Date of Award
Medical Doctor (MD)
In the United States, the frequency of skin cancers exceeds the frequency of all other cancers combined, with keratinocyte-derived carcinomas (KDCs) comprising the most common class of malignancies. A major type of KDC is the squamous cell carcinoma (SCC), which is responsible for approximately 5 million cases and 10,000 deaths each year. Although surgery remains the gold standard for treatment, there are several limitations to surgical excision, including recurrence, incomplete removal, and incompatibility with large surface areas. Alternative treatments such as radiotherapy, topical chemotherapy, and topical immunotherapy have often proven burdensome, costly, and ineffective, rendering a need for a novel, minimally invasive therapy for the local treatment of SCC. To address this need, we have developed a novel drug delivery platform harnessing the power of nanotechnology. Using the biodegradable polymer poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG), we encapsulated camptothecin (CPT) within either non-adhesive (NNPs) or bioadhesive nanoparticles (BNPs), specifically designed to augment adhesion within tumor microenvironments. Characterization of both NNPs and BNPs revealed significantly improved bioadhesiveness of BNPs, with enhanced anti-tumoral properties. Indeed, in vitro tumor cell association and toxicity using a murine SCC cell line (PDVC57) then evidenced a significant cytotoxic advantage of BNP-CPT in comparison to NNP-CPT and free drug controls. Furthermore, treatment of in vivo SCC tumors with BNP-CPT confirmed sustained tumoral association and extended intratumoral drug retention, which translated to increased survival of SCC mice in comparison to animals treated with NNP-CPT or free drug. Yet, despite these advantages, monotherapy with BNP-CPT was not sufficient to completely eradicate tumors in mice. Alternatively, combining BNP-CPT with the adjuvant immunostimulatory agent, CpG oligodeoxynucleotides, not only significantly increased animal survival in comparison to monotherapy, but also fully eradicated tumors in a portion of treated animals. Together, our results indicate that local delivery of chemotherapeutic agents via bioadhesive, biodegradable nanoparticles with adjuvant immunotherapy represents a viable, non-surgical alternative for cutaneous malignancy by offering improved intratumoral drug retention and bioavailability.
Hu, Jamie Katy, "Local Nanoparticle Delivery Of Anti-Tumor Agents In The Treatment Of Skin Cancer" (2020). Yale Medicine Thesis Digital Library. 3912.