Methyl-β-cyclodextrin\nEnhances Tumor Cellular\nUptake and Accumulation of α‑Linolenic Acid–Paclitaxel\nConjugate Nanoparticles

Improving nanomedicine uptake by tumor cells is key to\nachieving\nintracellular drug delivery. In this study, we found that methyl-β-cyclodextrin\n(MβCD) can significantly promote the intracellular accumulation\nof nanoparticulated α-linolenic acid-paclitaxel conjugates (ALA-PTX\nNPs) via enhanced clathrin-mediated endocytosis and limited degradation\nin lysosomes. Our in vitro results indicated that MβCD not only\nreduced the plasma membrane cholesterol content and increased plasma\nmembrane fluidity, leading to ALA-PTX NPs being more easily incorporated\ninto the plasma membrane, further enhancing membrane fluidity and\nmaking the plasma membrane more susceptible to tensile deformation,\nforming intracellular vesicles to enhance ALA-PTX NP cellular uptake,\nbut also destroyed lysosomes and then limited ALA-PTX NPs’\ndegradation in lysosomes. In HepG2 tumor-bearing mice, MβCD\nwas also able to enhance the antitumor activity of ALA-PTX NPs in\nvivo. Moreover, we found that MβCD specifically promoted PUFA-paclitaxel\nconjugate NP cellular uptake. The cellular uptake of PTX liposome\nwhich shares an endocytosis pathway with ALA-PTX NPs could be enhanced\nby MβCD combined with ALA or ALA-PTX NPs. Therefore, we suggested\nthat MβCD combined with polyunsaturated fatty acid-conjugation\nwould be an effective strategy for improving intracellular delivery\nof nanoparticulated chemotherapeutic drugs used for combination administration\nto enhance antitumor efficiency.