Antiangiogenic antitumor activity of HPMA copolymer-paclitaxel-alendronate conjugate on breast cancer bone metastasis mouse model

Mol Pharm. 2011 Aug 1;8(4):1052-62. doi: 10.1021/mp200083n. Epub 2011 May 17.

Abstract

Polymer therapeutics have shown promise as tumor-targeted drug delivery systems in mice. The multivalency of polymers allows the attachment of different functional agents to a polymeric backbone, including chemotherapeutic and antiangiogenic drugs, as well as targeting moieties, such as the bone-targeting agent alendronate (ALN). We previously reported the conjugation of ALN and the chemotherapeutic drug paclitaxel (PTX) with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. The in vitro physicochemical properties, cancer cytotoxicity and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate were extensively characterized. The reported results warranted in vivo evaluations of the conjugate. In this manuscript, we evaluated the in vivo anticancer and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate. The conjugate exhibited an antiangiogenic effect by decreasing microvessel density (MVD), and inducing apoptotic circulating endothelial cells (CEC) following treatment of the mice. Using intravital imaging system and mCherry-labeled breast cancer cell lines, we were able to monitor noninvasively the progression of orthotopic metastatic tumors injected into the tibia of the mice. HPMA copolymer-PTX-ALN conjugate showed the greatest antitumor efficacy on mCherry-labeled 4T1 mammary adenocarcinoma inoculated into the tibia, as compared with PTX alone or in combination with ALN. Treatment with the bone-targeted polymeric conjugate demonstrated improved efficacy, was better tolerated, and was more easily administered intravenously than the clinically used PTX formulated in Cremophor/ethanol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / chemistry*
  • Alendronate / chemistry*
  • Alendronate / therapeutic use*
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / secondary
  • Breast Neoplasms / complications
  • Breast Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Female
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Leukocyte Count
  • Mice
  • Mice, Inbred BALB C
  • Paclitaxel / chemistry*
  • Paclitaxel / therapeutic use*

Substances

  • Acrylamides
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Paclitaxel
  • N-(2-hydroxypropyl)methacrylamide
  • Alendronate