"OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer In Vivo

Kai Xiao, Yuanpei Li, Joyce S Lee, Abby M. Gonik, Tiffany Dong, Gabriel Fung, Eduardo Sanchez, Li Xing, Holland R. Cheng, Juntao Luo, Kit Lam

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Micellar nanoparticles based on linear polyethylene glycol (PEG) block dendritic cholic acids (CA) copolymers (telodendrimers), for the targeted delivery of chemotherapeutic drugs in the treatment of cancers, are reported. The micellar nanoparticles have been decorated with a high-affinity "OA02" peptide against α-3 integrin receptor to improve the tumor-targeting specificity which is overexpressed on the surface of ovarian cancer cells. "Click chemistry" was used to conjugate alkyne-containing OA02 peptide to the azide group at the distal terminus of the PEG chain in a representative PEG 5k-CA 8 telodendrimer (micelle-forming unit). The conjugation of OA02 peptide had negligible influence on the physicochemical properties of PEG 5k-CA 8 nanoparticles and as hypothesized, OA02 peptide dramatically enhanced the uptake efficiency of PEG 5k-CA 8 nanoparticles (NP) in SKOV-3 and ES-2 ovarian cancer cells via receptor-mediated endocytosis, but not in α-3 integrin-negative K562 leukemia cells. When loaded with paclitaxel, OA02-NPs had significantly higher in vitro cytotoxicity against both SKOV-3 and ES-2 ovarian cancer cells as compared with nontargeted nanoparticles. Furthermore, the in vivo biodistribution study showed OA02 peptide greatly facilitated tumor localization and the intracellular uptake of PEG 5k-CA 8 nanoparticles into ovarian cancer cells as validated in SKOV3-luc tumor-bearing mice. Finally, paclitaxel (PTX)-loaded OA02-NPs exhibited superior antitumor efficacy and lower systemic toxicity profile in nude mice bearing SKOV-3 tumor xenografts, when compared with equivalent doses of nontargeted PTX-NPs as well as clinical paclitaxel formulation (Taxol). Therefore, OA02-targeted telodendrimers loaded with paclitaxel have great potential as a new therapeutic approach for patients with ovarian cancer.

Original languageEnglish (US)
Pages (from-to)2100-2110
Number of pages11
JournalCancer Research
Volume72
Issue number8
DOIs
StatePublished - Apr 15 2012

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Cholic Acids
Paclitaxel
Ovarian Neoplasms
Nanoparticles
Peptides
Neoplasms
Integrins
Click Chemistry
Alkynes
Azides
K562 Cells
Micelles
Endocytosis
Heterografts
Nude Mice
Leukemia
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

"OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer In Vivo. / Xiao, Kai; Li, Yuanpei; Lee, Joyce S; Gonik, Abby M.; Dong, Tiffany; Fung, Gabriel; Sanchez, Eduardo; Xing, Li; Cheng, Holland R.; Luo, Juntao; Lam, Kit.

In: Cancer Research, Vol. 72, No. 8, 15.04.2012, p. 2100-2110.

Research output: Contribution to journalArticle

Xiao, Kai ; Li, Yuanpei ; Lee, Joyce S ; Gonik, Abby M. ; Dong, Tiffany ; Fung, Gabriel ; Sanchez, Eduardo ; Xing, Li ; Cheng, Holland R. ; Luo, Juntao ; Lam, Kit. / "OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer In Vivo. In: Cancer Research. 2012 ; Vol. 72, No. 8. pp. 2100-2110.
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AU - Li, Yuanpei

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AU - Dong, Tiffany

AU - Fung, Gabriel

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AB - Micellar nanoparticles based on linear polyethylene glycol (PEG) block dendritic cholic acids (CA) copolymers (telodendrimers), for the targeted delivery of chemotherapeutic drugs in the treatment of cancers, are reported. The micellar nanoparticles have been decorated with a high-affinity "OA02" peptide against α-3 integrin receptor to improve the tumor-targeting specificity which is overexpressed on the surface of ovarian cancer cells. "Click chemistry" was used to conjugate alkyne-containing OA02 peptide to the azide group at the distal terminus of the PEG chain in a representative PEG 5k-CA 8 telodendrimer (micelle-forming unit). The conjugation of OA02 peptide had negligible influence on the physicochemical properties of PEG 5k-CA 8 nanoparticles and as hypothesized, OA02 peptide dramatically enhanced the uptake efficiency of PEG 5k-CA 8 nanoparticles (NP) in SKOV-3 and ES-2 ovarian cancer cells via receptor-mediated endocytosis, but not in α-3 integrin-negative K562 leukemia cells. When loaded with paclitaxel, OA02-NPs had significantly higher in vitro cytotoxicity against both SKOV-3 and ES-2 ovarian cancer cells as compared with nontargeted nanoparticles. Furthermore, the in vivo biodistribution study showed OA02 peptide greatly facilitated tumor localization and the intracellular uptake of PEG 5k-CA 8 nanoparticles into ovarian cancer cells as validated in SKOV3-luc tumor-bearing mice. Finally, paclitaxel (PTX)-loaded OA02-NPs exhibited superior antitumor efficacy and lower systemic toxicity profile in nude mice bearing SKOV-3 tumor xenografts, when compared with equivalent doses of nontargeted PTX-NPs as well as clinical paclitaxel formulation (Taxol). Therefore, OA02-targeted telodendrimers loaded with paclitaxel have great potential as a new therapeutic approach for patients with ovarian cancer.

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