Affiliation:
1. Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
2. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110000, China
Abstract
Neutral/negatively charged nanoparticles are beneficial to reduce plasma protein adsorption and prolong their blood circulation time, while positively charged nanoparticles easily transverse the blood vessel endothelium into a tumor and easily penetrate the depth of the tumor via transcytosis. Γ-Glutamyl transpeptidase (GGT) is overexpressed on the external surface of endothelial cells of tumor blood vessels and metabolically active tumor cells. Nanocarriers modified by molecules containing γ-glutamyl moieties (such as glutathione, G-SH) can maintain a neutral/negative charge in the blood, as well as can be easily hydrolyzed by the GGT enzymes to expose the cationic surface at the tumor site, thus achieving good tumor accumulation via charge reversal. In this study, DSPE-PEG2000-GSH (DPG) was synthesized and used as a stabilizer to generate paclitaxel (PTX) nanosuspensions for the treatment of Hela cervical cancer (GGT-positive). The obtained drug-delivery system (PTX-DPG nanoparticles) was 164.6 ± 3.1 nm in diameter with a zeta potential of −9.85 ± 1.03 mV and a high drug-loaded content of 41.45 ± 0.7%. PTX-DPG NPs maintained their negative surface charge in a low concentration of GGT enzyme (0.05 U/mL), whereas they showed a significant charge-reversal property in the high-concentration solution of GGT enzyme (10 U/mL). After intravenous administration, PTX-DPG NPs mainly accumulated more in the tumor than in the liver, achieved good tumor-targetability, and significantly improved anti-tumor efficacy (68.48% vs. 24.07%, tumor inhibition rate, p < 0.05 in contrast to free PTX). This kind of GGT-triggered charge-reversal nanoparticle is promising to be a novel anti-tumor agent for the effective treatment of such GGT-positive cancers as cervical cancer.
Funder
CAMS Innovation Fund for Medical Sciences
Program for Guangdong YangFan Introducing Innovative and Entrepreneurial Teams
Reference33 articles.
1. Cancer statistics, 2022;Siegel;CA Cancer J. Clin.,2022
2. Paclitaxel: Application in Modern Oncology and Nanomedicine-Based Cancer Therapy;Quispe;Oxid. Med. Cell Longev.,2021
3. How Taxol/paclitaxel kills cancer cells;Weaver;Mol. Biol. Cell,2014
4. The battle of “nano” paclitaxel;Sofias;Adv. Drug Deliv. Rev.,2017
5. Paclitaxel formulations: Challenges and novel delivery options;Nehate;Curr. Drug Deliv.,2014
Cited by
4 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献