Date of Award

January 2018

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Michael Girardi

Abstract

Keratinocyte-derived carcinomas represent the most common type of malignancy worldwide, and while surgical removal is a first-line therapy, surgery may be impractical for certain patients and does not completely eliminate risk of recurrence. Previous studies have demonstrated the advantages of biodegradable poly(lactic acid)-hyperbranched polyglycerol non-bioadhesive nanoparticles (NNPs) and bioadhesive nanoparticles (BNPs) as chemotherapeutic drug delivery vehicles for the treatment of internal solid tumors. We are now investigating the use of this delivery system for the treatment of cutaneous malignancies, with the goal of maximizing drug efficacy while minimizing systemic effects and treatment-associated morbidity. After topical application of fluorescent dye-loaded NNPs to the intact skin of mice, epidermal penetration of the NNPs to the dermal-epidermal junction and accumulation within hair follicles was observed at time points ranging from 4 to 72 hours. Using the PDV squamous cell carcinoma (SCC) murine model, both dye- loaded NNPs and BNPs exhibited a dose- and time- dependent association with PDV cells in vitro by flow cytometry, and BNPs had increased association with cells compared to NNPs. Confocal microscopy confirmed internalization of NPs by cells. Camptothecin (CPT)-loaded NNPs and BNPs were developed; these particles contained 5% by weight CPT. There was no significant difference in effect on PDV cell proliferation in vitro among CPT, CPT/NNP, and CPT/BNP treatment groups. A pilot study using subcutaneously transplanted PDV tumors showed effective and complete destruction of the tumor after intratumoral injection of CPT/BNP. A subsequent study using an increased frequency of treatment and lower concentration of CPT compared CPT/intralipid (CPT/IL), CPT/NNP and CPT/BNP injections and showed prolonged survival in all CPT groups compared to control, and a trend toward prolonged survival in NNP and BNP groups compared to CPT/IL. However, none of the three treatments fully eliminated tumor burden in treated mice, suggesting that a higher concentration of drug may be optimal. Overall, our results indicate that both NNPs and BNPs rapidly associate with PDV tumor cells, and in vitro drug delivery is not inhibited by NP encapsulation. Further studies are needed to optimize the method, concentration, and frequency of nanoparticle and drug delivery to effectively and consistently treat SCC tumors.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/29/2021

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