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

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. Statement of significance Nuclear delivery and accumulation are critical for many anticancer drugs which targets (DNA or its associated enzymes) are generally located within the nucleus. However, it is very difficult for some negatively charged anticancer drugs such as 10-hydroxycamptothecine (HCPT). To address this issue, in this study, we developed a supramolecular hydrogel HCPT-FFFK-cyclen which with the nuclear localizing and ATP hydrolyzing properties, which could provide a synergistic therapeutic effect to cancer treatment. The results of cellular uptake, cytotoxicity, ATP depletion and tumor inhibition experiments confirmed that HCPT-FFFK-cyclen exhibited promising nuclear targeting anti-tumor efficacy in vitro and in vivo. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

This study developed a supramolecular hydrogel, HCPT-FFFK-cyclen, with nuclear targeting and ATP hydrolyzing properties for synergistic therapeutic effect in cancer treatment. HCPT-FFFK-cyclen exhibited promising nuclear targeting anti-tumor efficacy in vitro and in vivo.