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Development and characterization of a lipid-based nanoparticulate formulation of topotecan and its use in combination with doxil for treatment of relapsed ovarian cancer models

University of British Columbia

Platinum-refractory ovarian cancer is considered an incurable disease as current treatments are only palliative. Improvements in treatment will be realized as our understanding of the unique signaling pathways driving disease development increases and new therapeutics targeting these pathways are developed. It’s important to recognize, however, that at this time new molecularly targeted agents are not replacing the drugs being used to treat cancer; they are being used in combination with existing standards of care. In light of this, it is important to explore novel approaches using existing agents that are designed to achieve maximum therapeutic benefits in dosage forms that are well tolerated. Like most cancers, ovarian cancer is treated with a combination of drugs selected on the basis of complementary mechanisms of action and non-overlapping toxicities. Synergistic drug combinations can achieve therapeutic effects equal to that achieved with single agents, but at significantly lower and better tolerated doses. The factors that govern synergistic drug:drug interaction are, however, poorly understood and it is argued in this thesis that drug interactions favoring synergy will be influenced by drug exposure time. An effective method to enhance drug exposure time involves the use of drug carriers and a goal of this thesis was to develop an effective combination regimen against recurrent ovarian cancer using a novel lipid nanoparticle (LNP) formulation of topotecan and Doxil®; a LNP formulation of doxorubicin that has already been approved for the treatment of relapsed ovarian cancer. The LNP formulation of topotecan developed through this thesis research, referred to as TopophoreC™, was 2-to-3-fold more toxic than free topotecan, however this product candidate showed significantly better anti-tumor activity when compared to free topotecan administered at equivalent doses. Combinations of this LNP topotecan formulation with Doxil® were therapeutically superior to combinations of free topotecan and Doxil® as judged in two models of ovarian cancer. On the basis of these studies, it can be concluded that interaction between TopophoreC™ and Doxil® affect the pharmacokinetic behavior of Doxil® however the results provide proof of concept data to support the use of TopophoreC™ and Doxil® combination for treatment of recurrent ovarian cancer.

Text

2010-12-21

Attribution-NonCommercial-NoDerivs 3.0 Unported

http://hdl.handle.net/2429/30471

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/3.0/