PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma

Kai Xiao, Juntao Luo, Yuanpei Li, Joyce S Lee, Gabriel Fung, Kit Lam

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Doxorubicin (DOX) is one of most common anti-cancer chemotherapeutic drugs, but its clinical use is associated with dose-limiting cardiotoxicity. We have recently developed a series of PEG-oligocholic acid based telodendrimers, which can efficiently encapsulate hydrophobic drugs and self-assemble to form stable micelles in aqueous condition. In the present study, two representative telodendrimers (PEG 5k-CA 8 and PEG 2k-CA 4) have been applied to prepare DOX micellar formulations for the targeted delivery of DOX to lymphoma. PEG 2k-CA 4 micelles, compared to PEG 5k-CA 8 micelles, were found to have higher DOX loading capacity (14.8% vs. 8.2%, w/w), superior stability in physiological condition, and more sustained release profile. Both of these DOX-loaded micelles can be efficiently internalized and release the drug in Raji lymphoma cells. DOX-loaded micelles were found to exhibit similar in vitro cytotoxic activities against both T- and B-lymphoma cells as the free DOX. The maximum tolerated dose (MTD) of DOX-loaded PEG 2k-CA 4 micelles in mice was approximately 15 mg/kg, which was 1.5-fold higher of the MTD of free DOX. Pharmacokinetics and biodistribution studies demonstrated that both DOX-loaded micelles were able to prolong the blood retention time, preferentially accumulate and penetrate in B-cell lymphomas via the enhanced permeability and retention (EPR) effect. Finally, DOX-PEG 2k-CA 4 micelles achieved enhanced anti-cancer efficacy and prolonged survival in Raji lymphoma bearing mice, compared to free DOX and PEGylated liposomal DOX (Doxil®) at the equivalent dose. In addition, the analysis of creatine kinase (CK) and lactate dehydrogenase (LDH) serum enzymes level indicated that DOX micellar formulations significantly reduced the cardiotoxicity associated with free DOX.

Original languageEnglish (US)
Pages (from-to)272-281
Number of pages10
JournalJournal of Controlled Release
Volume155
Issue number2
DOIs
StatePublished - Oct 30 2011

Fingerprint

Micelles
B-Cell Lymphoma
Doxorubicin
Acids
Lymphoma
Maximum Tolerated Dose
T-Cell Lymphoma
Creatine Kinase
L-Lactate Dehydrogenase
Pharmaceutical Preparations
Permeability
Neoplasms
Pharmacokinetics

Keywords

  • Biodistribution
  • Cancer therapy
  • Cardiotoxicity
  • Doxorubicin
  • Drug delivery
  • Nanotherapeutics
  • Polymeric micelles

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma. / Xiao, Kai; Luo, Juntao; Li, Yuanpei; Lee, Joyce S; Fung, Gabriel; Lam, Kit.

In: Journal of Controlled Release, Vol. 155, No. 2, 30.10.2011, p. 272-281.

Research output: Contribution to journalArticle

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AU - Fung, Gabriel

AU - Lam, Kit

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AB - Doxorubicin (DOX) is one of most common anti-cancer chemotherapeutic drugs, but its clinical use is associated with dose-limiting cardiotoxicity. We have recently developed a series of PEG-oligocholic acid based telodendrimers, which can efficiently encapsulate hydrophobic drugs and self-assemble to form stable micelles in aqueous condition. In the present study, two representative telodendrimers (PEG 5k-CA 8 and PEG 2k-CA 4) have been applied to prepare DOX micellar formulations for the targeted delivery of DOX to lymphoma. PEG 2k-CA 4 micelles, compared to PEG 5k-CA 8 micelles, were found to have higher DOX loading capacity (14.8% vs. 8.2%, w/w), superior stability in physiological condition, and more sustained release profile. Both of these DOX-loaded micelles can be efficiently internalized and release the drug in Raji lymphoma cells. DOX-loaded micelles were found to exhibit similar in vitro cytotoxic activities against both T- and B-lymphoma cells as the free DOX. The maximum tolerated dose (MTD) of DOX-loaded PEG 2k-CA 4 micelles in mice was approximately 15 mg/kg, which was 1.5-fold higher of the MTD of free DOX. Pharmacokinetics and biodistribution studies demonstrated that both DOX-loaded micelles were able to prolong the blood retention time, preferentially accumulate and penetrate in B-cell lymphomas via the enhanced permeability and retention (EPR) effect. Finally, DOX-PEG 2k-CA 4 micelles achieved enhanced anti-cancer efficacy and prolonged survival in Raji lymphoma bearing mice, compared to free DOX and PEGylated liposomal DOX (Doxil®) at the equivalent dose. In addition, the analysis of creatine kinase (CK) and lactate dehydrogenase (LDH) serum enzymes level indicated that DOX micellar formulations significantly reduced the cardiotoxicity associated with free DOX.

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KW - Nanotherapeutics

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