Tumour microenvironment-responsive lipoic acid nanoparticles for targeted delivery of docetaxel to lung cancer.

Chunai Gong,Qingming Xia,Jing Tian,Zhongguang Tai,Yuan Gao,Shen Gao,Lijuan Zhang,Chuling Hu,Fenfen Gu,Chong Yao

doi:10.1038/srep36281

Abstract

In the present study, we developed a novel type of reduction-sensitive nanoparticles (NPs) for docetaxel (DTX) delivery based on cross-linked lipoic acid NPs (LANPs). The physicochemical properties, cellular uptake and in vitro cytotoxicity of DTX loaded LANPs (DTX-LANPs) on A549 cells were investigated. Furthermore, the in vivo distribution and in vivo efficacy of DTX-LANPs was evaluated. The results showed that DTX-LANPs had a particle size of 110 nm and a negative zeta potential of −35 mv with excellent colloidal stability. LANPs efficiently encapsulated DTX with a high drug loading of 4.51% ± 0.49% and showed remarkable reduction-sensitive drug release in vitro. Cellular uptake experiments demonstrated that LANPs significantly increased intracellular DTX uptake by about 10 fold as compared with free DTX. The cytotoxicity of DTX-LANPs showed significantly higher potency in inhibiting A549 cell growth than free DTX, while blank LANPs had a good biocompatibility. In addition, in vivo experiments demonstrated that DTX-LANPs could enhance tumour targeting and anti-tumour efficacy with low systemic toxicity. In conclusion, LANPs may prove to be a potential tumour microenvironment-responsive delivery system for cancer treatment, with the potential for commercialization due to the simple component, controllable synthesis, stability and economy.

Highlights

The verification of cross-linked lipoic acid by ultraviolet absorption and Gel Permeation Chromatography (GPC) is shown in Tables 1 and 2 and Fig. 2
With the cross-linking of lipoic acid, the molecular weight of the material was the largest in a 5:1 molar ratio of lipoic acid to cysteine at 8 h, when the overall increase was about 99.72% (Table 2)
The Polydispersity index (PDI) of all the NPs was less than 0.3 and the lowest PDI of NPs was in a 5:1 molar ratio of lipoic acid to cysteine at 8 h. These results indicated that the optimal synthesis condition was 8 h and a 5:1 molar ratio of lipoic acid to cysteine

Summary

Introduction

Disulphide cross-linked polymers can swiftly degrade in this setting, leading to a rapid drug release into the cytoplasm. Compared with high polymer materials such as polylactide-co-glycolide (PLGA), this novel material had stable “cross-linking scherm” that could prevent premature drug release and ensure long stability of NPs in circulation and break rapidly in response to the tumor microenvironment to release the drug totally. This novel material is synthesized, nontoxic, and biodegradable, will be suitable for commercialization

Methods

Results

Conclusion