Prevention of Metastasis Development by RGD-Bearing PGA-Paclitaxel Nanoconjugate: Adjuvant Treatment for Breast Cancer

Anat Eldar-Boock 1 Joaqiun Sanchis 2 Ruth Lupu 3 Maria J. Vicent 2 Ronit Satchi-Fainaro 1
1Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Israel
2Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Spain
3Mayo Medical Laboratories, Mayo Clinic, USA

Prevention of metastasis growth presents an unmet clinical need. Anti-angiogenic therapy might provide an alternative way to manipulate cancer, yet it did not materialize into clinical practice. Therefore, combination of anti-angiogenic therapy with cytotoxic therapy directed to the metastatic cancer cells, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug, however, its use is limited by severe side effects, caused by the hydrophobic drug and its solubilizing agents.

We designed and synthesized a novel polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nanoconjugate. Polymer conjugation converted PTX to a water-soluble macromolecule, which passively targeted the tumor tissue exploiting the enhanced permeability and retention (EPR) effect, while extravasating via the leaky tumor neovasculature. PGA is enzymatically-degradable by cathepsin B, leading to PTX release. The E-[c(RGDfK)2] serves as an active targeting to αvβ3 integrin. Integrins play a key role in cell matrix interactions. The highly restricted integrin αvβ3 is overexpressed on tumor endothelial and some epithelial cells, during tumor growth, invasion, and metastasis. PGA-PTX-E-[c(RGDfK)2] displayed a potent anti-angiogenic therapy. Mice bearing orthotopic mammary tumors demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decrease in toxicity compared with free PTX[1].

We used a mouse model that mimics the clinical setting, of mammary cancer metastases following resection of the primary tumor. Integrin αvβ3 expression was detected on circulating mCherry-labeled cancer cells of mice. Adguvant treatment with PGA-PTX-E-[c(RGDfK)2] conjugate prevented metastases formation.

Taken together, our conjugate alters the pharmacokinetics of free PTX. Inclusion of an active targeting moiety to integrin expressing-cells, have the potential to prevent breast cancer metastasis development as an anti-angiogenic and anticancer adjuvant therapy.

  1. Eldar-Boock et al. :2011;32(15):3862-74.








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