Issue 9, 2021

Nuclear-targeted nanocarriers based on pH-sensitive amphiphiles for enhanced GNA002 delivery and chemotherapy

Abstract

GNA002, a novel EZH2 inhibitor, exhibits significant anticancer efficiency in solid malignant tumor therapy; however, its poor water solubility and low enrichment at tumor sites limit its clinical application and translation. In this study, an original pH-sensitive nanocarrier (cyclo (RGDyCSH) (cRGD)-poly (ethylene glycol) (PEG)-hydrazine (Hyd)-hexa-arginine (R6)-stearic acid (SA)) was designed to precisely deliver GNA002 into the nuclei of cancer cells. The PEG-modified hydrophilic shell of the spherical GNA002-loaded nanoparticles with a mean size of 143.13 ± 0.20 nm effectively facilitated the passive target of tumor tissues and prolonged the blood circulation time. Meanwhile, cRGD was used as the active targeting ligand, which promoted the accumulation of the nanoparticles in cancer cells via ανβ3-receptor-mediated endocytosis. Furthermore, the acidic environment of lysosomes triggered the rupture of the pH-sensitive hydrazine bond and the rapid formation of penetrating peptide R6-shelled secondary nanoparticles, thus enabling the lysosomal escape of the nanoparticles and the ultimate R6-mediated nuclear-targeted delivery of GNA002. Consequently, the nuclear-enriched GNA002 effectively enhanced the cytotoxicity against cancer cells both in vitro and in vivo, thus providing an original and promising drug delivery system for the targeted delivery of GNA002.

Graphical abstract: Nuclear-targeted nanocarriers based on pH-sensitive amphiphiles for enhanced GNA002 delivery and chemotherapy

Supplementary files

Article information

Article type
Paper
Submitted
10 Oct 2020
Accepted
20 Nov 2020
First published
25 Jan 2021

Nanoscale, 2021,13, 4774-4784

Nuclear-targeted nanocarriers based on pH-sensitive amphiphiles for enhanced GNA002 delivery and chemotherapy

F. Li, X. Xu, Y. Liang, Y. Li, M. Wang, F. Zhao, X. Wang, Y. Sun and W. Chen, Nanoscale, 2021, 13, 4774 DOI: 10.1039/D0NR07239G

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