Drug Delivery and Translational Research最新文献

Bydureon^® is a once-weekly injection of poly(lactide-co-glycolide) (PLGA) microspheres containing exenatide acetate, a synthetic analog of the GLP-1 receptor agonist exendin-4. These microspheres are formulated by coacervation (i.e., phase separation), using a single-emulsion method. There remains a knowledge gap between how formulation variables affect product attributes and performance. We aimed to bridge this gap by evaluating the effect of formulation variables on encapsulating exenatide in PLGA microspheres at similar compositions to Bydureon^®. We first screened process variables without peptide to establish stability windows during coacervation, i.e., conditions that produced high yields of well-formed microspheres. We introduced exenatide during coacervation as a function of PLGA concentration, DCM (dichloromethane): water and DCM: Si oil (polydimethylsiloxane) volume ratios, hold time between Si oil addition and heptane bath immersion, and other manufacturing conditions. We evaluated the formulation yield, residual solvent content, encapsulation efficiency, and 24-h release. A PLGA concentration of 6% w/w was selected because of its wide range of stable formulations with varying DCM: Si oil phase volume ratios. The hold time between Si oil addition and heptane immersion was set at 1 min, although microspheres were stable between a range of 10 s to 2 min. The resultant formulations displayed elevated yields of > 50%, and a low in-vitro 24-h burst release of 2-6%. These formulations exhibited continuous release profiles of predominantly parent and glycolic acid acylated peptide for over 56 days in vitro, as expected by the commercial product. The framework of conditions and their effects on the formulations was established for loading exenatide in PLGA microspheres with desirable release characteristics. These results are useful for both microencapsulation of generic and new peptides in PLGA microspheres by coacervation.

Fungal keratitis (FK), caused by fungi like Aspergillus, Fusarium, and Candida, accounts for 20-60% of microbial keratitis cases and over 1 million visual impairments annually. Voriconazole (VOR) is effective against FK, but its eye drop formulations suffer from poor bioavailability, while intrastromal injections are invasive and carry risks. This study aimed to address these challenges by formulating a VOR nanosuspension (NS) and fabricating an ocular bilayer dissolving microneedle array patch (dMAP) incorporating the VOR NS for localized drug delivery to the cornea. The VOR NS was prepared using an aqueous media milling method with polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) as stabilizer and cryoprotectant, resulting in stable nanosized particles with a mean size of 270.11 ± 5.82 nm and a PDI of 0.217 ± 0.019. The formulation demonstrated a 1.71-fold increase in saturation solubility and a high drug content (72.5%). Both VOR NS and free VOR were incorporated into the MAP tips using a two-layer casting method. The VOR NS-loaded bilayer dMAP exhibited higher drug content (118.84 ± 20.67 µg) compared to the free VOR-loaded bilayer dMAP (83.08 ± 2.69 µg). Additionally, they demonstrated superior mechanical strength, greater insertion depth (~ 390 μm), and faster tip dissolution in excised porcine corneal tissue (~ 5 min) compared to the free VOR-loaded bilayer dMAP. Ex vivo studies showed that the VOR NS-loaded bilayer dMAP deposited 47.38 ± 8.08 µg of drug into the porcine cornea, 2.31 times more than the free VOR-loaded bilayer dMAP (20.43 ± 6.11 µg), closely approximating the clinical dose used in VOR intrastromal injections (50 µg/0.1 mL). Furthermore, the disc diffusion assay revealed that VOR NS and VOR NS-loaded bilayer dMAP had greater antifungal activity against Candida albicans and Aspergillus fumigatus compared to free VOR and free VOR-loaded bilayer dMAP. Biocompatibility was confirmed through a human corneal epithelial cell viability assay, and ocular irritation potential was evaluated using the HET-CAM assay, revealing a safe and non-irritant profile. Thus, this innovative NS-MAP hybrid system offers efficient drug delivery with minimal invasiveness and could potentially improve therapeutic outcomes in the management of FK.

Buccal and sublingual mucosae offer highly vascularized, patient-acceptable routes for systemic peptide delivery, providing a promising alternative to peptide injections and conventional oral peptide dosage forms that suffer from enzymatic degradation, limited permeability, and hepatic first-pass metabolism. Despite these advantages, achieving consistent peptide bioavailability from oromucosal dosage forms remain challenging due to salivary washout, enzymatic instability, and the compact, lipid-rich epithelial structure. This review provides a comprehensive overview of formulation strategies developed to overcome these barriers, with an emphasis on the use of permeation enhancers (PEs), mucoadhesive polymers, and multilayer film architectures. Advances in nanoparticle-integrated films are highlighted for their potential to improve peptide stability and mucosal permeation. The review concludes by addressing patient compliance, translational potential, and regulatory perspectives that shape the clinical advancement of peptide-loaded oromucosal films.

Breast cancer remains one of the most prevalent causes of cancer-related mortality worldwide. Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that has a poor prognosis and limited therapeutic options. Smart nanocarriers have been developed through significant advancements in nanotechnology over the past few years. To increase therapeutic effectiveness while reducing systemic toxicity, recent developments in nanotechnology have led to the creation of smart nanocarriers-nanosystems designed to carry drugs in a targeted, stimulus-responsive manner. Liposomes, dendrimers, micelles, carbon nanotubes, and polymeric nanoparticles are among the most common types of smart nanocarriers discussed in this study. Their design principles and functional features characterize the many forms of smart nanocarriers. Targeting techniques specific to breast cancer are highlighted, with a particular focus on active targeting via ligands and tumor microenvironment-responsive systems applicable to TNBC. By examining the integration of biodegradable materials, green synthesis methods, and alignment with the global Sustainable Development Goals (SDGs), the study also underscores the crucial role of sustainability in nanomedicine. Significant advancements have been made, but several biological, regulatory, and therapeutic issues still hinder the practical application of nanomedicine in treating TNBC. This review highlights key translational roadblocks and proposes strategic solutions to bridge the gap between the bench and the bedside.

Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctorius exhibit multi-target anti-AS potential, yet their compositional complexity limits clinical translation. This study aimed to systematically identify core anti-AS components from these herbs and enhance their anti-AS efficacy via machine learning-aided screening and nanotechnology-driven codelivery. We initially pioneered a machine learning-aided hybrid strategy integrating network pharmacology and quantitative activity relationship (QSAR) modeling to identify four core anti-AS polyphenols (i.e., salvianic acid A, salvianolic acid B, protocatechuic acid, and hydroxysafflor yellow A). Subsequently, a quaternary metal-phenolic network (SSPH-MPN) was engineered for plaque-targeted codelivery, optimized via the median-effect principle for achieving a synergistic effect based on ROS scavenging efficacy. The optimized SSPH-MPN was characterized by a series of studies, including molecular dynamics simulations, UV, DLS, TEM, FTIR, XPS, and ICP-MS. The anti-AS effect of the optimized SSPH-MPN was evaluated by monitoring oxidative status (ROS levels, antioxidant enzymes SOD, GSH-Px, MDA, T-AOC), inflammatory markers (IL-1β, IL-6, TNF-α), lipid metabolism (DiI-oxLDL uptake, cholesterol efflux, blood lipid levels, lipid accumulation), and plaque areas. The results demonstrated that the optimized SSPH-MPN showed great efficiency in inhibiting lipid uptake and accumulation, and mediating cholesterol efflux in RAW 264.7 cells, and exhibited improved lipid metabolism, attenuated oxidative stress and inflammation, thus acquired diminished plaque area in apoE^-/- mice. Furthermore, biocompatibility was assessed through hemolysis, cytotoxicity assays, and in vivo safety studies, confirming its suitability as a safe therapeutic agent. In conclusion, this work not only identified four anti-AS polyphenols from traditional herbs but also established an MPN-based co-delivery system for synergistic anti-AS therapy, providing a comprehensive paradigm from drug discovery to formulation development.

The"Breathing Lung-on-a-Chip,"a novel microfluidic device featuring a stretchable membrane, replicates the natural expansion and contraction of the human lung. It provides a more realistic in-vitro platform to study respiratory diseases, particle deposition, and drug delivery mechanisms. This device enables investigations into the effects of inhaled nanoparticles (NPs) on lung tissue and supports the development of advanced inhalation therapies. Uniform and optimal concentration delivery of NPs to cultured cells within the chip is critical, particularly as membrane stretching significantly influences particle dynamics. To address this, we developed a 3D numerical model that accurately simulates NP behavior under dynamic conditions, overcoming experimental limitations. The model, validated against experimental data, explores the effects of flow dynamics, particle size, membrane porosity, and stretching frequency/intensity on NP deposition in the air channel and transfer through the porous membrane into the medium channel. The results indicate that increased membrane stretch enhances the sedimentation rate of NPs in the air channel, thereby promoting their transfer to the medium channel, particularly in membranes with initially low porosity. Additionally, excessive stretching frequencies or intensities can introduce reverse flow and stagnation, leading to a longer residence time for NPs and altering their sedimentation patterns. These insights advance our understanding of NP transport in dynamic lung environments, paving the way for more effective applications of lung-on-a-chip technology in toxicological assessments and respiratory therapy innovations.

Exosomes are nano vesicles secreted by the cells that play an essential role in intercellular communication, enabling the transport of bioactive molecules, including proteins, lipids, and nucleic acids. Among them, plant-derived exosome-like nanovesicles have attracted considerable interest due to their prospective therapeutic implications, especially for neurological disorders. This article provides an overview of the biogenesis of plant-derived exosome-like nanovesicles, compares their characteristics with mammalian-derived exosomes, and investigates their bioavailability and chemical composition. The article also discusses the mechanisms through which they are uptaken by cells, highlighting several cellular uptake pathways and their significance for targeted drug delivery. Moreover, it explains the molecular basis of neurological disorders and investigates how plant-derived exosome-like nanovesicles regulate intracellular signaling pathways, providing potential therapeutic benefits. Finally, it provides the latest advancements in engineering research, emphasizing biochemical modifications on the exosomal surface, loading therapeutic molecules into exosomes, and exosomes derived from genetically engineered plants, for more effective therapies in neurological disorders.

Owing to faulty DNA damage repair system, triple negative breast cancer (TNBC) exhibits high susceptibility towards DNA damaging drugs such as platinum compounds e.g., oxaliplatin. Nevertheless, the clinical utility of oxaliplatin (OXA) has been constrained due to chemoresistance and chronic toxicities. Hence, to confer systemic inertness, tumor specific delivery, and multifaceted action, a octahedral OXA-CBL prodrug was synthesized using chlorambucil (CBL) as an axial ligand. The combination of OXA and CBL exhibited synergistic anti-cancer action in TNBC cell lines. Further, to potentiate the cellular internalization, targeting efficiency, and in-vivo performance, the synthesized prodrug was loaded into bovine serum albumin nanoparticles (OXA-CBL/BSA-NPs). The prepared nanoparticles had optimal particle size < 200 nm and high drug loading (∼ 5.863 ± 0.16%). As relative to free conjugate, the nanoparticles exhibited amplified cellular internalization and reduced the IC₅₀ in 4T1 (∼ 1.38-fold) and MDA-MB-231 (∼ 1.43-fold) cell line. The anti-cancer study in 4T1-based TNBC model in BALB/c mice demonstrated significantly higher tumor inhibition rate, and reduced tumor burden in OXA-CBL/BSA-NPs treated group. Toxicity assessment revealed no signs of hepato- and/or renal toxicity. Also, nanoparticles exhibited sufficient compatibility with erythrocytes. Overall, delivery of OXA-CBL via virtue of albumin nanoparticles presents safer and efficacious approach to combat TNBC.

Most vaccines require refrigerated transport and storage, which is costly, challenging in low-resource settings, and results in the loss of up to 50% of vaccines globally due to "cold-chain" failures. Here, tetanus toxoid vaccine (TT) was thermostabilized by encapsulation within a metal-organic framework (MOF), zeolitic imidazolate framework-8 (TT@ZIF-8). Its physicochemical properties were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and confocal microscopy. Unencapsulated TT fell below the 80% activity threshold within 4 days at 40˚C and 60˚C according to immunoassay analysis. Aqueous suspensions of TT@ZIF-8 also declined below 80% activity within a week at both temperatures, likely due to MOF degradation in water. Dried TT@ZIF-8 performed better, retaining 80% stability for 33 days at 40˚C and 22 days at 60˚C. When TT@ZIF-8 was suspended in a non-aqueous mixture of propylene glycol and ethanol, it remained 80% stable for approximately 4 months at 40˚C and 2.5 months at 60˚C. Arrhenius modeling predicted this formulation may qualify for "controlled temperature chain" designation, allowing partial vaccine removal from the cold chain. These studies suggest that MOF encapsulation of vaccines like TT can enable dramatic improvements in vaccine stability during storage without refrigeration.