Drug Delivery最新文献

Although numerous drugs have been developed for intravaginal administration, the implementation of personalized intravaginal treatment options is limited. The MedRing overactive bladder (OAB) system is a medical device for intravaginal oxybutynin administration via patient-controlled schedules. The primary aim was to assess the feasibility, tolerability, and safety of intravaginal oxybutynin administration via the MedRing OAB system. Second, the functioning of the MedRing OAB system, user satisfaction and quality of life (QoL) were assessed. Female OAB patients were included to receive the MedRing OAB system. Treatment was divided into three periods with increasing dosing flexibility: 2 mg at three fixed timepoints daily, 2 mg at three patient-defined timepoints daily, and flexible dosing up to 6 mg/day of 1 or 2 mg doses. Feasibility, tolerability, satisfaction, and QoL were assessed via questionnaires, safety via treatment-emergent adverse events (TEAEs), device deficiencies (DDs) and physical examination and functioning via pharmacokinetics and MedRing logs. Thirteen patients were enrolled, of whom three patients discontinued the study prematurely. Most patients reported low user burden, found the system practical and expressed positive opinions. The TEAEs were consistent with known oxybutynin effects and local TEAEs were comparable to other intravaginal devices. Most DDs were synchronization difficulties, which improved after a software update. After 10 minutes, oxybutynin levels were detected in 12 of the 13 patients. This study showed that the MedRing OAB system appears to be a feasible, tolerable and safe alternative intravaginal oxybutynin administration for 28 days in OAB patients, offering a potential alternative to existing treatment options and introducing personalized patient care.

The instability of liposomes in blood samples during clinical drug research and drug monitoring results in the inability to accurately determine the actual drug concentrations in the body at the time of collection, mainly due to lipid deterioration, particle fusion or aggregation, and phase separation degradation, resulting in payload leakage. To improve drug monitoring accuracy, we developed a cryopreservation strategy in this study by innovatively combining cryoprotective agents (CPAs), such as L-proline, sucrose, and polyvinyl alcohol (PVA), to prevent liposomal leakage and maintain stability for reliable drug monitoring and clinical drug research applications. Doxorubicin liposomes were prepared, and the CPAs were tested at various concentrations and under different freeze‒thaw protocols in biological matrices, with the stability and leakage of the liposomes assessed. Each CPA contributes distinct stabilization mechanisms, with L-proline's osmoprotective ability, sucrose's hydrogen bonding, and PVA's steric hindrance to form a protective barrier. The optimized CPA combination demonstrated superior performance at 85% (v/v) by preserving liposomal integrity, offering the best cryoprotective effect for liposomes in plasma stored at -20 °C, achieving about 90% entrapment efficiency, compared to about 60% in the control group without CPAs. Mechanistic investigations confirmed that CPAs protect liposomes against mechanical stress, prevent membrane disruption, and reduce ice damage by inhibiting recrystallization and adjusting bilayer hydration. These findings offer practical solutions for accurate pharmacokinetic assessments and reliable personalized dosing, safer alternative for liposomal drug research, biobanking, and real-world therapeutic monitoring.

Oral insulin delivery represents a transformative approach to diabetes management, offering improved patient compliance and physiological insulin delivery patterns compared to subcutaneous injection. However, multiple gastrointestinal barriers, including enzymatic degradation, mucus entrapment, epithelial impermeability, and first-pass metabolism, have limited oral bioavailability to below 1% for unmodified insulin. This review comprehensively examines contemporary strategies to overcome these barriers. We analyze structural modifications of insulin, including PEGylation, lipidation, cyclization, and glycoengineering, which enhance stability while maintaining biological activity. The analysis extends to sophisticated formulation technologies incorporating nanocarriers (polymer-based, lipid-based, inorganic nanocarriers, and metal organic frameworks), biomimetic systems, and stimuli-responsive mechanisms for protection and delivery. A central focus is on absorption-enhancing strategies, which range from chemical permeation enhancers to precise biological mechanisms like receptor-mediated transcytosis and other active transport pathways. Emerging tools such as microbiome-based carriers and smart devices are also discussed. Despite significant progress in preclinical models, challenges remain in manufacturing scalability, inter-patient variability, long-term safety, and regulatory approval. Future directions emphasize hybrid delivery systems, digital health integration, and personalized formulations. Realizing clinically viable oral insulin requires continued multidisciplinary collaboration addressing biological, technological, and translational barriers to transform diabetes care.

Peritoneal metastasis (PM), as a terminal stage of malignant tumors with extremely poor prognosis, remains a clinical challenge. Intraperitoneal (IP) administration enhances local drug concentrations, improving survival outcomes for PM patients. However, rapid drug clearance and uneven distribution limit its therapeutic potential. In recent years, hydrogel-based drug delivery systems have garnered attention due to their excellent biocompatibility, drug loading capacity, and controlled release properties. The use of hydrogel-loaded drugs via IP injection can significantly improve anti-cancer efficacy by increasing the local drug concentration, prolonging the retention time of the drug in the peritoneal cavity, and decreasing systemic toxicity. This review summarizes the pathogenesis and current treatment strategies of PM, emphasizing various drugs (including chemotherapy agents, immunotherapeutics, targeted drugs, radioactive isotopes, and herbal medicines) delivered via hydrogel-based IP administration. Furthermore, it highlights the potential of nanoparticles and microparticle-hydrogel composites to further improve drug delivery, offering new strategies for PM treatment and theoretical basis for clinical rational drug use.

Human serum albumin (HSA) has attracted significant attention in drug delivery since the approval of Abraxane in 2005. Abraxane is a nanoparticle albumin-bound paclitaxel (nab-PTX) formulation. Although HSA offers advantages such as prolonged circulation time (half-life ~19 days) and intrinsic hydrophobic pockets, the translation of other HSA-based nanomedicines remains limited. In fact, the significant differences between native and pharmaceutical HSA in protein structure and biological interactions could hinder their translational use in drug delivery. In this study, we demonstrate that pharmaceutical HSA (α-helix = 17%) is structurally denatured compared with native HSA (α-helix = 68%), leading to rapid clearance (<1 h) from the circulation and that drug loading is driven by pharmaceutical HSA's amphiphilicity rather than by its hydrophobic pockets. Here, we revealed that Nab-PTX is composed of protein-coated PTX solid cores. These nanosystems have insufficient surface charge (ζ = -13.7 mV), leading to aggregation, and low colloidal stability, resulting in premature drug release upon dilution (<0.1  mg/mL). To address these shortcomings, we developed HSA-polylactic acid (HSA-PLA) nanoparticles with enhanced negative surface charge (ζ = -27.4 mV) and improved colloidal stability to reduce the premature release of encapsulated PTX upon dilution (<0.01  mg/mL). In tumor models, comparative pharmacokinetics, biodistribution, and efficacy studies demonstrated that HSA-PLA (PTX) nanoparticles reduce premature drug release, resulting in greater tumor exposure (129 ± 3 vs. 90 ± 12 µg·h/g, p < 0.01) and superior antitumor efficacy compared with Abraxane. These improvements further suggest that optimization may require only a simple modification when guided by proper theoretical principles.

Recombinant DNA vaccines offer significant potential for disease prevention and therapy, but their clinical success is often limited by poor immunogenicity, low cellular uptake, instability, and inefficient delivery without proper carriers. To address these challenges, we developed a series of novel cationic delivery systems by modifying branched polyethyleneimine (PEI, 25 kDa) with biocompatible carboxylic acids either lactic acid or glycolic acid and incorporating choline-based ionic liquids (choline glycolate [CG] and choline lactate [CL]) to create advanced mPEI/ionic liquid (IL) formulations. These systems were designed to enhance DNA complexation, protect against enzymatic degradation, improve nanoparticle stability, and fine-tune physicochemical properties for optimal cellular interaction. The resulting polyplexes formed stable nanoparticles with diameters 100 -125 nm and surface charges of +24 to +29 mV, supporting efficient cellular uptake. Compared to unmodified PEI, the modified formulations showed markedly reduced cytotoxicity and significantly improved transfection performance. Among all tested combinations, the combination of lactic acid-modified PEI with choline glycolate (LA-mPEI + CG) was the most effective, achieving a 76% increase in transfection efficiency, a 66% improvement in cellular uptake, and 66% enhanced in cell viability. These findings highlight the synergistic advantage of combining carboxylic acid modification PEI with ionic liquid incorporation, providing a promising strategy for safer and more effective non-viral DNA delivery. This platform may serve as a foundation for future advancements in gene therapy and DNA vaccine development.

Targeted drug delivery systems represent a promising strategy for enhancing the efficacy and specificity of cancer therapy. In this study, 35 nm folate-targeted gold nanoparticles are presented as nanoparticle-drug conjugates obtained by anchoring on their surface lipoyl terminating doxorubicin prodrug (proDoxo) releasable at the endolysosomal acidic pH to prevent off-site toxic effects. Colloidal stable nanoparticles with a density of proDoxo up to 1000 molecules/particle and 2 kDa mPEG-SH coating were obtained. At pH 5, Doxo was completely released from the nanoparticles in 5 days while only 13% was released over the same period at pH 7.4. The nanoparticle decoration with folic acid as a targeting agent bestowed nanosystems with selective drug delivery to folate receptor (FR)-overexpressing cancer cells and controlled intracellular release. This led to enhanced cancer cell killing by folated nanoparticles compared to their nontargeted counterparts. Moreover, folated nanoparticles were found to distribute more homogeneously inside KB^FR+ cancer cell spheroids than non-targeted nanoparticles, resulting in higher spheroid volume reduction.

This study aimed to develop alginate-based raft-forming systems incorporating propolis-whey protein isolate (5%) nanocomplexes to alleviate reflux symptoms and enable the sustained, gastric-specific delivery of propolis for ulcer management. Propolis-protein complexes were prepared at four ratios (2.5:100, 5:100, 7.5:100, and 10:100 w/v) by heating at 85 °C for 5 h at pH 2, producing nanofibrils characterized by thioflavin T fluorescence, intrinsic fluorescence, encapsulation efficiency (up to 78%), and antioxidant activity. The optimal complex was incorporated into alginate rafts at 5%, 10%, and 15% (w/v). Rafts exhibited prolonged floatability (>8 h), increased thickness (from 3.2 ± 0.4 mm to 4.7 ± 0.3 mm with higher propolis loading), enhanced mechanical strength (up to 1.6-fold improvement), and improved reflux resistance. SEM imaging revealed a more compact and uniform porous structure, while FT-IR confirmed molecular interactions between alginate and the propolis-protein complex. In vitro release studies in simulated gastric fluid showed suppression of initial burst release, with sustained propolis release over 6-8 h. Overall, alginate rafts containing propolis-protein nanocomplexes demonstrated enhanced structural performance, controlled release behavior, and promising potential for targeted gastric delivery in the management of gastric ulcers.