Based on multi-pathway induction of tumor immunogenic death and three-mode highly integrated strategy: A nanocomposite system loaded with irinotecan for colorectal cancer Therapy

Abstract

Irinotecan (CPT-11), a first-line chemotherapeutic agent for colorectal cancer, faces challenges like tumor drug resistance and severe toxicities such as neutropenia and diarrhea. Current nanocarriers for CPT-11 have limitations in achieving high drug loading and stimuli-responsive drug release. In this study, we developed a novel nanosystem (ICP@PDA-PP@HA NPs) by first coordinating CPT-11 and curcumin (Cur) with Fe3+ to form infinite coordination polymer nanoparticles (CPT11-Fe(III)-Cur ICPs), which were subsequently surface-modified with polydopamine (PDA) to yield ICP@PDA NPs. These NPs were then encapsulated in micelles composed of aldehyde-modified poly(ethylene glycol) (PEG) and poly(ethyleneimine) (PEI), followed by further modification with hyaluronic acid. The resulting nanosystem achieves efficient tumor targeting and ultra-sensitive pH-responsive drug release. CPT-11 induces immunogenic cell death (ICD) in tumor cells, while Cur enhances CPT-11 intracellular accumulation and reduces resistance. PDA-mediated photothermal therapy, when combined with dual-drug chemotherapy, synergistically induces ICD through non-repetitive multiple pathways, thereby enhancing the antitumor immune response. In vivo experiments showed that low-dose ICP@PDA-PP@HA NPs achieved a tumor inhibition rate of 95.8% after 21 days, and when combined with anti-PD-L1, the tumor inhibition rate reached 100% with no recurrence within 90 days.