Development of core-shell structured nanoparticle for sequential release of tariquidar and docetaxel to overcome multi drug-resistant cancer

초록

Purpose: We developed a core–shell (CS) nanoparticle, docetaxel (DTX)-loaded core and tariquidar (TRQ)-loaded shell conjugated with PEG and RIPL peptide (D/C-T/S-PR), which sequentially releases TRQ and DTX to overcome multidrug resistant (MDR) cancer. Methods: D/C-T/S-PR was fabricated by two-step method, including the formation of a DTX-loaded nanostructured lipid carrier (D/NLC) core by solvent emulsification-evaporation and a TRQ-loaded lipid bilayer shell using a film hydration method. CSs with a lipid mass ratio of shell to core from 1 to 5 (CS1–CS5) were prepared and purified by sucrose density gradient centrifugation. The physicochemical properties of the CSs were evaluated to select an optimal ratio. Additionally, CS formation was confirmed by transmission microscopy (TEM) and confocal laser scanning microscope (CLSM) images. In vitro drug release was evaluated and in vitro cellular uptake and cytotoxicity were assessed against MCF7 and MCF7/ADR cells. Results: The amounts of CSs acquired after purification were increased with increasing lipid ratio. CS3 was selected as the final formulation due to its high drug loading. Using TEM, we observed the distinct formation of the shell coating the core in the D/C-T/S-PR, while CLSM was used to confirm the co-loading of two fluorescent probes in different layers. D/C-T/S-PR showed a burst release of TRQ from the shell, followed by sustained release of DTX from the core. D/C-T/S-PR showed enhanced uptake and cytotoxicity in both cell types. Conclusion: We successfully developed a CS exhibiting sequential release of TRQ and DTX, which may represent a promising strategy to overcome MDR. © 2023, The Author(s) under exclusive licence to The Korean Society of Pharmaceutical Sciences and Technology.

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