Pharmaceutics

Central nervous system (CNS) disorders remain difficult to treat because many pharmacologically active molecules do not achieve adequate exposure in the brain. The blood–brain barrier (BBB), blood-cerebrospinal fluid (CSF) barrier, efflux transporters, extracellular matrix, and local clearance mechanisms impose different constraints according to the target compartment and administration route. Nanocarriers can protect unstable payloads, alter pharmacokinetics, and support receptor-mediated or local delivery, but the same properties that promote transport can also increase immune recognition, tissue retention, and neurotoxicity. This review critically examines how nanoparticles (NPs) size, surface charge, composition, degradability, ligand density, and release kinetics should be matched to intravenous, intranasal, intrathecal, intracranial, and oral administration. Rather than treating these routes as interchangeable, we compare the barriers encountered by each route, the payloads for which it is best suited, and the experimental conditions that limit interpretation of reported brain uptake. Particular attention is given to the weak correspondence between many rodent efficacy studies and human delivery constraints, including protein-corona formation after systemic dosing, species differences in BBB and nasal anatomy, limited parenchymal penetration from cerebrospinal fluid, and the procedural risks of direct administration. The resulting route-specific framework is intended to support application-driven formulation design and more informative preclinical evaluation of CNS nanomedicines.

Background/Objectives: As a fungus-sourced sterol endoperoxide, ergosterol peroxide possesses extensive antitumor properties. However, unfavorable aqueous solubility, rapid in vivo clearance, and poor accumulation within tumor sites constitute major obstacles restricting its progression toward clinical application. Methods: Herein, we constructed a novel phospholipid nanoformulation by supramolecular self-assembly of ergosterol peroxide with soybean phosphatidylcholine via a thin-film dispersion method. Results: The optimized ergosterol peroxide–soybean phosphatidylcholine nanoformulation exhibited a uniform spherical morphology (~98 nm), excellent colloidal stability in serum-containing medium, and pH-responsive drug release behavior. In vitro, the ergosterol peroxide–soybean phosphatidylcholine nanoformulation demonstrated significantly enhanced cellular uptake in HeLa cervical cancer cells compared with free ergosterol peroxide, achieving markedly superior antiproliferative and pro-apoptotic efficacy through amplified reactive oxygen species generation. Furthermore, the ergosterol peroxide–soybean phosphatidylcholine nanoformulation effectively induced immunogenic-cell-death-associated damage-associated molecular patterns. In TC-1 tumor-bearing mice, intravenous administration of the ergosterol peroxide–soybean phosphatidylcholine nanoformulation exhibited potent dose-dependent antitumor efficacy, with biodistribution analysis confirming enhanced intratumoral ergosterol peroxide accumulation via the enhanced permeability and retention effect. Of particular note, ergosterol peroxide–soybean phosphatidylcholine nanoformulation treatment led to a substantial increase in the abundance of splenic B cells, NK cells, CD4⁺ helper T-cells and CD8⁺ cytotoxic T-cells; hematology testing together with histopathological examination further demonstrated only marginal systemic toxicity after treatment. Conclusions: Collectively, this soybean phosphatidylcholine-based nanoplatform provides a feasible and promising pharmaceutical strategy for overcoming the inherent delivery limitations of ergosterol peroxide, offering a potential candidate for cervical cancer treatment.

Background/Objectives: This study aimed to develop a novel polymeric micelle formulation using poloxamer 184 with ethanol and various terpenes to improve the skin penetration of resveratrol. Methods: The terpenes used in this study were monoterpenes, namely, d-limonene, citral, and cineole. Polymeric micelles were prepared by direct dissolution method. The prepared polymeric micelles were composed of 1% terpenes, 25% poloxamer 184, 5% ethanol, and 69% water. Resveratrol was successfully loaded into the polymeric micelles at a concentration of 0.24 mg/mL. The obtained polymeric micelles were characterized for their size, surface charge, and size distribution. The skin penetration pathway of the micelles was investigated using dual fluorescently labeled particles and observed via confocal laser scanning microscopy. Results: The average particle size of the prepared polymeric micelles ranged from 29.02 ± 2.28 to 57.16 ± 8.32 nm, exhibiting a neutral surface charge and an acceptable size distribution. The in vitro skin penetration study revealed that polymeric micelles with ethanol and d-limonene significantly increased the skin penetration of resveratrol compared with the resveratrol ethanolic solution as control. These polymeric micelles penetrated the skin primarily via the intercellular and transcellular pathways, whereas the transfollicular pathway served as a minor route. The particles also penetrated the skin through the intercluster pathway. Conclusions: The polymeric micelles with d-limonene effectively enhanced dermal delivery of resveratrol by facilitating its penetration through the skin via intercellular and transcellular pathway as major penetration pathway.