Co-delivery of antibiotics and topoisomerase inhibitors to overcome chemoresistance
Mentor: Tayyaba Hasan, PhD (Massachusetts General Hospital)
In patients with recurrent platinum-resistant epithelial ovarian cancer, topoisomerase inhibitors (TPIs) are the most active second-line chemoagents; however, treatment response is underwhelming due to both drug resistance and systemic toxicity of TPIs. Topoisomerases are enzymes that cleave DNA strands to mediate relaxation of supercoiled DNA, allowing for the continuation of DNA replication and transcription. TPIs disrupt this process by trapping topoisomerase-DNA cleavage complexes, increasing the rate of topoisomerase-crosslinked DNA strand breaks. Tdp1 is an emerging therapeutic target that repairs the topoisomerase-DNA adduct by cleaving the 3’(5’)-tyrosyl-DNA bond between topoisomerase and DNA in cells, reducing the efficacy of the TPI. This function of Tdp1 makes it a potential therapeutic target that may be incorporated into treatment. Nanotechnology is used in this study to assist in targeting these enzymes by repurposing Tdp-1-inhibiting antibiotics in a mechanistically interactive combination with TPIs to provide a more effective treatment. The underlying hypothesis is that the ability of tetracycline antibiotics to reduce DNA repair inhibition of Tdp1 removes a barrier that mitigates camptothecin action. This combination, unbalancing the rate of DNA cleavage and religation, is anticipated to enhance cancer cell death. Co-encapsulation and co-delivery of the agents at high payloads in nanoliposomes will also aid in reducing systemic toxicity.The goal of the study will be achieved in two aims under the mentorship of Dr. Tayyaba Hasan (PI) and postdoctoral fellows (Drs. Huang and Obaid): Aim 1 (1-4 months) will synthesize and characterize multi-compartmental nanoliposomes to co-delivery tetracycline (antibiotic) and camptothecin (TPI). Aim 2 (4-6 months) will evaluate the combination treatment response in monolayer cultures of OVCAR-5-cisR (cisplatin-resistant ovarian cancer cell line derived from solid tumor).
Nanoliposomes will be used to co-deliver a Tdp1-inhibiting antibiotic (tetracycline) and a topoisomerase inhibitor (camptothecin) to cancer cells, enhancing cell death with less systematic toxicity. Source: