The effect of autophagy inhibitors on drug delivery using biodegradable polymer nanoparticles in cancer treatment

Abstract Nanoparticles of biodegradable polymers (NPs) have been widely used for drug delivery. However, there has been little research on their fate after internalized into the cells. We show in this research by using docetaxel as a model anticancer drug, which is formulated in the cholic acid conj...

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Bibliographic Details
Published in:Biomaterials 2014-02, Vol.35 (6), p.1932-1943
Main Authors: Zhang, Xudong, Dong, Yichen, Zeng, Xiaowei, Liang, Xin, Li, Xiaoming, Tao, Wei, Chen, Hongbo, Jiang, Yuyang, Mei, Lin, Feng, Si-Shen
Format: Article
Language:English
Subjects:
3-Methyladenine
Adenine - analogs & derivatives
Adenine - chemistry
Adenine - pharmacology
Adenine - therapeutic use
Advanced Basic Science
Animals
Autophagy - drug effects
Cancer nanotechnology
Cell Line, Tumor
Chloroquine
Chloroquine - chemistry
Chloroquine - pharmacology
Chloroquine - therapeutic use
Dentistry
Drug Delivery Systems - standards
Endocytosis
Female
Humans
Immunoblotting
Lactic Acid - chemistry
Lactic Acid - pharmacology
Lactic Acid - therapeutic use
Mice, SCID
Nanomedicine
Nanoparticles - chemistry
Pharmaceutical nanotechnology
Polyglycolic Acid - chemistry
Polyglycolic Acid - pharmacology
Polyglycolic Acid - therapeutic use
Polymers - chemistry
Polymers - therapeutic use
Xenograft Model Antitumor Assays
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Summary:Abstract Nanoparticles of biodegradable polymers (NPs) have been widely used for drug delivery. However, there has been little research on their fate after internalized into the cells. We show in this research by using docetaxel as a model anticancer drug, which is formulated in the cholic acid conjugated nanoparticles of poly(lactic-co-glycolic acid (PLGA NPs) that the NPs induce autophagy of the cancer cells and thus may hinder the advantages of the nanomedicine. Moreover, we show both in vitro and in vivo that co-administration of autophagy inhibitors such as 3-methyladenine (3-MA) and Chloroquine (CQ) could greatly enhance the therapeutic effects of the nanoparticle formulation. The IC50 values of the drug formulated in the PLGA NPs after 24 h treatment with no autophagy inhibitor or in combination with 10 m m 3-MA or 30 μ m CQ are 38.27 ± 1.23, 6.7 ± 1.05, 4.78 ± 1.75 μg/mL, which implie 5.7 or 8,0 fold efficient by the autophagy inhibition respectively. Moreover, both the volume and the weight of the shrunk tumor of the mice after 20 day treatment with the PLGA NPs formulation combined with 3-MA or CQ are found to be only about a half in comparison with the treatment with the PLGA NPs formulation alone. In this research, we reported such a new mechanism of cancer cells to have PLGA NPs captured and degraded by auto-lysosomes. The findings provide advanced knowledge for development of nanomedicine for clinical application.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2013.10.034