Co-delivery of polymeric metformin and cisplatin by self-assembled core-membrane nanoparticles to treat non-small cell lung cancer

Autor: Leaf Huang, Lei Miao, C. Michael Lin, Yang Xiong, Yi Zhao
Rok vydání: 2016
Předmět:
0301 basic medicine
Lung Neoplasms
Pharmaceutical Science
Apoptosis
02 engineering and technology
Bioinformatics
Polyethylene Glycols
Mice
chemistry.chemical_compound
Carcinoma
Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
Medicine
Tissue Distribution
Cationic liposome
Drug Synergism
021001 nanoscience & nanotechnology
Metformin
female genital diseases and pregnancy complications
Polyglutamic Acid
Female
0210 nano-technology
medicine.drug
inorganic chemicals
Cell Survival
Surface Properties
Mice
Nude
Article
Nephrotoxicity
03 medical and health sciences
In vivo
Cell Line
Tumor
Animals
Humans
Particle Size
neoplasms
PI3K/AKT/mTOR pathway
Cisplatin
business.industry
Phosphatidylethanolamines
Polyglutamic acid
Drug Liberation
030104 developmental biology
chemistry
Liposomes
Cancer research
Nanoparticles
business
Zdroj: Journal of Controlled Release. 244:63-73
ISSN: 0168-3659
DOI: 10.1016/j.jconrel.2016.11.005
Popis: Clinically, combined therapy of cisplatin (CDDP) and metformin is an effective treatment for non-small cell lung cancer (NSCLC). The success is attributed to synergistic effects between the two drugs. Therefore, we hypothesize that co-encapsulation of CDDP and metformin will avoid the prominent toxicity of CDDP while maintaining the synergy between the regimens. CDDP was first conjugated to polyglutamic acid (PGA) to form anionic PGA-CDDP which was electrostatically complexed with the cationic polymeric metformin (polymet). The nano-sized complex was then stabilized with cationic liposomes composed of DOTAP (2, 3-Dioleoyloxy-propyl)-trimethylammonium/Cholesterol/DSPE-PEG-anisamide aminoethyl. Both in vitro and in vivo experiments confirmed the synergy between polymet and CDDP. CDDP delivered with nanoparticles (NPs) exhibited significantly increased tumor accumulation over free CDDP and suppressed tumor growth through apoptosis in NSCLC H460 tumor-bearing mice without nephrotoxicity. The synergistic effect of polymet alongside CDDP demonstrates that polymet-CDDP NPs can activate the AMP-activated protein kinase α (AMPKα) pathway and inhibit mammalian target rapamycin (mTOR) activity to enhance growth suppression. In all, this platform is the first to successfully co-load polymet, a polymeric metformin, and CDDP into the same nanoparticle for successful treatment of NSCLC.
Databáze: OpenAIRE
Externí odkaz: