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

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...

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Bibliographic Details
Published in:Nanoscale 2022-10, Vol.14 (41), p.15384-15392
Main Authors: Wang, Dongyuan, Tian, Yuan, Zhang, Yu, Sun, Xiaona, Wu, Yuxuan, Liu, Ruping, Zeng, Fang, Du, Jingjing, Hu, Kuan
Format: Article
Language:English
Subjects:
Anticancer properties
Apoptosis
Assembly
Cancer
Nanospheres
Nuclei (cytology)
Nucleic acids
Peptides
Proteins
Translations
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Summary: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. Nucleic acid therapy is attracting great attention in diverse clinical translations because of its therapeutic advantages.
ISSN:2040-3364
2040-3372
DOI:10.1039/d2nr02118h