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

Anat Eldar-Boock, Keren Miller, Joaquin Sanchis, Ruth Lupu, María J. Vicent, Ronit Satchi-Fainaro

Research output: Contribution to journalArticle

94 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3862-3874
Number of pages13
JournalBiomaterials
Volume32
Issue number15
DOIs
StatePublished - May 2011

Fingerprint

Bearings (structural)
Paclitaxel
Drug delivery
Integrins
Tumors
Polymers
Endothelial cells
Acids
Pharmaceutical Preparations
Neoplasms
Endothelial Cells
Therapeutics
Polyglutamic Acid
Peptidomimetics
Macromolecules
Fibrinogen
Vascular Endothelial Growth Factor A
Toxicity
Capillary Permeability
Cells

Keywords

  • Angiogenesis
  • Integrin
  • Paclitaxel
  • Polyglutamic acid
  • Polymer therapeutics
  • RGD peptidomimetic

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

Cite this

Eldar-Boock, A., Miller, K., Sanchis, J., Lupu, R., Vicent, M. J., & Satchi-Fainaro, R. (2011). Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel. Biomaterials, 32(15), 3862-3874. https://doi.org/10.1016/j.biomaterials.2011.01.073

Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel. / Eldar-Boock, Anat; Miller, Keren; Sanchis, Joaquin; Lupu, Ruth; Vicent, María J.; Satchi-Fainaro, Ronit.

In: Biomaterials, Vol. 32, No. 15, 05.2011, p. 3862-3874.

Research output: Contribution to journalArticle

Eldar-Boock, A, Miller, K, Sanchis, J, Lupu, R, Vicent, MJ & Satchi-Fainaro, R 2011, 'Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel', Biomaterials, vol. 32, no. 15, pp. 3862-3874. https://doi.org/10.1016/j.biomaterials.2011.01.073
Eldar-Boock, Anat ; Miller, Keren ; Sanchis, Joaquin ; Lupu, Ruth ; Vicent, María J. ; Satchi-Fainaro, Ronit. / Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel. In: Biomaterials. 2011 ; Vol. 32, No. 15. pp. 3862-3874.
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