Chitosan-tripolyphosphate nanoparticles functionalized with a pH-responsive amphiphile improved the in vitro antineoplastic effects of doxorubicin.

Delivery systems with pH-responsiveness behavior are of particular interest because they could allow exploring the various pH gradients within the body, for example, between healthy tissue and tumor tissue, or between extracellular tissue and some cell compartments. Likewise, modifications in nanocarriers with polyethylene glycol (PEG) and poloxamer could be a potential approach to improve the effectiveness of cancer treatments. On these premises, we prepared pH-responsive DOX-loaded chitosan-tripolyphosphate nanoparticles (NPs), modified or not with PEG or poloxamer, and incorporating an anionic dyacyl lysine-based surfactant with sodium counterion (77KS) as a pH-sensitive adjuvant. Owing to its pH-sensitivity, the CS-NPs showed membranolytic behavior upon reducing the pH value of surrounding media to 6.6 and 5.4, which are characteristic of the endosomal compartments. The in vitro antiproliferative assays with MCF-7 and HeLa tumor cells indicated that the NPs themselves had no associated significant cytotoxicity, while DOX-loaded NPs induced higher cytotoxicity than free drug. Additionally, DOX-loaded CS-NPs displayed greater selectivity to tumor cells than to the non-tumor 3T3 fibroblasts. The feasibility of using these NPs to target tumor microenvironment was proven, as cytotoxicity against cancer cell models was higher in a mildly acidic environment. Finally, the hemocompatibility of NPs was demonstrated, indicating their suitability for intravenous administration. Altogether, the results suggest that the combination of endosomal acidity with the potential endosomolytic capability of these pH-responsive nanocarriers could increase the intracellular delivery of DOX and, thus, might enhance its antineoplastic efficacy.