Date on Master's Thesis/Doctoral Dissertation

5-2018

Document Type

Master's Thesis

Degree Name

M. Eng.

Department

Bioengineering

Committee Chair

Steinbach-Rankins, Jill

Committee Co-Chair (if applicable)

Frieboes, Hermann

Committee Member

Frieboes, Hermann

Committee Member

Hein, David

Author's Keywords

nanoparticles; cervical cancer; 3D cell culture; tumor spheroid; nanoparticle transport

Abstract

A major challenge associated with delivery of active agents in the female reproductive tract (FRT) is the ability of agents to efficiently diffuse through the cervicovaginal mucosa (CVM) and reach the underlying sub-epithelial immune cell layer and vasculature. A variety of drug delivery vehicles have been employed to improve the delivery of agents across the CVM and offer the capability to increase the longevity and retention of active agents to treat infections of the female reproductive tract. Nanoparticles (NPs) have been shown to improve retention, diffusion, and cell-specific targeting via specific surface modifications, relative to other delivery platforms. In particular, polymeric NPs represent a promising option that has shown improved distribution through the CVM. This work summarizes recent experimental studies that have evaluated NP transport in the FRT, and highlights research areas that more thoroughly and efficiently inform polymeric NP design, including mathematical modeling.

The studies presented below further expand on this to investigate the application of NPs in treating cancers found within the FRT. Advanced stage cancer treatments are often invasive and painful—typically comprised of surgery, chemotherapy, and/or radiation treatment. In addition to the poor transport associated with intravaginal delivery, low transport efficiency during systemic chemotherapy may require high chemotherapeutic doses to effectively target cancerous tissue, resulting in systemic toxicity. Nanotherapeutic platforms have been proposed as an alternative to more safely and effectively deliver therapeutic agents directly to tumor sites. However, cellular internalization and tumor penetration are often diametrically opposed, with limited access to tumor regions distal from vasculature, due to irregular tissue morphologies.

To address these transport challenges, NPs are often surface-modified with ligands to enhance transport and longevity after localized or systemic administration. In the work presented below, the effect of surface modification with stealth polyethylene–glycol (PEG), cell-penetrating (MPG), and CPP-stealth (MPG/PEG) poly(lactic-co-glycolic-acid) (PLGA) NP co-treatment strategies on NP distribution and chemotherapeutic efficacy, which is defined in this work as the ability of NPs to impart drug cytotoxicity and potency, was evaluated with the use of 3D cell culture models representing hypo-vascularized cervical cancerous tissue.

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