International Journal of Pharmaceutics: X最新文献

Erythropoietin (EPO) shows promise for Alzheimer's disease (AD) but has poor brain penetration, necessitating high doses that cause hematopoietic side effects. To improve brain delivery, EPO was fused to a transferrin receptor monoclonal antibody (TfRMAb), and this study evaluated the pharmacokinetics (PK), safety, and efficacy of repeated TfRMAb-EPO dosing in mice to further its preclinical development. C57BL/6J male mice (10 weeks old, n = 4-5/dose) received subcutaneous (SQ) low (1 mg/kg), mid (3 and 6 mg/kg), or high (20 mg/kg) TfRMAb-EPO doses for 4 weeks. The 1 mg/kg dose showed no adverse effects and resulted in sustained brain and plasma exposure, making it suitable for longitudinal dosing. Paradoxically, higher doses reduced plasma and brain exposure, and altered hematocrit, TfR expression, and spleen weight; these changes were largely reversible. Anti-drug antibodies and TfR expression changes likely contributed to reduced plasma exposure at higher doses. Subsequently, 5.5-month-old APP_SAA knock-in (KI) mice (n = 6) received 1 mg/kg TfRMAb-EPO SQ for 14 weeks. Controls included vehicle-treated APP_SAA KI and APP wild-type mice (n = 4-5/group). Despite the low dose, TfRMAb-EPO showed profound brain Aβ-lowering effects measured by immunostaining (70-80 % reduction, p < 0.001) and improved spatial memory in the Y maze (p < 0.05). These findings offer important preclinical data to guide dose optimization in longitudinal studies using TfRMAb-based therapeutics, specifically TfRMAb-EPO, given the movement of TfRMAb-based therapeutics into clinical trials for AD, and show the robust therapeutic potential of low-dose TfRMAb-EPO in APP_SAA KI AD mice.

Glioblastoma treatment is hindered by the blood-brain barrier (BBB), which limits the penetration and accumulation of chemotherapeutic agents. Paclitaxel (PTX), an effective chemotherapeutic drug, faces clinical challenges due toits poor solubility and restricted ability to traverse the BBB. Consequently, there is an urgent need for advanced drug delivery systems to facilitate the efficient and safe translocation of PTX across the BBB. In this study, PTX was encapsulated within nanoemulsions (NEs) conjugated to lactoferrin (Lf) via electrostatic interactions, followed by the optimization of its formulation. To investigate cellular uptake and BBB penetration, fluorescent dye coumarin 6 (C6) was incorporated into NEs. Uptake was evaluated in GL261 cells and BBB penetration in hCMEC/D3 cells. Further studies were conducted on the biodistribution in mice and the therapeutic efficacy in murine intracranial glioblastoma model. Characterization of PTX@Lf-NE demonstrated stability, biological safety, and favorable release properties. Notably, the fluorescence intensity of C6@Lf-NE was twice of C6@NE in one hour post-administration, and the drug uptake rate decreased with the addition of free Lf, confirming that Lf promotes the ability of NEs to traverse the BBB. In vivo distribution further revealed that Lf-NE increased brain distribution while reduced accumulation in other organs. In the glioblastoma model, it was found that the bioluminescent intensity of PTX@Lf-NE was significantly lower than that of PTX@NE on the 15th day of administration, indicating that the modification with Lf facilitated the targeted delivery of PTX and enhanced its therapeutic efficacy. This study successfully designed and developed an effective drug delivery system for glioblastoma treatment, which improves the translocation of drugs across the BBB.

Sexually transmitted infections (STIs) remain a major global health challenge, highlighting the urgent need for effective and user-friendly vaginal prevention strategies. This study presents a novel composite system for vaginal application, consisting of mucoadhesive electrospun nanofibres with inherent antiviral potential embedded within a pH-responsive film. The film is designed to preserve the integrity of the nanofibres in the acidic vaginal environment and to dissolve rapidly upon contact with seminal fluid - released during sexual intercourse -, triggering nanofibre hydration and interaction with the mucosal surface. Electrospinning successfully produced uniform and defect-free nanofibres consisting of polyvinyl alcohol (PVA) blended with either κ- or ι-carrageenans (CAR), sulphated polysaccharides known for their mucoadhesive, gelling and intrinsic antiviral properties. Different solutions containing Eudragit® polymers (EL100 or EL100-55) and plasticisers (polyethylene glycol or glycerol) were prepared and cast to identify the most suitable composition for developing the composite system. Solutions capable of forming films with optimal mechanical flexibility and rapid solubility under mildly alkaline conditions were selected. The composite system was fabricated by embedding nanofibres between two partially dried layers of the selected pH-responsive solutions, forming a uniform composite structure that ensured complete fibre incorporation. The outer film effectively protected the nanofibrous core in acidic environments; upon pH increase (pH ∼7.5), the film rapidly dissolved, allowing the nanofibres to hydrate and form a cohesive, strongly mucoadhesive hydrogel, potentially enhancing their retention within the vaginal cavity. Overall, the composite system exhibited good structural integrity, pH-responsiveness, biocompatibility and antiviral potential, offering a promising, non-hormonal strategy for on-demand STI prevention.

Cancer represents a significant global health threat, and traditional chemotherapy (CT) often encounters limitations in efficacy due to systemic toxic side effects and tumor heterogeneity. The combination of chemodynamic Therapy (CDT) and CT offers a potential solution to overcome the constraints of single-agent therapies. However, many CT/CDT collaborative systems have critical shortcomings, including insufficient active targeting capabilities, depletion of H₂O₂ substrates leading to a reduction in CDT effectiveness, and the heterogeneity of redox within tumor cells, which can result ultimately limit overall efficacy. This study developed a redox heterogeneity-responsive CT/CDT nanoparticle, named HFMD, with the goal of overcoming the limitations associated with traditional CT/CDT nanoparticles. In vitro experiments demonstrated that HFMD exhibits redox-sensitive drug release characteristics and the capacity to generate hydroxyl free radicals. Additionally, HFMD enhances H₂O₂ supply, improves CDT efficiency, and shows significant inhibitory effects on multiple cancer cell lines. In vivo experiments further validated that HFMD possesses excellent tumor-targeting enrichment capabilities and remarkable anti-cancer efficacy, achieving a tumor inhibition rate of approximately 80.1 %. The biological safety assessment indicated that HFMD demonstrates good biocompatibility and successfully mitigates the dose-limiting toxicity associated with free doxorubicin. Overall, this study presents a promising strategy for enhancing anti-cancer efficacy.

Ring layer granulation is a wet granulation process, which can be applied for the continuous production of pharmaceutical granules as an alternative to other continuous granulation techniques like twin screw granulation or continuous fluidised bed granulation. However, the ring layer process itself has so far been the subject of only little fundamental scientific investigation. Additionally, for the few published studies, medium to large scale ring layer granulators were utilized for which large quantities of sample material was necessary. This shortfall is addressed in the present study, in which the unique lab scale ring layer granulator Granucon®1, giving the possibility of small scale experiments and production campaigns, was investigated. The ring layer process was studied for the wet granulation of microcrystalline cellulose, an insoluble primary material, with variation of the process parameters tip speed, binder supply rate and solid feed rate. Moisture content showed the most significant effect on the granulation results, while shaft speed and solid feed rate influence the residence time of the granules inside the ring layer granulator. Further, while a certain shaft speed had to be reached for the ring layer to form, it also had a strong effect on the granule morphology due to its effect on the mechanical stress acting on the granules.

Non-small cell lung cancer (NSCLC) currently stands as the predominant etiological factor underlying lung cancer-related mortality on a global scale. Conventional drug delivery methods are associated with significant toxic side effects, highlighting the necessity to develop novel targeted delivery systems to improve the therapeutic efficacy of lung cancer treatment. Here, we aimed to develop a pulmonary drug delivery system for triptolide (TP) to treat orthotopic lung cancer. Herein, triptolide-loaded liposomes (TP-lip) were prepared to reduce the toxicity and improve the solubility of triptolide. Macrophage membranes (MM), rich in Siglec-10, were engineered onto the liposomes to enhance the tumor targeting through specific binding to Cluster of differentiation 24 (CD24), a molecule overexpressed on lung tumor cells. Regardless of macrophage polarization, the high Siglec-10 expression on cell membranes ensures effective tumor cell targeting. After modifying different types of MMs on TP-lip and nebulizing them, the aerodynamic fine particle fraction (FPF) of TP formulations exceeded 50%, and the mass median aerodynamic diameter (MMAD) was below 5 μm, suitable for pulmonary delivery. MM-modified liposomes showed higher cellular uptake and stronger inhibitory effects on LLC lung tumor cells. Pharmacokinetic studies showed that intratracheal administration (aerosolized drug delivery) of MM-lip could reduce the systemic drug exposure compared to intravenous injection, while achieving effective accumulation in lung tissues. Pulmonary delivery of M0-TP-lip significantly enhanced the anti-tumor efficacy and improved the lifespan of orthotopic lung tumor-bearing mice, with no apparent systemic toxicity observed. Overall, this highlights the potential of inhalable, biomimetic triptolide loaded liposomes for pulmonary tumor treatment through Siglec-10-mediated targeting.