Lani
02-10-2011, 04:24 AM
Still preclinical, but combines several important ideas
better delivery
able to evade Muc 4 and get through to cell cytoplasm
targeted by herceptin
blocks new tumor vasculature
blocks synthesis of new her2 receptors
increased apoptosis among others
several good ideas here!
Cancer Res. 2011 Feb 8. [Epub ahead of print]
Polymalic Acid-Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity.
Inoue S, Ding H, Portilla-Arias J, Hu J, Konda B, Fujita M, Espinoza A, Suhane S, Riley M, Gates M, Patil R, Penichet ML, Ljubimov AV, Black KL, Holler E, Ljubimova JY.
Authors' Affiliations: Departments of Neurosurgery and Surgery, Cedars-Sinai Medical Center; Division of Surgical Oncology, Department of Surgery, The Molecular Biology Institute, Department of Microbiology, Immunology, and Molecular Genetics, and Jonsson Comprehensive Cancer Center, University of California Los Angeles; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; and Institut für Biophysik und physikalische Biochemie der Universität Regensburg, Regensburg, Germany.
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.
PMID: 21303974
better delivery
able to evade Muc 4 and get through to cell cytoplasm
targeted by herceptin
blocks new tumor vasculature
blocks synthesis of new her2 receptors
increased apoptosis among others
several good ideas here!
Cancer Res. 2011 Feb 8. [Epub ahead of print]
Polymalic Acid-Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity.
Inoue S, Ding H, Portilla-Arias J, Hu J, Konda B, Fujita M, Espinoza A, Suhane S, Riley M, Gates M, Patil R, Penichet ML, Ljubimov AV, Black KL, Holler E, Ljubimova JY.
Authors' Affiliations: Departments of Neurosurgery and Surgery, Cedars-Sinai Medical Center; Division of Surgical Oncology, Department of Surgery, The Molecular Biology Institute, Department of Microbiology, Immunology, and Molecular Genetics, and Jonsson Comprehensive Cancer Center, University of California Los Angeles; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; and Institut für Biophysik und physikalische Biochemie der Universität Regensburg, Regensburg, Germany.
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.
PMID: 21303974