Co-delivery of platinum drug and siNotch1 with micelleplex for enhanced hepatocellular carcinoma therapy

Abstract

As part of HCC tumor cellularity, cancer stem cells (CSCs) are considered a major obstacle to eradicate hepatocellular carcinoma (HCC), which is the third most common cause of cancer-related death worldwide, and the accumulation of chemotherapeutic drug-resistant CSCs invariably accounts for poor prognosis and HCC relapse. In the present study, we explored the efficacy of co-delivery of platinum drug and siRNA targeting Notch1 to treat CSCs-harboring HCC. To overcome the challenging obstacles of platinum drug and siRNA in the systemic administration, we developed a micellar nanoparticle (MNP) to deliver platinum(IV) prodrug and siNotch1, hereafter referred to as (Pt(IV))MNP/siNotch1. We demonstrated that (Pt(IV))MNP/siNotch1 was able to efficiently deliver two drugs into both non-CSCs and CSCs of SMMC7721, a HCC cell line. We further found that siRNA-mediated inhibition of Notch1 suppression can increase the sensitivity of HCC cells to platinum drugs and decrease the percentage of HCC CSCs, and consequently resulting in enhanced proliferation inhibition and apoptosis induction in HCC cells in vitro. Moreover, our results indicated that the combined drug delivery system can remarkably augment drug enrichment in tumor tissues, substantially suppressing the tumor growth while avoiding the accumulation of CSCs in a synergistic manner in the SMMC7721 xenograft model.

Keywords: Cancer stem cells; Co-delivery; Hepatocellular carcinoma; Micelleplex; Notch1; Platinum drug.