fulltext.study @t Gmail

Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel

Paper ID Volume ID Publish Year Pages File Format Full-Text
8330 586 2011 13 PDF Available
Title
Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel
Abstract

Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a targeted conjugate of PTX, a polymer and an integrin-targeted moiety resulting in a polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. Polymer conjugation converted PTX to a macromolecule, which passively targets the tumor tissue exploiting the enhanced permeability and retention effect, while extravasating via the leaky tumor neovasculature. The cyclic RGD peptidomimetic enhanced the effects previously seen for PGA–PTX alone, utilizing the additional active targeting to the αvβ3 integrin overexpressed on tumor endothelial and epithelial cells. This strategy is particularly valuable when tumors are well-vascularized, but they present poor vascular permeability. We show that PGA is enzymatically-degradable leading to PTX release under lysosomal acidic pH. PGA-PTX-E-[c(RGDfK)2] inhibited the growth of proliferating αvβ3-expressing endothelial cells and several cancer cells. We also showed that PGA-PTX-E-[c(RGDfK)2] blocked endothelial cells migration towards vascular endothelial growth factor; blocked capillary-like tube formation; and inhibited endothelial cells attachment to fibrinogen. Orthotopic studies in mice demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced anti-tumor efficacy and a marked decrease in toxicity as compared with free PTX-treated mice.

Keywords
Angiogenesis; Polymer therapeutics; Polyglutamic acid; Paclitaxel; RGD peptidomimetic; Integrin
First Page Preview
Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel
Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 32, Issue 15, May 2011, Pages 3862–3874
Authors
, , , , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering