期刊
JOURNAL OF CONTROLLED RELEASE
卷 74, 期 1-3, 页码 325-333出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/S0168-3659(01)00343-1
关键词
camptothecin; topoisomerase I; silatecan; liposome; human serum albumin
资金
- NCI NIH HHS [CA63653, CA75761] Funding Source: Medline
- NIGMS NIH HHS [GM31678] Funding Source: Medline
The novel silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) is 25- to 50-times more lipophilic than camptothecin and readily incorporates into lipid bilayers. Using the method of fluorescence anisotropy titration, we determined that DB-67 bound to small unilamellar vesicles composed of dilaurylphosphatidylcholine (DLPC) with an association constant (K value) of 5000 M-1. This association constant is significantly higher than the K DLPC value observed for camptothecin (K-DLPC value of 110 M-1). Using HPLC methods, we demonstrated that the presence of liposomal membranes readily stabilize the lactone form of DB-67. At drug and lipid concentrations of 10 muM and 0.3 mM, respectively, the lactone form of DB-67 persisted in liposome suspension after 3 h of incubation at 37 degreesC. Thus an advantage of a liposomal formulation of DB-67 is that the presence of lipid bilayers assists with stabilizing the key pharmacophore of the agent. The highly lipophilic character of DB-67, in combination with its 10-hydroxy moiety (which functions to enhance lactone stability in the presence of human serum albumin), results in DB-67 having superior stability in human blood with a percent lactone at equilibrium value of 30 [Cancer Res. 59 (1999) 4898: J. Med. Chem, 43 (2000) 3970], Potent cytotoxicities against a broad range of cancer cells were observed for DB-67, indicating that DB-67 is of comparable potency to camptothecin. The impressive human blood stability and cytotoxicity profiles for DB-67 indicate it is an excellent candidate for comprehensive in vivo pharmacological and efficacy studies. Based on these promising attributes, DB-67 is currently being developed under the NCI RAID program. Due to its potent anti-topoisomerase I activity and its intrinsic blood stability, DB-67 appears as an attractive novel camptothecin for clinical development. (C) 2001 Elsevier Science BM All rights reserved.
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