Abstract
Abstract Overcoming drug resistance, emerging either on recurring cancer or metastasis, is a major target of cancer treatments. The combination of anti-angiogenic therapy with cytotoxic therapy offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug, which also exhibits anti-angiogenic activity at low doses. The use of the hydrophobic PTX to its full potential is limited by severe side effects, caused by the drug and its solubilizing agents. Integrins play a key role in cell matrix interactions. The highly restricted expression of integrin αvβ3, overexpressed on tumor endothelial and some epithelial cells, during tumor growth, invasion, and metastasis present an interesting molecular target for metastatic breast tumors. In addition, PTX acquired resistance correlated with integrin αvβ3 overexpression on breast cancer cells. We designed and synthesized a novel polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. 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. The E-[c(RGDfK)2] enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the αvβ3 integrin. PGA is enzymatically-degradable by cathepsin B, leading to PTX release. PGA-PTX-E-[c(RGDfK)2] displayed a potent anti-angiogenic therapy, determined by several, well-established, in vitro assays. Mice bearing orthotopic mammary tumors demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decreased in toxicity compared with free PTX. The correlation between αvβ3 integrin expression on tumor cells and acquired PTX-resistance was determined by in vitro manipulation of αvβ3 overexpressing-cells and by examining subsets of primary versus metastatic or recurring tumors of PTX-treated patients as well as free and conjugated-PTX-treated tumor-bearing mice. Taken together, our conjugate alters the pharmacokinetics of free PTX. Inclusion of an active targeting moiety to integrin expressing-cells, have the potential to manipulate and overcome acquired drug resistance, which will hopefully warrant it as a novel targeted, anti-angiogenic and anticancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5225. doi:1538-7445.AM2012-5225
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