Redox-sensitive prodrug nanoassemblies based on linoleic acid-modified docetaxel to resist breast cancers.
10.1016/j.apsb.2018.08.008
- Author:
Meng LI
1
;
Liwen ZHAO
1
;
Tao ZHANG
1
;
Yue SHU
1
;
Zhonggui HE
1
;
Yan MA
2
;
Dan LIU
3
;
Yongjun WANG
1
Author Information
1. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
2. School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
3. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
- Publication Type:Journal Article
- Keywords:
ALT, alanine transaminase;
AST, aspartate transaminase;
AUC, area under the curve;
Antitumor efficacy;
BUN, blood urea nitrogen;
C-6, coumarin-6;
CREA, creatinine;
DDS, drug delivery system;
DMSO, dimethyl sulfoxide;
DSPE-PEG2K, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000];
DTT, d,l-dithiothreitol;
DTX, docetaxel;
Docetaxel;
EDCI, N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride;
FBS, fetal bovine serum;
GSH, glutathione;
H2O2, hydrogen peroxide;
HOBt, 1-hydroxybenzotriazole monohydrate;
HPLC, high-performance liquid chromatography;
IC50, half maximal inhibitory concentration;
LA, linoleic acid;
Linoleic acid;
MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide;
Mono thioether bond;
Nanoassemblies;
PBS, phosphate buffer saline;
PDI, polydispersity index;
PTX, paclitaxel;
Pharmacokinetics;
ROS, reactive oxygen species;
SD, standard deviation;
TLC, thin layer chromatography
- From:
Acta Pharmaceutica Sinica B
2019;9(2):421-432
- CountryChina
- Language:English
-
Abstract:
Prodrug nanoassemblies, which can refrain from large excipients, achieve higher drug loading and control drug release, have been placed as the priority in drug delivery system. Reasoning that glutathione (GSH) and reactive oxygen species (ROS) are highly upgraded in tumor tissues which makes them attractive targets for drug delivery system, we designed and synthetized a novel prodrug which utilized mono thioether bond as a linker to bridge linoleic acid (LA) and docetaxel (DTX). This mono thioether-linked conjugates (DTX-S-LA) could self-assemble into nanoparticles without the aid of much excipients. The mono thioether endowed the nanoparticles redox sensitivity resulting in specific release at the tumor tissue. Our studies demonstrated that the nanoassemblies had uniform particle size, high stability and fast release behavior. DTX-S-LA nanoassemblies outperformed DTX solution in pharmacokinetic profiles for it had longer circulation time and higher area under curve (AUC). Compared with DTX solution, the redox dual-responsive nanoassemblies had comparable cytotoxic activity. Besides, the antitumor efficacy was evaluated in mice bearing 4T1 xenograft. It turned out this nanoassemblies could enhance anticancer efficacy by increasing the dose because of higher tolerance. Overall, these results indicated that the redox sensitivity nanoassemblies may have a great potential to cancer therapy.
