Within this grant application we present exciting new data that demonstrate long-circulating liposomal formulations of camptothecins markedly improve blood stabilities, enhance drug circulation half-lives, and dramatically potentiate and enhance anti-tumor activities. We also describe our very recent synthetic efforts which have developed highly potent A,B,E-ring modified camptothecins displaying markedly improved human blood stabilities. We now intend to combine the rational drug design with liposomal delivery approaches to generate long-circulating and tumor- targeted liposomal camptothecin formulations for the treatment of cancer.
Our specific aims i nclude: 1) to develop novel and potent 7-alkylamino- homocamptotechin as well as 7-silylalkylaminohomocamptothecin topoisomerase I inhibitors capable of being remote-loaded into stealth-like, long-circulating liposomes; 2) to formulate long-circulating and is highly preferred by the pharmaceutical industry for manufacturing reasons) and to implement our synthetic abilities to create the camptothecin agents that display optimal retention in liposomes thereby optimizing drug delivery to the tumor; 3) to characterize the cellular pharmacology and blood chemistry of the new analogues and their liposomal formulations; 4) to determine in vivo anti-tumor activities, and tumor localization of the various camptothecin liposomal formulations against human xenografts; 5) to utilize fluorescence imaging methods to non-invasively study in situ the accumulation camptothecins delivered in liposomes at tumor sites in athymic nude mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA063653-05A1
Application #
2907996
Study Section
Special Emphasis Panel (ZRG1-ET-2 (03))
Program Officer
Fu, Yali
Project Start
1994-05-01
Project End
2002-08-31
Budget Start
1999-09-13
Budget End
2000-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Song, Lin; Bevins, Robert; Anderson, Bradley D (2006) Kinetics and mechanisms of activation of alpha-amino acid ester prodrugs of camptothecins. J Med Chem 49:4344-55
Lopez-Barcons, Lluis A; Zhang, Junhong; Siriwitayawan, Gunching et al. (2004) The novel highly lipophilic topoisomerase I inhibitor DB67 is effective in the treatment of liver metastases of murine CT-26 colon carcinoma. Neoplasia 6:457-67
Liu, Xinli; Zhang, Junhong; Song, Lin et al. (2004) Degradation of camptothecin-20(S)-glycinate ester prodrug under physiological conditions. J Pharm Biomed Anal 35:1113-25
Du, Wu; Curran, Dennis P; Bevins, Robert L et al. (2002) Synthesis and evaluation of a novel E-ring modified alpha-hydroxy keto ether analogue of camptothecin. Bioorg Med Chem 10:103-10
Liu, Xinli; Lynn, Bert C; Zhang, Junhong et al. (2002) A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs. J Am Chem Soc 124:7650-1
Bom, D; Curran, D P; Zhang, J et al. (2001) The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity. J Control Release 74:325-33
Bom, D; Curran, D P; Kruszewski, S et al. (2000) The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem 43:3970-80
Bom, D; Curran, D P; Chavan, A J et al. (1999) Novel A,B,E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities. J Med Chem 42:3018-22
Pollack, I F; Erff, M; Bom, D et al. (1999) Potent topoisomerase I inhibition by novel silatecans eliminates glioma proliferation in vitro and in vivo. Cancer Res 59:4898-905
Shenderova, A; Burke, T G; Schwendeman, S P (1999) The acidic microclimate in poly(lactide-co-glycolide) microspheres stabilizes camptothecins. Pharm Res 16:241-8

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