amino acid transporter inhibitors by focusing on the amino acid transporters ASCT2 (SLC1A5), LAT1 (SLC7A5), xCT (SLC7A11), SNAT1 (SLC38A1), SNAT2 (SLC38A2), and PAT1 (SLC36A1). We discuss the function of the transporters, their implication in cancer, their known inhibitors, issues regarding selective inhibitors, and the efforts and strategies of discovering inhibitors. The goal is to encourage researchers to continue the search and development within the field of cancer treatment research targeting amino acid transporters. Full article

Innovations in drug delivery systems are crucial for enhancing therapeutic efficiency. Our research presents a novel approach based on using electro-fluid dynamic atomization (EFDA) to fabricate core-shell monophasic particles (CSMp) from sodium alginate blends of varying molecular weights. This study explores the morphological characteristics of these particles in relation to material properties and process conditions, highlighting their potential in drug delivery applications. A key aspect of our work is the development of a mathematical model that simulates the release kinetics of small molecules, specifically sodium diclofenac. By assessing the diffusion properties of different molecules and gel formulations through transport and rheological models, we have created a predictive tool for evaluating the efficiency of these particles in drug delivery. Our findings underscore two critical, independent parameters for optimizing drug release: the external shell thickness and the diffusivity ratios within the dual layers. This allows for precise control over the timing and intensity of the release profile. This study advances our understanding of EFDA in the fabrication of CSMp and offers promising avenues for enhancing drug delivery systems by tailoring release profiles through particle characteristic manipulation. Full article

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients’ needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence. Full article

Aerosol delivery using conventional nebulizers with fixed maximal output rates is limited and unpredictable under high-flow conditions. This study measured regulated aerosol delivery to the lungs of normal volunteers using a nebulizer designed to overcome the limitations of HFNC therapy (i-AIRE (InspiRx, Inc., Somerset, NJ, USA)). This breath-enhanced jet nebulizer, in series with the high-flow catheter, utilizes the high flow to increase aerosol output beyond those of conventional devices. Nine normal subjects breathing tidally via the nose received humidified air at 60 L/min. The nebulizer was connected to the HFNC system upstream to the humidifier and received radio-labeled saline as a marker for drug delivery (^99mTc DTPA) infused by a syringe pump (mCi/min). The dose to the subject was regulated at 12, 20 and 50 mL/h. Rates of aerosol deposition in the lungs (µCi/min) were measured via a gamma camera for each infusion rate and converted to µg NaCl/min. The deposition rate, as expressed as µg of NaCl/min, was closely related to the infusion rate: 7.84 ± 3.2 at 12 mL/h, 43.0 ± 12 at 20 mL/h and 136 ± 45 at 50 mL/h. The deposition efficiency ranged from 0.44 to 1.82% of infused saline, with 6% deposited in the nose. A regional analysis indicated peripheral deposition of aerosol (central/peripheral ratio 0.99 ± 0.27). The data were independent of breathing frequency. Breath-enhanced nebulization via HFNC reliably delivered aerosol to the lungs at the highest nasal airflows. The rate of delivery was controlled simply by regulating the infusion rate, indicating that lung deposition in the critically ill can be titrated clinically at the bedside. Full article

The combination of aztreonam (ATM) and ceftazidime–avibactam (CAZ-AVI; CZA) has shown therapeutic potential against serine-β-lactamase (SBL)- and metallo-β-lactamase (MBL)-producing Enterobacterales. However, the ability of CZA to restore the antibiotic activity of ATM is severely limited in MBL-producing multidrug-resistant (MDR) Pseudomonas aeruginosa strains because of the myriad of intrinsic and acquired resistance mechanisms associated with this pathogen. We reasoned that the simultaneous inhibition of multiple targets associated with multidrug resistance mechanisms may potentiate the antibiotic activity of ATM against MBL-producing P. aeruginosa. During a search for the multitarget inhibitors through a molecular docking study, we discovered that di-F-Q, the previously reported efflux pump inhibitor of MDR P. aeruginosa, binds to the active sites of the efflux pump (MexB), as well as various β-lactamases, and these sites are open to the 3-O-position of di-F-Q. The 3-O-substituted di-F-Q derivatives were thus synthesized and showed hereto unknown multitarget MDR inhibitory activity against various ATM-hydrolyzing β-lactamases (AmpC, KPC, and New Delhi metallo-β-lactamase (NDM)) and the efflux pump of P. aeruginosa, presumably by forming additional hydrophobic contacts with the targets. The multitarget MDR inhibitor 27 effectively potentiated the antimicrobial activity of ATM and reduced the MIC of ATM more than four-fold in 19 out of 21 MBL-producing P. aeruginosa clinical strains, including the NDM-producing strains which were highly resistant to various combinations of ATM with β-lactamase inhibitors and/or efflux pump inhibitors. Our findings suggest that the simultaneous inhibition of multiple MDR targets might provide new avenues for the discovery of safe and efficient MDR reversal agents which can be used in combination with ATM against MBL-producing MDR P. aeruginosa. Full article

Hybrid nanoparticles (HNPs) were designed by combining a PLGA core with a lipid shell that incorporated PEG–Lipid conjugates with various functionalities (-RGD, -cRGD, -NH₂, and -COOH) to create targeted drug delivery systems. Loaded with a neutral lipid orange dye, the HNPs were extensively characterized using various techniques and investigated for their uptake in human monocyte-derived macrophages (MDMs) using FC and CLSM. Moreover, the best-performing HNPs (i.e., HNP-COOH and HNP-RGD as well as HNP-RGD/COOH mixed) were loaded with the anti-inflammatory drug BRP-201 and prepared in two size ranges (d_H ~140 nm and d_H ~250 nm). The HNPs were examined further for their stability, degradation, MDM uptake, and drug delivery efficiency by studying the inhibition of 5-lipoxygenase (5-LOX) product formation, whereby HNP-COOH and HNP-RGD both exhibited superior uptake, and the HNP-COOH/RGD (2:1) displayed the highest inhibition. Full article

Solid tumors are composed of a highly complex and heterogenic microenvironment, with increasing metabolic status. This environment plays a crucial role in the clinical therapeutic outcome of conventional treatments and innovative antitumor nanomedicines. Scientists have devoted great efforts to conquering the challenges of the tumor microenvironment (TME), in respect of effective drug accumulation and activity at the tumor site. The main focus is to overcome the obstacles of abnormal vasculature, dense stroma, extracellular matrix, hypoxia, and pH gradient acidosis. In this endeavor, nanomedicines that are targeting distinct features of TME have flourished; these aim to increase site specificity and achieve deep tumor penetration. Recently, research efforts have focused on the immune reprograming of TME in order to promote suppression of cancer stem cells and prevention of metastasis. Thereby, several nanomedicine therapeutics which have shown promise in preclinical studies have entered clinical trials or are already in clinical practice. Various novel strategies were employed in preclinical studies and clinical trials. Among them, nanomedicines based on biomaterials show great promise in improving the therapeutic efficacy, reducing side effects, and promoting synergistic activity for TME responsive targeting. In this review, we focused on the targeting mechanisms of nanomedicines in response to the microenvironment of solid tumors. We describe responsive nanomedicines which take advantage of biomaterials’ properties to exploit the features of TME or overcome the obstacles posed by TME. The development of such systems has significantly advanced the application of biomaterials in combinational therapies and in immunotherapies for improved anticancer effectiveness. Full article

Cancer is defined as the uncontrolled proliferation of heterogeneous cell cultures in the body that develop abnormalities and mutations, leading to their resistance to many forms of treatment. Left untreated, these abnormal cell growths can lead to detrimental and even fatal complications for patients. Radiation therapy is involved in around 50% of cancer treatment workflows; however, it presents significant recurrence rates and normal tissue toxicity, given the inevitable deposition of the dose to the surrounding healthy tissue. Chemotherapy is another treatment modality with excessive normal tissue toxicity that significantly affects patients’ quality of life. To improve the therapeutic efficacy of radiotherapy and chemotherapy, multiple conjunctive modalities have been proposed, which include the targeting of components of the tumour microenvironment inhibiting tumour spread and anti-therapeutic pathways, increasing the oxygen content within the tumour to revert the hypoxic nature of the malignancy, improving the local dose deposition with metal nanoparticles, and the restriction of the cell cycle within radiosensitive phases. The tumour microenvironment is largely responsible for inhibiting nanoparticle capture within the tumour itself and improving resistance to various forms of cancer therapy. In this review, we discuss the current literature surrounding the administration of molecular and nanoparticle therapeutics, their pharmacokinetics, and contrasting mechanisms of action. The review aims to demonstrate the advancements in the field of conjugated nanomaterials and radiotherapeutics targeting, inhibiting, or bypassing the tumour microenvironment to promote further research that can improve treatment outcomes and toxicity rates. Full article

The popularity of Glycosaminoglycans (GAGs) in drug delivery systems has grown as their innate ability to sequester and release charged molecules makes them adept in the controlled release of therapeutics. However, peptide therapeutics have been relegated to synthetic, polymeric systems, despite their high specificity and efficacy as therapeutics because they are rapidly degraded in vivo when not encapsulated. We present a GAG-based nanoparticle system for the easy encapsulation of cationic peptides, which offers control over particle diameter, peptide release behavior, and swelling behavior, as well as protection from proteolytic degradation, using a singular, organic polymer and no covalent linkages. These nanoparticles can encapsulate cargo with a particle diameter range spanning 130–220 nm and can be tuned to release cargo over a pH range of 4.5 to neutral through the modulation of the degree of sulfation and the molecular weight of the GAG. This particle system also confers better in vitro performance than the unencapsulated peptide via protection from enzymatic degradation. This method provides a facile way to protect therapeutic peptides via the inclusion of the presented binding sequence and can likely be expanded to larger, more diverse cargo as well, abrogating the complexity of previously demonstrated systems while offering broader tunability. Full article

Biofilm formation is considered one of the primary virulence mechanisms in Gram-positive and Gram-negative pathogenic species, particularly those responsible for chronic infections and promoting bacterial survival within the host. In recent years, there has been a growing interest in discovering new compounds capable of inhibiting biofilm formation. This is considered a promising antivirulence strategy that could potentially overcome antibiotic resistance issues. Effective antibiofilm agents should possess distinctive properties. They should be structurally unique, enable easy entry into cells, influence quorum sensing signaling, and synergize with other antibacterial agents. Many of these properties are found in both natural systems that are isolated from plants and in synthetic systems like nanoparticles and nanocomposites. In this review, we discuss the clinical nature of biofilm-associated infections and some of the mechanisms associated with their antibiotic tolerance. We focus on the advantages and efficacy of various natural and synthetic compounds as a new therapeutic approach to control bacterial biofilms and address multidrug resistance in bacteria. Full article

Electrospinning is an advanced manufacturing strategy used to create innovative medical devices from continuous nanoscale fibers that is endowed with tunable biological, chemical, and physical properties. Innovative medical patches manufactured entirely by electrospinning are discussed in this paper, using a specific plant-derived formulation “1 Primary Wound Dressing©” (1-PWD) as an active pharmaceutical ingredient (API). 1-PWD is composed of neem oil (Azadirachta indica A. Juss.) and the oily extracts of Hypericum perforatum (L.) flowers, according to the formulation patented by the ENEA of proven therapeutic efficacy as wound dressings. The goal of this work is to encapsulate this API and demonstrate that its slow release from an engineered electrospun patch can increase the therapeutic efficacy for wound healing. The prototyped patch is a three-layer core–shell membrane, with a core made of fibers from a 1-PWD-PEO blend, enveloped within two external layers made of medical-grade polycaprolactone (PCL), ensuring mechanical strength and integrity during manipulation. The system was characterized via electron microscopy (SEM) and chemical and contact angle tests. The encapsulation, release, and efficacy of the API were confirmed by FTIR and LC-HRMS and were validated via in vitro toxicology and scratch assays. Full article

With the development of nanotechnology and confronting the problems of traditional pharmaceutical formulations in treating lung diseases, inhalable nano-formulations have attracted interest. Inhalable nano-formulations for treating lung diseases allow for precise pulmonary drug delivery, overcoming physiological barriers, improving aerosol lung deposition rates, and increasing drug bioavailability. They are expected to solve the difficulties faced in treating lung diseases. However, limited success has been recorded in the industrialization translation of inhalable nano-formulations. Only one relevant product has been approved by the FDA to date, suggesting that there are still many issues to be resolved in the clinical application of inhalable nano-formulations. These systems are characterized by a dependence on inhalation devices, while the adaptability of device formulation is still inconclusive, which is the most important issue impeding translational research. In this review, we categorized various inhalable nano-formulations, summarized the advantages of inhalable nano-formulations over conventional inhalation formulations, and listed the inhalable nano-formulations undergoing clinical studies. We focused on the influence of inhalation devices on nano-formulations and analyzed their adaptability. After extensive analysis of the drug delivery mechanisms, technical processes, and limitations of different inhalation devices, we concluded that vibrating mesh nebulizers might be most suitable for delivering inhalable nano-formulations, and related examples were introduced to validate our view. Finally, we presented the challenges and outlook for future development. We anticipate providing an informative reference for the field. Full article

Gene therapy displays great promise in the treatment of cervical cancer. The occurrence of cervical cancer is highly related to persistent human papilloma virus (HPV) infection. The HPV oncogene can be cleaved via gene editing technology to eliminate carcinogenic elements. However, the successful application of the gene therapy method depends on effective gene delivery into the vagina. To improve mucosal penetration and adhesion ability, quaternized chitosan was introduced into the poly(β-amino ester) (PBAE) gene-delivery system in the form of quaternized chitosan-g-PBAE (QCP). At a mass ratio of PBAE:QCP of 2:1, the polymers exhibited the highest green fluorescent protein (GFP) transfection efficiency in HEK293T and ME180 cells, which was 1.1 and 5.4 times higher than that of PEI 25 kD. At this mass ratio, PBAE–QCP effectively compressed the GFP into spherical polyplex nanoparticles (PQ–GFP NPs) with a diameter of 255.5 nm. In vivo results indicated that owing to the mucopenetration and adhesion capability of quaternized CS, the GFP transfection efficiency of the PBAE–QCP hybrid system was considerably higher than those of PBAE and PEI 25 kD in the vaginal epithelial cells of Sprague–Dawley rats. Furthermore, the new system demonstrated low toxicity and good safety, laying an effective foundation for its further application in gene therapy. Full article

Currently, there is insufficient information on the variability in levocetirizine pharmacometrics among individuals, a crucial aspect for establishing its clinical use. The gender differences in pharmacokinetics and the extent of variation in pharmacodynamics have not been definitively identified. The primary goal of this study was to investigate gender differences in levocetirizine pharmacokinetics and quantitatively predict and compare how these gender-related pharmacokinetic differences impact pharmacodynamics, using population pharmacokinetic–pharmacodynamic modeling. Bioequivalence results for levocetirizine (only from the control formulation) were obtained from both healthy Korean men and women. Physiological and biochemical parameters for each individual were utilized as pharmacokinetic comparison and modeling data between genders. Pharmacodynamic modeling was performed using reported data on antihistamine responses following levocetirizine exposure. Gender, weight, body surface area, peripheral distribution volume, albumin, central–peripheral inter-compartmental clearance, and the fifth sequential absorption rate constant were explored as effective covariates. A comparison of the model simulation results showed a higher maximum concentration and faster plasma loss in females than in males, resulting in a faster recovery to baseline of the antihistamine effect; however, the absolute differences between genders in the mean values were not large within 10 ng/mL (for plasma concentrations) or % (wheal and flare size changes). Regarding the pharmacokinetics and pharmacodynamics of levocetirizine, the gender effect may not be significant when applying the usual dosage (5 mg/day). This study will be useful for bridging the knowledge gap in scientific precision medicine by introducing previously unconfirmed information regarding gender differences in levocetirizine pharmacometrics. Full article