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A Chimeric Cetuximab-Functionalized Corona as a Potent Delivery System for Microtubule-Destabilizing Nanocomplexes to Hepatocellular Carcinoma Cells: A Focus on EGFR and Tubulin Intracellular Dynamics

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Title A Chimeric Cetuximab-Functionalized Corona as a Potent Delivery System for Microtubule-Destabilizing Nanocomplexes to Hepatocellular Carcinoma Cells: A Focus on EGFR and Tubulin Intracellular Dynamics
 
Creator POOJARI, R
KINI, S
SRIVASTAVA, R
PANDA, D
 
Subject GROWTH-FACTOR RECEPTOR
COMBRETASTATIN A4
IN-VITRO
DRUG-DELIVERY
KINETIC STABILIZATION
ANTICANCER ACTIVITIES
TUMOR NEOVASCULATURE
COMBINATION THERAPY
TARGETED DELIVERY
CANCER-THERAPY
combretastatin A4
2-methoxyestradiol
cetuximab
copolymer-chimeric nanocomplexed delivery system
hepatocellular carcinoma cells
intracellular dynamics
 
Description In this study, we have developed microtubule destabilizing agents combretastatin A4 (CA4) or 2-methoxyestradiol (2ME) encapsulated poly(d,l-lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) nanocomplexes for targeted delivery to human hepatocellular carcinoma (HCC) cells. An epidermal growth factor receptor (EGFR) is known to be overexpressed in HCC cells. Therefore, the targeting moiety cetuximab (Cet), an anti-EGFR chimeric monoclonal antibody, is functionalized on the surface of these diblock copolymeric coronas. Cetuximab is associated with the extracellular domain of the EGFR; therefore, the uptake of the cetuximab conjugated nanocomplexes occurred efficiently in EGFR overexpressing HCC cells indicating potent internalization of the complex. The cetuximab targeted-PLGA-b-PEG nanocomplexes encapsulating CA4 or 2ME strongly inhibited phospho-EGFR expression, depolymerized microtubules, produced spindle abnormalities, stalled mitosis, and induced apoptosis in Huh7 cells compared to the free drugs, CA4 or 2ME. Further, the combinatorial strategy of targeted nanocomplexes, Cet-PLGA-b-PEG-CA4 NP and Cet-PLGA-b-PEG-2ME NP, significantly reduced the migration of Huh7 cells, and markedly enhanced the anticancer effects of the microtubule-targeted drugs in Huh7 cells compared to the free drugs, CA4 or 2ME. The results indicated that EGFR receptor-mediated internalization via cetuximab facilitated enhanced uptake of the nanocomplexes leading to potent anticancer efficacy in Huh7 cells. Cetuximab-functionalized PLGA-b-PEG nanocomplexes possess a strong potential for the targeted delivery of CA4 or 2ME in EGFR overexpressed HCC cells, and the strategy may be useful for selectively targeting microtubules in these cells.
 
Publisher AMER CHEMICAL SOC
 
Date 2016-01-15T06:14:55Z
2016-01-15T06:14:55Z
2015
 
Type Article
 
Identifier MOLECULAR PHARMACEUTICS, 12(11)3908-3923
1543-8384
http://dx.doi.org/10.1021/acs.molpharmaceut.5b00337
http://dspace.library.iitb.ac.in/jspui/handle/100/17906
 
Language en