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Selective eradication of tumor vascular pericytes by peptide-conjugated nanoparticles for antiangiogenic therapy of melanoma lung metastasis.

Abstract
Antiangiogenic cancer therapy based on nanoparticulate drug delivery systems (nano-DDS) is emerging as a promising new approach besides the proved molecular-targeted antiangiogenic agents. The current nano-DDS are restricted to the targeting to tumor vascular endothelial cells, but seldom efforts have been made to target the tumor vascular pericytes which are also actively involved in tumor angiogenesis. In this study, we developed a new nano-DDS, TH10 peptide (TAASGVRSMH) conjugated nanoparticles loading docetaxel (TH10-DTX-NP) that can target the NG2 proteoglycan highly expressed in tumor vascular pericytes, for the investigation of therapeutic efficacy in the mice bearing B16F10-luc-G5 melanoma experimental lung metastasis. The results demonstrated that TH10-DTX-NP achieved controlled drug release in PBS and the mixture of rat plasma and PBS (1:1, v/v), and exhibited favorable in vivo long-circulating feature. TH10 peptide conjugation facilitated the nanoparticle internalization in pericytes via the interaction between TH10 and NG2 receptor, leading to more inhibition of pericyte viability and migration. TH10-conjugated nanoparticles could accurately target the vascular pericytes of B16F10-luc-G5 lung metastasis, where DTX-induced pronounceable pericyte apoptosis. TH10-DTX-NP significantly prolonged the mice survival with no obvious toxicity, and this enhanced antitumor effect was closely related with the decreased pericyte density and microvessel density in the lung metastases. The present research reveals the potency and significance of targeting tumor vascular pericytes using nano-DDS in antiangiogenic cancer therapy.
AuthorsYing-Yun Guan, Xin Luan, Jian-Rong Xu, Ya-Rong Liu, Qin Lu, Chao Wang, Hai-Jun Liu, Yun-Ge Gao, Hong-Zhuan Chen, Chao Fang
JournalBiomaterials (Biomaterials) Vol. 35 Issue 9 Pg. 3060-70 (Mar 2014) ISSN: 1878-5905 [Electronic] Netherlands
PMID24393268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Angiogenesis Inhibitors
  • Peptides
  • Taxoids
  • docetaxel
Topics
  • Amino Acid Sequence
  • Angiogenesis Inhibitors (pharmacology, therapeutic use)
  • Animals
  • Brain (blood supply, pathology)
  • Cell Movement (drug effects)
  • Cell Proliferation (drug effects)
  • Endocytosis (drug effects)
  • Female
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms (blood supply, drug therapy, secondary)
  • Male
  • Melanoma, Experimental (pathology)
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Sequence Data
  • Nanoparticles (chemistry, ultrastructure)
  • Neovascularization, Pathologic
  • Peptides (chemistry, pharmacology, therapeutic use)
  • Pericytes (drug effects, metabolism, pathology)
  • Rats
  • Rats, Sprague-Dawley
  • Taxoids (pharmacology, therapeutic use)

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