Supramolecular nanomedicine for enhanced chemotherapy against drug-resistant colorectal cancer

Abstract

The presence of Fusobacterium nucleatum (F. nucleatum) in the community of colorectal cancer (CRC) accounts for its chemotherapy resistance, which underlies the clinical failure of chemotherapeutics in the treatment of CRC. To resolve this drawback, we manufactured a novel multifaceted supramolecular nanomedicine capable of eliminating F. nucleatum, minimizing the non-specific toxicity to normal tissues, and maximizing anti-tumor efficacy. The supramolecular nanomedicine was constructed by conjugating lauric acid (LA) and platinum (IV) oxaliplatin prodrug (OxPt-COOH) to hyperbranched poly(glycidol) (PG), followed by addition of cucurbit[7]uril (CB[7]) to elicit supramolecular assembly. In principle, LA is schemed to eliminate the F. nucleatum in CRC, thereby enhancing chemotherapeutic efficacy of OxPt. CB[7] facilitates host − guest complexation with OxPt, allowing its activation specifically in the spermine-overexpressed CRC tumors and thus reducing the potential toxicity to normal tissues. Moreover, CB[7] conduces to supramolecular assembly between the self-assembly units of PG-Pt-LA nanoparticles, representing a novel size-transformable supramolecular nanomedicine (PG-Pt-LA/CB[7]), whose hydrodynamic diameter is approximately 200 nm in blood circulation and decreases to approximately 10 nm upon arrival at tumors due to its responsiveness to spermine, which can address the dilemma of long circulation and deep penetration existed in nanomedicine. In vivo investigations reveal that our proposed supramolecular nanomedicine possesses prolonged blood circulation, enhanced permeation and retention effect in tumors. In F. nucleatum co-localized HT29 mouse model, PG-Pt-LA/CB[7] is validated to be a targeted, safe and effective nanomedicine that substantially promoted the chemotherapeutic efficacy in the treatment of drug-resistant CRC through inhibiting autophagy induced by F. nucleatum. These findings demonstrate our multifaceted supramolecular nanomedicine can effectively overcome drug resistance of chemotherapy caused by bacteria, providing a valid strategy for clinic treatment of intractable CRC.