Targeting human clonogenic acute myelogenous leukemia cells via folate conjugated liposomes combined with receptor modulation by all-trans retinoic acid

Hong Li, Yanhui Lu, Longzhu Piao, Jun Wu, Shujun Liu, Guido Marcucci, Manohar Ratnam, Robert J. Lee

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Our previous data demonstrated that folate receptor β (FR-β) targeted liposomal doxorubicin (FT-L-DOX) showed enhanced cytotoxicity relative to non-targeted liposomal doxorubicin (CON-L-DOX), and the effect was enhanced by selective FR-β upregulation by all-trans retinoic acid (ATRA) in AML blast cells. In this study, the enhanced cytotoxicity was investigated in the proliferating human AML clonogenic cells by combining FT-L-DOX with ATRA. Also, pharmacokinetic properties by pretreatment of ATRA were evaluated using FR-targeted liposomal calcein (FT-L-Calcein). Pharmacokinetic study showed that the area under the concentration curve (AUC) of FT-L-Calcein was decreased and total clearance was increased by pretreatment with ATRA. Meanwhile, the volume of distribution was significantly increased by pretreatment of ATRA. Moreover, calcein level in the liver, spleen and kidney was increased following intravenous administration of FT-L-Calcein by pretreatment of ATRA. In vitro cytotoxicity of FT-L-DOX was higher than that of CON-L-DOX and was increased by pretreatment with ATRA. Colony formation in AML cells was lower due to treatment with FT-L-DOX compared with CON-L-DOX and colony formation further decreased upon pretreatment with ATRA. Moreover, FT-L-DOX was more toxic to AML clonogenic cells than to AML blast cells. The results demonstrate that the efficiency of FR-mediated targeting of FT-L-DOX was preferentially enhanced by ATRA induced FR-β upregulation in AML clonogenic cells.

Original languageEnglish (US)
Pages (from-to)57-63
Number of pages7
JournalInternational journal of pharmaceutics
Volume402
Issue number1-2
DOIs
StatePublished - Dec 15 2010
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by NIH R01grants CA095673 and CA080183, and NCI SPORE grant P50 CA140158.

Keywords

  • Acute myeloid leukemia
  • All-trans retinoic acid
  • Clonogenic cell
  • Doxorubicin
  • Folate receptor
  • Liposomes
  • Targeted drug delivery

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