RSC Pharmaceutics最新文献

Engineered living materials (ELMs), which integrate live microorganisms into biocompatible matrices, are emerging as powerful platforms for therapeutic applications. Among these, hydrogels encapsulating engineered live biotherapeutic products (eLBPs) offer enhanced microbial stability, targeted delivery, and functional versatility for treating human disease. By protecting microbes from environmental stress and immune clearance while supporting nutrient diffusion and activity, hydrogel systems address key challenges in microbial therapeutic delivery. This review highlights recent advances in hydrogel-based delivery of eLBPs, focusing on material design, microbial engineering, and performance metrics critical for clinical translation. We provide a framework for designing next-generation living materials for human health, emphasizing opportunities and challenges in bringing these systems from bench to bedside.

Engineered live biotherapeutic products (LBPs) offer a promising avenue for targeted drug delivery, particularly within the gastrointestinal (GI) tract. Among microbial chassis, Saccharomyces cerevisiae (S. cerevisiae) is recognized as a highly favorable platform due to its safety profile, genetic amenability, and potential for dual functionality as both a therapeutic protein producer and probiotic. However, oral delivery of LBPs remains challenging due to the harsh conditions of the GI tract, which compromise microbial viability and therapeutic efficacy. To address this, we developed alginate-based hydrogel particles designed to encapsulate S. cerevisiae for oral administration and systematically evaluated their performance under simulated physiological conditions. Notably, we demonstrated that colony size can be tuned through specific alginate formulations, and that colony morphology significantly influences cell survival. Our findings establish key design principles for optimizing hydrogel carriers to enhance the viability and therapeutic potential of engineered microbial therapeutics.

Many kinds of drug are sparingly soluble in the acidic gastric fluid, and are practically insoluble in the pH-neutral intestinal fluid. The efficacy of oral therapies employing such drugs is often limited by the amount of drug that can be delivered into the blood stream. For enhancing the amount delivered, in the present work an expandable, solid-solution fibrous dosage form is presented. The dosage form investigated was a cross-ply structure of fibers comprising 200 mg of the sparingly-soluble drug nilotinib molecularly dispersed in hydroxypropyl methylcellulose (HPMC)-based excipient. Upon administering to a dog, it expanded to a normalized radial expansion of 0.5 within an hour and resided in the stomach for about five hours. The drug concentration in blood rose to a maximum of 1.82 µg ml⁻¹ by 4 hours, and decayed exponentially thereafter. The bioavailability (area under the drug concentration in blood versus time curve) was 10.81 µg h ml⁻¹. For comparison, the maximum drug concentration of an immediate-release capsule filled with 200 mg crystalline nilotinib particles was 0.68 µg ml⁻¹ by 2.5 hours. The bioavailability was 2.94 µg h ml⁻¹, a third of that of the fibrous form. Models suggest that the greater bioavailability of the fibrous dosage form is due to increased gastric residence time and supersaturation of the gastric fluid with the drug.

Liposomes are effective nanocarriers for targeted therapeutic delivery, yet challenges regarding the extent and specificity of cargo release persist. Many disease conditions result in metabolite concentration dysregulation, increasing the appeal to harness overly abundant metabolite concentrations as triggers for targeted delivery and cargo release. Here, we introduce a novel stimuli-responsive liposomal platform with a tunable response to either guanosine triphosphate (GTP) or tripolyphosphate (TPi) that was achieved through incorporation of a novel bis-phosphonium-based lipid switch (BPLS) and strategic manipulation of liposome composition. This platform enables selective cargo release triggered by GTP, a metabolite upregulated in many fast-growing cancer cells. Fine-tuning of liposome composition also allows for TPi triggered release, a model phosphate compound to illustrate the dual response of this system. Hydrophobic and hydrophilic dye release assays, dynamic light scattering, transmission electron microscopy, and kinetic cargo release studies confirmed metabolite-responsive membrane perturbation driven by BPLS, inciting controlled release of both polar and non-polar cargo. By fine-tuning liposome composition to control metabolite selectivity and release kinetics, this platform offers a versatile framework for addressing complex metabolite profiles in diseased cells, expanding the stimuli-responsive liposome toolbox toward the potential of customized drug delivery.

Boron neutron capture therapy (BNCT) aimed at treating brain tumors is deteriorated by the poor aqueous solubility of the BNCT agent, boronophenylalanine (BPA). Solubilizers, such as sorbitol, mannitol and xylitol and their mixing formulas, the storage temperature and time, acid adjusters, and antioxidants, as well as lyophilization conditions were studied. HPLC, ¹H-NMR, and scanning electron microscopy (SEM) were used to investigate the alditol–BPA samples. HPLC results showed that the stability of sorbitol–BPA samples improved when the antioxidant Na₂S₂O₅ was used, 98.25 ± 0.31% vs. 94.37 ± 1.24%, P < 0.05. The osmolality ratio of sorbitol–BPA, 0.83 ± 0.03, was lower than that of saline, 1.0, making it physiologically compatible. SEM results of the lyophilized samples showed a proportion of sorbitol–BPA vs. H₂O in a molar ratio of 1 : 10. Sorbitol was the best solubilizer according to the ¹H-NMR-derived integral ratio in the decreasing order of sorbitol–BPA, mannitol–BPA, fructose–BPA and xylitol–BPA with the values of 12.15 ± 1.30, 6.65 ± 0.61, 6.13 ± 1.90 and 4.77 ± 0.72, P < 0.05, respectively. The antioxidant Na₂S₂O₅ improved the stability of sorbitol–BPA at 25 °C according to the ¹H-integral ratio of 17.60 ± 2.15 vs. 12.67 ± 1.62, P = 0.10. The differences were not statistically significant. From both the HPLC and ¹H-integral results, sorbitol emerges as the optimal solubilizer for PBA for further in vivo studies.

Tridax procumbens is a widely recognized medicinal plant known for its remarkable antimicrobial and wound-healing effects. Nevertheless, its therapeutic efficacy is often restricted due to low bioavailability. This study aimed to formulate and evaluate a Tridax procumbens-loaded phospholipid complex (phytosome) gel to enhance its transdermal delivery and therapeutic efficacy. The optimization of the phytosomal gel was conducted using a central composite design, where soy lecithin and cholesterol were the primary independent variables affecting particle size and entrapment efficiency. The ideal formulation showed a particle diameter of 460.2 nm and a loading capacity of 93.14%, ensuring improved permeation and prolonged drug release. Antimicrobial studies demonstrated improved efficacy against E. coli, with the phospholipid complex gel exhibiting a zone of inhibition (ZOI) of 32 mm, compared to 28 mm for the ethanolic extract and 30 mm for the standard drug amikacin. In vitro wound healing studies using L929 fibroblast cells showed that the phospholipid complex gel achieved 54.34% wound closure after 48 hours, compared to 41.57% for the ethanolic extract and 87.53% for the standard drug cipladine. These results suggest that the phospholipid complex (phytosome) system significantly enhances the bioavailability and therapeutic potential of Tridax procumbens for wound healing and antimicrobial applications.

Lipid nanoparticles (LNPs) are self-assembled nanocarriers made up of ionizable cationic lipids, membrane lipids, sterols, and PEGylated lipids in a predetermined proportion to encapsulate nucleic acid payloads. According to recent findings, following local administration (intramuscular, intratumoral), LNPs diffuse into the systemic circulation and subsequently show liver transfection. Liver transfection can result in both liver toxicity and undesirable cargo distribution. To address this issue, we synthesized a novel cholesterol derivative, glutamate–cholesterol (GA–Chol), which, when incorporated in LNPs (GA–Chol LNPs), improved in vitro transfection efficiency by approximately 10-fold and 20-fold in HEK293T and HeLa cells, respectively. Furthermore, when GA–Chol LNPs were injected intramuscularly or intratumorally, robust localized transfection was observed in either the injected muscle or the flank tumors, without significant transfection in the liver. This observation was consistent across multiple cell lines, representing various types of cancer. Leverage local delivery strategy, mRNA encoding for constitutively active caspase-3 was encapsulated with GA–Chol LNPs and delivered intratumorally in 4T1 tumor-bearing BALB/c mice, resulting in a significantly reduced and sustained tumor burden. Overall, these findings describe the potential application of a synthetic cholesterol derivative for the localized transfection of LNPs.

Delivery of azithromycin via liposomal formulation (L-AZM) has been shown to improve the therapeutic index and activity of AZM in a preclinical model of cardiac injury, suggesting strong potential for clinical translation to treat inflammation after a myocardial infarction. However, conventional thin film hydration (TFH) utilized to prepare L-AZM limits its clinical development due to scalability and reproducibility concerns. To overcome these manufacturing challenges, we performed a systematic optimization of the L-AZM formulation utilizing microfluidic nanoprecipitation which has been successfully used for large scale manufacturing of lipid-based therapeutics in a reproducible manner. We adjusted the microfluidic operation parameters and evaluated the resultant liposomes for critical quality attributes (CQAs) of size, polydispersity index (PDI), encapsulation efficiency, and leakage. The optimal flow rate ratio (FRR) and total flow rate (TFR) for the lead formulation was determined to be 4 : 1 and 10 mL min⁻¹, respectively. Utilizing these manufacturing parameters with formulations of different molar ratios resulted in an optimized formulation consisting of DSPC : DSPG : Chol : AZM (1 : 1 : 1 : 0.5) based on the CQAs with decreased size and PDI as compared to TFH. Notably, there is no difference in in vitro macrophage polarization activity between the two formulation methods. Collectively, these data guide continued preclinical development as we advance this formulation toward clinical use.

Tuberculosis (TB) is the second deadliest communicable disease caused by Mycobacterium tuberculosis and mainly affects the lungs. Current TB therapy typically involves the oral administration of antitubercular drugs (ATDs). However, this approach is often associated with challenges, such as drug toxicity, suboptimal pulmonary drug concentration, and issues with patient adherence. Moreover, isoniazid (INH) therapy frequently induces pyridoxine (PDX) deficiency in TB patients, potentially leading to neuropathy. In this study, INH–PDX nano-embedded microparticles (NEMs) were developed as a dry powder formulation to enhance pulmonary TB treatment. The formulation was optimised using a microreactor through a three-factor, three-level Box–Behnken design (BBD). The optimised dry powder achieved a product yield of 48.36% (w/w) and a drug-loading efficiency of 24.14 ± 2.86% (w/w). The particles exhibited a spherical morphology. Furthermore, aerosolization performance demonstrated the formulation's suitability for deep lung deposition, with a mass median aerodynamic diameter (MMAD) of 5.97 ± 1.10 µm, a fine particle fraction (FPF) of 36.63 ± 3.12%, and a geometric standard deviation (GSD) of 1.73 ± 0.23. In conclusion, the Design of Experiments (DoE)-based optimisation approach successfully optimised the process parameters and produced a dry powder formulation suitable for pulmonary delivery in patients with TB, addressing both treatment efficacy and neuropathy concerns.

The development of safe and effective anticancer drugs remains a significant challenge for the scientific community. A broad range of chemotherapeutic agents has been extensively evaluated for their efficacy across various patient populations. Among them, epirubicin has exhibited strong anti-cancer potential across different tumor models. In this study, epirubicin-loaded bovine serum albumin nanoparticles (EPI@BSA) were prepared using the desolvation method to explore their potential in lung cancer therapy. Physicochemical characterization confirmed that the nanoparticles were spherical and highly monodispersed. Cytotoxicity testing on the A549 cell line revealed enhanced cell death with the nanoparticle formulation compared to that with the free drug. Furthermore, semi-quantitative RT-PCR analysis indicated that the nanoparticles effectively induced apoptosis. These findings support the potential of a protein-based biodegradable carrier system to enhance the therapeutic efficacy of epirubicin in cancer treatment.