| Development of EGFR-Targeted Polymer Blend Nanocarriers for Combination Paclitaxel/Lonidamine Delivery To Treat Multi-Drug Resistance in Human Breast and Ovarian Tumor Cells. | |
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MedLine Citation:
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PMID: 20942457 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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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 IC(50) 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. |
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Authors:
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Lara Milane; Zhenfeng Duan; Mansoor Amiji |
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Publication Detail:
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Type: Journal Article Date: 2010-11-24 |
Journal Detail:
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Title: Molecular pharmaceutics Volume: 8 ISSN: 1543-8392 ISO Abbreviation: Mol. Pharm. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-02-07 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101197791 Medline TA: Mol Pharm Country: United States |
Other Details:
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Languages: eng Pagination: 185-203 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States, Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, United States, and Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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