RNA Aptamers that Internalize into Cancer Cells for Drug Delivery

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2023

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Abstract

There has been a long history of humans fighting against cancer. Conventional treatments including surgery, radiation therapy, and chemotherapy remain the mainstream approaches, but an increasing understanding of tumor formation and advances in technology have revealed a new approach to cancer treatment: personalized medicine. Personalized medicine considers tumor heterogeneity and tailors treatments to individual patients based on their genetic information and their tumors. Targeted therapy, for example, could precisely attack specific types of cells that express targeted proteins. In recent years, a subclass of targeted therapy, antibody-drug conjugates (ADC), has received vast clinical attention due to their ability to deliver highly toxic drugs to cancer cells and effectively kill them while sparing healthy cells. Intrigued by the working philosophy of ADCs while acknowledging their limitations, a group of scientists, including our lab, proposed the use of aptamers to create a new class of targeted therapeutics. Aptamers are RNA or DNA ligands that do not require humanization and pose minimal immunogenic risks to patients. Previously, our group reported an RNA aptamer, named E3, which was selected to target prostate cancer cells and demonstrated the ability to effectively eliminate cancer cells when conjugated with drugs. Here, I observe that E3 can also target a broad range of other cancer types, leading me to investigate its molecular target. The following study shows that the E3 aptamer targets human transferrin receptor 1 (hTfR) to enter the cancer cells, consistent with the upregulated expression of hTfR in most cancer types. However, I encountered challenges in the next-step laboratory development of E3 since it did not exhibit cross-reactivity in murine cells. Therefore, I demonstrated that E3 also targets canine cancer cells, which highlights the potential to test E3 in canine models. To further develop a TfR targeting aptamer that can work in both mouse models and against human cancer, I performed a new selection for an aptamer using 2’OMe A, C, U, and 2’OH G modified RNA library that can recognize both human and murine TfR with better resistance for nuclease degradation. Additionally, a non-transferrin (Tf) competing TfR-aptamer is also identified in the study with more nuclease resistance. The results of this study offer several potential weapons used for treating cancers. E3 aptamer targeting hTfR works well in human cancer xenograft mouse models but encounters challenges for characterizations in vivo. Therefore, I select and report a panel of TfR-targeting aptamers that can be used for mouse study or clinical development. Through this study, I aim to contribute to the advancement of targeted delivery and improve drug efficacy in cancer patients.

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Song, Xirui (2023). RNA Aptamers that Internalize into Cancer Cells for Drug Delivery. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/29152.

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