Redox-sensitive prodrug nanoassemblies based on linoleic acid-modified docetaxel to resist breast cancers

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.

Tumor microenvironment responsive drug delivery systems

“…The thioether groups exhibit both GSH and H 2 O 2 responsiveness. Wang et al introduced thioether into docetaxel prodrugs to resist breast cancers [100] . Compared with single stimuli sensitive DDSs, the system showed a faster release of docetaxel because responding to two opposite stimuli [100] .…”

“…Wang et al introduced thioether into docetaxel prodrugs to resist breast cancers [100] . Compared with single stimuli sensitive DDSs, the system showed a faster release of docetaxel because responding to two opposite stimuli [100] . Compared with free DTX, the redox dual-responsive platform had comparable cytotoxic activity [100] .…”

“…Compared with single stimuli sensitive DDSs, the system showed a faster release of docetaxel because responding to two opposite stimuli [100] . Compared with free DTX, the redox dual-responsive platform had comparable cytotoxic activity [100] . Besides, the antitumor efficacy was estimated in 4T1 tumors bearing mice.…”

Oleic Acid Copolymer as A Novel Upconversion Nanomaterial to Make Doxorubicin-Loaded Nanomicelles with Dual Responsiveness to pH and NIR

“…It also has natural tumor-targeting properties, because OA can increase the intake of fatty acids in tumors as a source of nutrition, and has great potential in tumor treatment [ 5 , 8 ]. The prodrug nanoparticles based on OA modification have improved the stability of anticancer drugs and achieved the role of nutritional targeted delivery of drugs [ 9 ]. However, in clinical trials, the drug release rate of these nanoparticles at the tumor site was extremely low, and almost no free drug was released in 24 h [ 10 , 11 ], so that OA is seldom used in the nanocarrier of anticancer drugs.…”

Active targeting drug-gold nanorod hybrid nanoparticles for amplifying photoacoustic signal and enhancing anticancer efficacy

“…In recent years, for example, peptides and proteins (mainly antibodies or their fragments), small molecules (folic acid), and nucleic acids (aptamers) have been modied onto drug nanocarrier surfaces for active targeting. 18,23 Arginine-glycine-aspartic acid (RGD), a widely used targeting ligand, has been modied onto many inorganic nanoparticles (e.g., gold NP, AuNR, and iron oxide NP), organic nanoparticles, or polymeric micelles, showing active targeting ability to positive a v b 3 -expressing cancer cells. [24][25][26][27][28] Another big challenge of active targeting has been the non-specic binding between the targeting molecules and non-target molecules expressed on healthy cells, usually leading to non-specic uptake of targeting ligand-modied nanoparticles by healthy or non-cancerous cells.…”