Enhanced cellular uptake by non-endocytic pathway for tumor therapy

Abstract

Endosome/lysosome, as the potential risk of therapeutic inactivation resulting from physical obstruction and a number of acid hydrolases, is a bottleneck in effective intracellular delivery which needs to be overcome. One promising strategy to avoid this barrier is to deliver therapeutic agents directly into the cytoplasm. In this study, CLIP6 peptide (KVRVRVRV^DPPTRVRERVK-NH₂) which can facilitate non-endosomal cell entry and anticancer drug doxorubicin (DOX) were covalently grafted to N-(2-hydroxypropyl)methacrylamide (HPMA) backbone (P-DOX-CLIP6). As a result, CLIP6 peptide modification increased the cellular uptake of DOX-loaded HPMA copolymers. Importantly, it effectively reduced lysosomal accumulation, leading to stronger proliferation inhibition and superior growth inhibition effect on three-dimensional tumor spheroids, compared to unmodified HPMA copolymer conjugates. Furthermore, P-CLIP6-DOX induced the highest therapeutic efficacy in HeLa tumor-bearing nude mice. Meanwhile, no significant systemic toxicity was observed during the treatment. In conclusion, this study provided a promising strategy to efficiently deliver drug candidates which were limited by endo/lysosomal trapping.