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Therapeutics, Targets, and Chemical Biology

Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity

Satoshi Inoue, Hui Ding, Jose Portilla-Arias, Jinwei Hu, Bindu Konda, Manabu Fujita, Andres Espinoza, Sonal Suhane, Marisa Riley, Marcus Gates, Rameshwar Patil, Manuel L. Penichet, Alexander V. Ljubimov, Keith L. Black, Eggehard Holler and Julia Y. Ljubimova
Satoshi Inoue
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Hui Ding
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Jose Portilla-Arias
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Jinwei Hu
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Bindu Konda
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Manabu Fujita
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Andres Espinoza
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Sonal Suhane
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Marisa Riley
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Marcus Gates
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Rameshwar Patil
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Manuel L. Penichet
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Alexander V. Ljubimov
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Keith L. Black
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Eggehard Holler
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Julia Y. Ljubimova
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DOI: 10.1158/0008-5472.CAN-10-3093 Published February 2011
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Abstract

Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report the characterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, and nonimmunogenic PMLA [poly(β-l-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemic treatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties were covalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directed against HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab (Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptor antibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the host endothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth of HER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neu receptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopy demonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemic treatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth and tumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab or AON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLA nanoplatform for combination cancer therapy. Cancer Res; 71(4); 1454–64. ©2011 AACR.

  • Received August 23, 2010.
  • Revision received October 18, 2010.
  • Accepted December 7, 2010.
  • ©2011 American Association for Cancer Research.
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Cancer Research: 71 (4)
February 2011
Volume 71, Issue 4
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Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity
Satoshi Inoue, Hui Ding, Jose Portilla-Arias, Jinwei Hu, Bindu Konda, Manabu Fujita, Andres Espinoza, Sonal Suhane, Marisa Riley, Marcus Gates, Rameshwar Patil, Manuel L. Penichet, Alexander V. Ljubimov, Keith L. Black, Eggehard Holler and Julia Y. Ljubimova
Cancer Res February 15 2011 (71) (4) 1454-1464; DOI: 10.1158/0008-5472.CAN-10-3093

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Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity
Satoshi Inoue, Hui Ding, Jose Portilla-Arias, Jinwei Hu, Bindu Konda, Manabu Fujita, Andres Espinoza, Sonal Suhane, Marisa Riley, Marcus Gates, Rameshwar Patil, Manuel L. Penichet, Alexander V. Ljubimov, Keith L. Black, Eggehard Holler and Julia Y. Ljubimova
Cancer Res February 15 2011 (71) (4) 1454-1464; DOI: 10.1158/0008-5472.CAN-10-3093
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