Supramolecular nanofibers increase the efficacy of 10-hydroxycamptothecin by enhancing nuclear accumulation and depleting cellular ATP

Abstract

Poor nuclear delivery and accumulation are the main reasons for the reduced drug efficacy of many anticancer drugs that target DNA or enzymes in the nucleus, and it is a major obstacle to successful cancer therapy. To address this problem, developing practical drug delivery systems for nuclear delivery is urgently needed. Here we develop a supramolecular hydrogel by conjugating the anticancer agent 10-hydroxycamptothecine (HCPT) and macrocyclic polyamine cyclen to a self-assembling peptide. The cyclen fragment possesses nuclear localization and ATP hydrolysis properties, which can provide a synergistic therapeutic effect for cancer treatment. The HCPT-FFFK-cyclen nanofibers showed improved nuclear accumulation and inhibition capacity in cancer cells including drug-resistant cancer cells in vitro. The nanofibers also exhibited favorable ATP consuming ability in vitro. Moreover, the obtained nanomedicine showed enhanced anticancer efficiency and favorable biocompatibility in vivo when administered to mice via tail vein injection. This constructed self-delivery drug system significantly improved the delivery efficiency of the small molecule agents into the nucleus and showed favorable ATP consuming ability, offering new strategies for developing nanomedicines for cancer combination therapy.