20(S)-camptothecin (CPT) is a natural product with potent anti-tumor activity and two CPT analogs have been approved as anticancer treatments. However, CPT is insoluble, poorly stable and can cause significant toxicities. Insert Therapeutics (Insert) proposes to develop in this grant a novel delivery system that will reduce the toxicity and improve the efficacy of CPT. Our delivery system (Cyclosert) consists of cyclodextrin (CD) polymers that are non-toxic, non-immunogenic, and can easily form covalently-linked complexes with CPT. We have synthesized a family of Cyclosert-CPT prodrugs that are highly water-soluble, stable under physiological conditions, release CPT in a controlled fashion in mouse and human serum and demonstrate potent anti-tumor activity against a range of cancer cell lines in vitro. In vivo studies have demonstrated that our Cyclosert-CPT formulations are well tolerated in mice and treatment with our Cyclosert-CPT conjugates resulted in more effective and prolonged tumor suppression than irinotecan. Furthermore, the long lasting tumor suppression we found after only three doses of Cyclosert-CPT was not seen with CPT alone or irinotecan and suggests that our Cyclosert delivery system enhances accumulation of CPT at the tumor and provides a slow, long lasting release of active drug. These initial studies indicate that our delivery system significantly improves the pharmacological profile of CPT and supports further evaluation of our Cyclosert-CPT prodrugs as anti-cancer agents. In this grant we propose to optimize the pharmacokinetic and pharmacological properties of our lead Cyclosert-CPT conjugates. At the completion of these studies, we will select the Cyclosert-CPT conjugate with the optimal therapeutic index to enter into GLP-toxicology studies, with the ultimate goal of testing in humans. In addition, we will evaluate alternative linker chemistries that will be used to conjugate CPT to our CD polymers to further optimize the release of CPT. These novel linker chemistries will be used to develop second generation Cyclosert conjugates with improved delivery capabilities. Our goal is to enhance the therapeutic index of CPT with our unique delivery system so that it can be employed as a safe and effective chemotherapeutic agent. ? ? ?
