仑伐替尼仿生纳米颗粒的pH响应释放特性与机制OA

Objective To develop a cancer cell membrane-coated biomimetic nanoparticle(L-P-S-CM)for lenvatinib(LEN)delivery,aiming to improve its solubility,enhance the potential for homotypic targeted delivery,and investigate its pH-responsive release kinetics.Methods L-P-S-CM was fabricated via a double emulsion solvent evaporation method coupled with physical extrusion.The nanopar-ticles were comprehensively characterized for size,zeta potential,drug loading(DL),and encapsulation efficiency(EE).In vitro release profiles were evaluated under simulated physiological(pH7.4)and tumor microenvironment(pH5.5)conditions.The release data were fitted using various kinetic models,including zero-order,first-order,Higuchi,and Korsmeyer-Peppas models.Based on the dose-response curve of free LEN,the IC50 for Huh-7 cells was calculated.Accordingly,LEN-equivalent concentrations(2,4 μg/mL)were chosen for cytotoxicity evaluation.Huh-7 hepatocellular carcinoma cells were treated with free LEN and nanoparticle formulations(PLGA,L-P,P-S,L-P-S,and L-P-S-CM),whereas THLE-2 normal human liver cells were treated with PLGA,L-P-S,and L-P-S-CM,at the selected LEN-equivalent concentrations.Cell viability was measured using the cell counting kit-8(CCK-8)assay.Results L-P-S-CM achieved a high encapsulation efficiency(93.33%)and exhibited faster drug release at pH 5.5 than at pH7.4(12 h:42.71%vs 17.10%;72 h:76.40%vs 55.64%),demonstrating pH-dependent release.Among the compared kinetic models,the first-order model showed the best goodness of fit(R2≥0.982).Korsmeyer-Peppas model analysis indicated that the cell membrane coating shifted the release mechanism from Fickian diffusion(n≈0.43)to non-Fickian diffusion(n=0.567)at pH7.4,suggesting the introduction of a polymer matrix relaxation effect.The membrane layer delayed the initial burst release and exhibited a buffering effect under acidic conditions.Cytotoxicity assays showed that the half-maximal inhibitory concentration(IC50)of free LEN for Huh-7 cells was 1.665 2 μg/mL.At a LEN-equivalent concentration of 4 μg/mL,the viability of Huh-7 and THLE-2 cells in the L-P-S-CM group was(16.91±0.22)%and(82.09±0.21)%,respectively.Conclusion L-P-S-CM is successfully constructed and exhibits pH-responsive release(faster release under acidic conditions).At LEN-equivalent concentrations,L-P-S-CM can reduce Huh-7 cell viability,at the same time,THLE-2 cells maintain relatively high viability.