Repurposing of camptothecin: An esterase-activatable prodrug delivered by a self-emulsifying formulation that improves efficacy in colorectal cancer

The global burden of colorectal cancer (CRC), the third most commonly diagnosed malignancy, continues to rise. Therefore, more effective and less toxic therapies are needed for CRC. CPT-11 (also called irinotecan), the standard-of-care treatment for CRC, has only had limited effects on survival outcomes. In vivo, CPT-11 must be converted to an active metabolite, SN38, to exert antitumor activity in the presence of carboxylesterases, but the conversion rate is extremely low (usually less than 8%). To fully harness the active SN38 compound, we showed here that esterification of SN38 using α-linolenic acid (LNA) generated a prodrug (termed LSN38), which can be formulated in pharmaceutically acceptable surfactants, such as polysorbate 80. Upon blending with an aqueous ethanolic solution, the mixture of LSN38/polysorbate 80 formed self-emulsifying nanomicelles (termed LSN38 NMs), enabling systemic injection. Unlike the insufficient release of active SN38 from CPT-11, drug activation from the LSN38 prodrug was quantitative and relied on esterase, which is abundant in cancerous cells. Pharmacokinetics studies revealed that polysorbate 80-based nanomicelles stably constrained the prodrug in the reservoir and prolonged blood circulation compared to CPT-11. Furthermore, LSN38 NMs showed superior therapeutic efficacy against a colorectal xenograft-bearing mouse model that failed to be treated with clinically approved CPT-11. Overall, these studies highlight the feasibility of converting a chemotherapeutic agent that is not miscible or compatible with pharmaceutical surfactants into an injectable self-emulsifying formulation. This approach could be applied to rescue other drugs or drug candidates that are abandoned in the preclinical stages due to pharmaceutical challenges.

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