期刊
ANALYTICAL BIOCHEMISTRY
卷 332, 期 1, 页码 168-177出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ab.2004.05.034
关键词
folate receptors; cancer cell targeting.; liposomes; peptide synthesis; cytotoxicity; doxorubicin
资金
- NCI NIH HHS [R01CA58919] Funding Source: Medline
- NICHD NIH HHS [R01HD39295] Funding Source: Medline
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-gamma-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-gamma-glutamate-cysteine synthesis is one of the crucial starting steps in the preparation of pteroyl-gammaglutamate-cysteine-PEG-DSPE. However, published methods for the synthesis of pteroyl-gamma-glutamate-cysteine provide low yields and are not easily reproducible. Therefore, we developed a modified synthetic method for the removal of the N-10-trifluoroacetyl group after cleavage/deprotection that is reliable, is easily reproducible, and has high yield (38%) compared with ail unreliable yield of 3-20% with the earlier methods. Folate-tethered liposomes containing calcein or doxorubicin were prepared using pteroyl-gamma-glutamate-cysteine-PEG-DSPE Lis 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. (C) 2004 Elsevier Inc. All rights reserved.
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