An assembly-inducing PDC enabling the efficient nuclear delivery of nucleic acid for cancer stem-like cell suppression?

Nanoscale Pub Date: 2022-10-06 DOI: 10.1039/D2NR02118H

Abstract

Nucleic acid therapy is attracting great attention in diverse clinical translations because of its therapeutic advantages. As a renowned oligonucleotide therapeutical candidate in the clinical stage, AS1411 has shown outstanding tumor suppressing effects; however, its efficient delivery to the cell nucleus is critical for its anticancer effect. Herein, we identified a multifunctional peptide drug conjugate (PDC) as a safe and efficient carrier to achieve the nuclear delivery of AS1411. This PDC consists of the cell penetration peptide RW9, an HDAC inhibitor warhead (peptide C-terminus), and 5-FU (peptide N-terminus), which can coassemble with AS1411 to form nanospheres. The PDC efficiently delivered AS1411 to the nucleus of several types of cancer cells. Moreover, it reversed the stemness of a cancer stem-like cell line. Significantly, due to the assembly-induced accumulation enhancement and retention, a safe single agent concentration of PDC showed unexpected synergy with AS1411 to augment the cancer cell suppression efficiency, exemplified by the downregulation of the stemness-related proteins and the upregulation of apoptosis-related proteins. Therefore, our work presents a powerful strategy for the nuclear delivery of nucleic acid drugs by leveraging cancer-suppressing PDC as assembly inducers, which provides a powerful combination regimen in treating cancer stem-like cells.

Graphical abstract: An assembly-inducing PDC enabling the efficient nuclear delivery of nucleic acid for cancer stem-like cell suppression
Recommended Literature