Receptor-Targeted Liposomal Delivery of Boron-Containing Cholesterol Mimics for Boron Neutron Capture Therapy (BNCT)
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- 作者：B.T.S. Thirumamagal ; Xiaobin B. Zhao ; Achintya K. Bandyopadhyaya ; Sureshbabu Narayanasamy ; Jayaseharan Johnsamuel ; Rohit Tiwari ; Danold W. Golightly ; Vimalkumar Patel ; Brian T. Jehning ; Marina V. Back
- 刊名：Bioconjugate Chemistry
- 出版年：2006
- 出版时间：September 2006
- 年：2006
- 卷：17
- 期：5
- 页码：1141 - 1150
- 全文大小：307K
- 年卷期：v.17,no.5(September 2006)
- ISSN：1520-4812
文摘
Liposomes have been a main focus of tumor-selective boron delivery strategies in boron neutron capture therapy(BNCT), a binary method for the treatment of cancer that is based on the nuclear reaction between boron atomsand low-energy thermal neutrons. Three novel carboranyl cholesterol derivatives were prepared as lipid bilayercomponents for the construction of nontargeted and receptor-targeted boronated liposomes for BNCT. A majorstructural feature of these novel boronated cholesterol mimics is the replacement of the B and the C ring ofcholesterol with a carborane cluster. Computational analyses indicated that all three boronated compounds havestructural features and physicochemical properties that are very similar to those of cholesterol. One of the synthesizedboronated cholesterol mimics was stably incorporated into non-, folate receptor (FR)-, and vascular endothelialgrowth factor receptor-2 (VEGFR-2)-targeted liposomes. No major differences were found in appearance, sizedistribution, and lamellarity between conventional dipalmitoylphosphatidylcholine (DPPC)/cholesterol liposomes,nontargeted, and FR-targeted liposomal formulations of this carboranyl cholesterol derivative. FR-targeted boronatedliposomes were taken up extensively in FR overexpressing KB cells in vitro, and the uptake was effectivelyblocked in the presence of free folate. In contrast, a boronated cholesterol mimic incorporated into nontargetedliposomes showed significantly lower cellular uptake. There was no apparent in vitro cytotoxicity in FRoverexpressing KB cells and VEGFR-2 overexpressing 293/KDR cells when these were incubated with boronatedFR- and (VEGFR-2)-targeted liposomes, respectively, although the former accumulated extensively in KB cellsand the latter effectively interacted with VEGFR-2 by causing autophosphorylation and protecting 293/KDRcells from SLT (Shiga-like toxin)-VEGF cytotoxicity.