Development of Curcumin-Loaded Hybrid Lipid-Polymeric Nanoparticles for Hypoxia-Related Applications.

Introduction: Hypoxic and ischemia-associated tissues are often characterized by acidic microenvironments, highlighting the need for drug delivery systems that enable enhanced drug release under acidic conditions. Curcumin (CUR) has antioxidant and cytoprotective properties, but its therapeutic application is limited by poor aqueous solubility and low bioavailability. This study aimed to optimize hybrid lipid-polymeric nanoparticles (HLPNs) as a CUR delivery platform and evaluate their physicochemical properties, colloidal stability, CUR release at pH 7.4 and pH 5.5, and cellular effects under normoxic and hypoxia-mimetic conditions. Methods: In this study, hybrid lipid-polymeric nanoparticles (HLPNs) were optimized as a curcumin (CUR) delivery platform by varying the lipid-to-polymer ratio (DSPE-PEG/cholesterol: PLGA). Particle size, polydispersity index, and zeta potential were determined by dynamic light scattering (DLS) and laser Doppler electrophoresis. The formulations were further characterized in terms of colloidal stability, encapsulation efficiency, morphology, and in vitro CUR release at pH 7.4 and pH 5.5. The effect on cell viability of CUR-loaded HLPNs and free CUR was evaluated in human foreskin fibroblasts (HF) using the MTT assay under normoxic and CoCl Results: Among the tested formulations, HLPNs with lipid-to-polymer ratios of 1:2 and 1:3 showed the most favourable physicochemical profile, with initial particle sizes of ~127 and ~144 nm, respectively, low polydispersity index (~0.12), and negative zeta potentials around -42 mV. After CUR loading, particle size increased to 160 nm for HLPN-CUR 1:2 and 173 nm for HLPN-CUR 1:3. In contrast, encapsulation efficiency reached 38.6% and 40.0%, respectively. Both formulations exhibited pH-dependent CUR release, with minimal release during the first 6 h (<2.0%) and markedly higher cumulative release at pH 5.5 than at pH 7.4 after 72 h. In HF, both CUR-loaded formulations reduced cell viability in a concentration-dependent manner. Free CUR was generally better tolerated than the nanoparticle-loaded formulations. HLPN-CUR 1:3 produced a higher MTT signal under hypoxia-mimetic conditions than under normoxia at 10 µM. However, higher concentrations were associated with marked morphological changes, including cell rounding, aggregation, and reduced cell density. Conclusion: Among the tested formulations, HLPN-CUR 1:3 demonstrated suitable physicochemical properties, colloidal stability, CUR encapsulation, and enhanced CUR release under acidic conditions at later time points. However, the concentration-dependent effects on cell viability and morphology indicate that further studies are needed to confirm its biological activity and potential relevance for hypoxia-related applications.