Document Detail


Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells.
MedLine Citation:
PMID:  20942457     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multi-drug resistant (MDR) cancer is a significant clinical obstacle and is often implicated in cases of recurrent, nonresponsive disease. Targeted nanoparticles were made by synthesizing a poly(D,L-lactide-co-glycolide)/poly(ethylene glycol)/epidermal growth factor receptor targeting peptide (PLGA/PEG/EGFR-peptide) construct for incorporation in poly(epsilon-caprolactone) (PCL) nanoparticles. MDR was induced in a panel of nine human breast and ovarian cancer cell lines using hypoxia. EGFR-targeted polymer blend nanoparticles were shown to actively target EGFR overexpressing cell lines, especially upon induction of hypoxia. The nanoparticles were capable of sustained drug release. Combination therapy with lonidamine and paclitaxel significantly improved the therapeutic index of both drugs. Treatment with a nanoparticle dose of 1 μM paclitaxel/10 μM lonidamine resulted in less than 10% cell viability for all hypoxic/MDR cell lines and less than 5% cell viability for all normoxic cell lines. Comparatively, treatment with 1 μM paclitaxel alone was the approximate IC₅₀ value of the MDR cells while treatment with lonidamine alone had very little effect. The PLGA/PEG/EGFR-peptide delivery system actively targets a MDR cell by exploiting the expression of EGFR. This system treats MDR by inhibiting the Warburg effect and promoting mitochondrial binding of pro-apoptotic Bcl-2 proteins (lonidamine), while hyperstabilizing microtubules (paclitaxel). This nanocarrier system actively targets a MDR associated phenotype (EGFR receptor overexpression), further enhancing the therapeutic index of both drugs and potentiating the use of lonidamine/paclitaxel combination therapy in the treatment of MDR cancer.
Authors:
Lara Milane; Zhenfeng Duan; Mansoor Amiji
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-24
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  8     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-07     Completed Date:  2011-05-11     Revised Date:  2013-12-19    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  185-203     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / administration & dosage,  chemistry,  pharmacology
Breast Neoplasms / metabolism,  pathology*
Cell Line, Tumor
Drug Carriers / chemistry*
Drug Resistance, Multiple / drug effects
Female
Humans
Indazoles / administration & dosage,  chemistry,  pharmacology*
Nanoparticles / chemistry*
Ovarian Neoplasms / metabolism,  pathology*
Paclitaxel / administration & dosage,  chemistry,  pharmacology*
Polymers / chemistry*
Receptor, Epidermal Growth Factor / metabolism*
Grant Support
ID/Acronym/Agency:
R01 CA-119617/CA/NCI NIH HHS; R01 CA-119617S1/CA/NCI NIH HHS; R01 CA119617/CA/NCI NIH HHS; R21 CA-135594/CA/NCI NIH HHS; R21 CA135594/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Drug Carriers; 0/Indazoles; 0/Polymers; 33069-62-4/Paclitaxel; EC 2.7.10.1/Receptor, Epidermal Growth Factor; U78804BIDR/lonidamine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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