Pteroyl-γ-glutamate-cysteine synthesis and its application in folate receptor-mediated cancer cell targeting using folate-tethered liposomes

Yonghua Zhang, Lili Guo, Roger W. Roeske, Aśok C. Antony, Hiremagalur N. Jayaram

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Cell membrane-associated folate receptors are selectively overexpressed in certain human tumors. The high affinity of folic acid for folate receptors provides a unique opportunity to use folic acid as a targeting ligand to deliver chemotherapeutic agents to cancer cells. Folate-tethered liposomes bearing pteroyl-γ-glutamate-cysteine-polyethylene glycol (PEG)- distearoylphosphatidylethanolamine (DSPE) as the targeting component are under investigation as mediators of drug and gene delivery to cancer cells that overexpress folate receptors. Pteroyl-γ-glutamate-cysteine synthesis is one of the crucial starting steps in the preparation of pteroyl-γ- glutamate-cysteine-PEG-DSPE. However, published methods for the synthesis of pteroyl-γ-glutamate-cysteine provide low yields and are not easily reproducible. Therefore, we developed a modified synthetic method for the removal of the N10-trifluoroacetyl group after cleavage/deprotection that is reliable, is easily reproducible, and has high yield (38%) compared with an unreliable yield of 3-20% with the earlier methods. Folate-tethered liposomes containing calcein or doxorubicin were prepared using pteroyl-γ-glutamate-cysteine-PEG-DSPE as the targeting component along with nontargeted liposomes with PEG-DSPE. The results of the uptake of calcein and cytotoxicity of doxorubicin in human cervical cancer HeLa-IU1 cells and human colon cancer Caco-2 cells demonstrated that folate-tethered liposomes were efficient in selective delivery to cancer cells overexpressing folate receptors. The improvement in yield of the targeting component can significantly facilitate "scale up" of folate receptor-mediated liposomal cancer therapy to the preclinical and clinical levels of investigations.

Original languageEnglish (US)
Pages (from-to)168-177
Number of pages10
JournalAnalytical biochemistry
Volume332
Issue number1
DOIs
StatePublished - Sep 1 2004

Keywords

  • Cancer cell targeting
  • Cytotoxicity
  • Doxorubicin
  • Folate receptors
  • Liposomes
  • Peptide synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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