pH-Sensitive Pt Nanocluster Assembly Overcomes Cisplatin Resistance and Heterogeneous Stemness of Hepatocellular Carcinoma

Abstract

Response rates to conventional chemotherapeutics remain unsatisfactory for hepatocellular carcinoma (HCC) due to the high rates of chemoresistance and recurrence. Tumor-initiating cancer stem-like cells (CSLCs) are refractory to chemotherapy, and their enrichment leads to subsequent development of chemoresistance and recurrence. To overcome the chemoresistance and stemness in HCC, we synthesized a Pt nanocluster assembly (Pt-NA) composed of assembled Pt nanoclusters incorporating a pH-sensitive polymer and HCC-targeting peptide. Pt-NA is latent in peripheral blood, readily targets disseminated HCC CSLCs, and disassembles into small Pt nanoclusters in acidic subcellular compartments, eventually inducing damage to DNA. Furthermore, treatment with Pt-NA downregulates a multitude of genes that are vital for the proliferation of HCC. Importantly, CD24+ side population (SP) CSLCs that are resistant to cisplatin are sensitive to Pt-NA, demonstrating the immense potential of Pt-NA for treating chemoresistant HCC.

Peptide‐Coated Platinum Nanoparticles with Selective Toxicity against Liver Cancer Cells

“…[2,3] Thus there is an eed for specific chemotherapeutics against HCC. [6][7][8][9][10] However,p revious studies with various cancer cell lines neither showed improved cytotoxicityn or tumor selectivity of PtNPs over cisplatin. [4,5] Platinum nanoparticles (PtNPs) are promising alternatives to cisplatin and other platinum-based complexes.…”

“…[6][7][8][9][10] However,p revious studies with various cancer cell lines neither showed improved cytotoxicityn or tumor selectivity of PtNPs over cisplatin. [10] Upon entry of the multicomponent system into HCC cells,the polymer matrix disassembled and the released PtNPs exhib-ited cytotoxicity.W ee nvisioned that suitably functionalized PtNPs should allow for selective toxicity against HCC cells without the need for immobilization in ap olymeric matrix. Liver cancer cells have ah igher oxidative state than other cells owing to high concentration of reactive oxygen species.…”

“…[4,5] Platinum nanoparticles (PtNPs) are promising alternatives to cisplatin and other platinum-based complexes. [6][7][8][9][10] However,p revious studies with various cancer cell lines neither showed improved cytotoxicityn or tumor selectivity of PtNPs over cisplatin. [6][7][8][9] Within PtNPs,cytotoxic Pt II ions [5] are masked as inert Pt 0 atoms and oxidation of Pt 0 to Pt II is required to unleash cytotoxicity.P tNPs should therefore have ap articularly high toxicity in cellular environments with ah igh oxidation potential.…”

“…[11,12] PtNPs should therefore be ideally suited to target HCC.Arecent report on pH-responsive polymer particles that had been functionalized with atargeting ligand for HCC and contained PtNPs supported this assumption. [10] Upon entry of the multicomponent system into HCC cells,the polymer matrix disassembled and the released PtNPs exhib-ited cytotoxicity.W ee nvisioned that suitably functionalized PtNPs should allow for selective toxicity against HCC cells without the need for immobilization in ap olymeric matrix. Such PtNPs have to be water-soluble,small, [13] and bear acoat of molecules that a) prevent aggregation of the PtNPs, b) enable cellular uptake,a nd c) allow for oxidation of Pt 0 to Pt II inside HCC cells.…”

Synthesis and Biomedical Applications of Multifunctional Nanoparticles

“…Moreover, incorporated fluorescent dye, chlorin e6, enabled not only the fluorescence/MRI bimodal imaging but also the PDT of tumors (Figure c). Xia et al reported the pH‐sensitive Pt nanocluster assemblies that were functionalized with hepatocellular carcinoma (HCC)‐targeting peptides for in vivo HCC therapy . The low pH of endosomes and lysosomes in tumor cells initiated the release of the loaded Pt nanoclusters, which worked as an effective anticancer drug by inducing DNA damages.…”