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In the current study, we aimed to develop lyotropic crystalline nanoconstructs (LCNs) based on poly(l-glutamic acid) (PLG) with a two-tier strategy. The first objective was to confer pH-responsive charge conversion properties to facilitate the delivery of both doxorubicin (DOX) and buparvaquone (BPQ) in combination (B + D@LCNs) to harness their synergistic effects. The second goal was to achieve targeted delivery to sigma receptors within the tumor tissues. To achieve this, we designed a pH-responsive charge conversion system using a polymer consisting of poly(ethylenimine), poly(l-lysine), and poly(l-glutamic acid) (PLG), which was then covalently coupled with methoxybenzamide (MBA) for potential sigma receptor targeting. The resulting B + D@LCNs were further modified by surface functionalization with PLG–MBA to confer both sigma receptor targeting and pH-responsive charge conversion properties. Our observations indicated that at physiological pH 7.4, P/B + D-MBA@LCNs exhibited a negative charge, while under acidic conditions (pH 5.5, characteristic of the tumor microenvironment), they acquired a positive charge. The particle size of P/B + D-MBA@LCNs was determined to be 168.23 ± 2.66 nm at pH 7.4 and 201.23 ± 1.46 nm at pH 5.5. The crystalline structure of the LCNs was confirmed through small-angle X-ray scattering (SAXS) diffraction patterns. Receptor-mediated endocytosis, facilitated by P/B + D-MBA@LCNs, was confirmed using confocal laser scanning microscopy and flow cytometry. The P/B + D-MBA@LCNs formulation demonstrated a higher rate of G2/M phase arrest (55.20%) compared to free B + D (37.50%) and induced mitochondrial depolarization (59.39%) to a greater extent than P/B + D@LCNs (45.66%). Pharmacokinetic analysis revealed significantly improved area under the curve (AUC) values for both DOX and BPQ when administered as P/B + D-MBA@LCNs, along with enhanced tumor localization. Tumor regression studies exhibited a substantial reduction in tumor size, with P/B + D-MBA@LCNs leading to 3.2- and 1.27-fold reductions compared to B + D and nontargeted P/B + D@LCNs groups, respectively. In summary, this two-tier strategy demonstrates substantial promise for the delivery of a drug combination through the prototype formulation. It offers a potential chemotherapeutic option by minimizing toxic effects on healthy cells while maximizing therapeutic efficacy.

An attempt has been made for controlling the drug release of antifungal drug fluconazole (FCZ) thereby formulating nanoliposomes (NLs) with increasing residence time by applying QbD approach. FCZ, an antifungal agent, having a low partition coefficient (logP 0.5) exhibits limited bioavailability due to washing off by tear fluid calls for repeated administration of dose; narrowing patient compliance. Box-Behnken design was applied for formulating thin-film hydration-based liposomes bearing FCZ; considering lipid amount, sonication time, and hydration time as independent variables. FCZ loaded NLs (FCZ-NLs) were optimized on the basis of particle size (268 ± 3.6 nm), ζ potential (−23.15 ± 3.12 mV), and % entrapment efficiency (69.75 ± 4.45%). The amount of cryoprotectant for lyophilization was also optimized. Zero-order release kinetics was close-fitting and higher ex-vivopermeation flux was observed for FCZ-NLs compared to marketed formulation. No hemolysis and ocular irritation were observed in a preclinical study. AUC (0–∞),MRT, and drug availability above the MIC of FCZ-NLs were increased up to 2.36, 3.05, and 4.57 folds, respectively as compared to the marketed formulation. The optimized FCZ-NLs could be further exploited as a potential ocular drug delivery system.