Sustained Release Systems For Endometrial Cancer

Author

Claire E. Rowlands, University of KentuckyFollow

Author ORCID Identifier

https://orcid.org/0009-0004-9409-0760

Date Available

8-1-2025

Year of Publication

2024

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Engineering

Department/School/Program

Chemical and Materials Engineering

First Advisor

Dr. Brittany E. Givens

Abstract

Endometrial cancer (EC) is the sixth most common cancer in women worldwide and is the most common cancer of female reproductive organs. From 2007-2016 there has been a global rise in incidence of EC of 1.3 %. Typically, EC is treated with surgery, but at later stages surgery is less effective requiring chemotherapy and/or radiation therapy. These treatment options are less effective than surgery and there are very few FDA approved chemotherapies for EC. The minuscule number of effective treatment options as well as an increase in incidence shows the need for creating improved treatments for EC. There has been a shift toward using micro- and nano-sized particles as drug delivery systems for chemotherapies due to their ability to decrease side effects of the treatment and increase bioavailability, circulation time, and accumulation of the drug in the tumor. The particles are typically biodegradable polymers and/or lipids.

Paclitaxel (PTX) loaded poly(caprolactone) (PCL) particles were chosen because PTX successfully treats other female cancers, and PCL is biodegradable by hydrolysis. We investigated the effects of size separating particles by centrifugation made with the solvent emulsion evaporation method and subsequent cell viability, as well as comparing in vitro efficacy in PTX-sensitive and PTX-resistant cells. The PTX-PCL particles have an encapsulation efficiency of 62.6% and a biphasic drug release over 30 days reaching over 60% release. These particles showed a reduction in cell viability in Ishikawa and KLE cells while the blank-loaded particles had negligible effect on viability. PCL particles were loaded with rhodamine B for uptake studies, and it was found that KLE cell had higher uptake of particles at both 4 and 24 hours.

With the first emulsion solvent evaporation method used, particles collected averaged 1500 nm and 900 nm. By varying solvents (dichloromethane and chloroform), surfactant concentration (poly (vinyl alcohol)), and water-to-oil ratios, particles were made as small as 300 nm. Chloroform, lower PVA concentrations, and lower water-to-oil ratios produced particles with smaller diameters. Blank particles showed a reduction in cell viability at higher particle concentrations in cancerous cells than normal cells. When uptake was compared between large and small particles, the smaller particles had increased uptake at both 4 and 24 hours. The cancerous cells had the majority of their uptake in the first 4 hours while the normal cells saw an increase in uptake between 4 and 24 hours.

In collaboration with the Fogg Lab at Oregon State University, the small paclitaxel loaded particles were evaluated in a novel three-dimensional multilayer multicellular model of endometrial cancer. Not only were the particles tested in a more realistic model than 2-D cell culture, but they were also compared to free paclitaxel. The nanoparticle formulation had a decreased cell viability in KLE, Ishikawa, and HEC-1A cells when compared to free paclitaxel in the 3D model.

While paclitaxel showed some reduction in cell viability in these endometrial cancer cells, introducing another agent to for an enhanced treatment option would be beneficial. Copper (II) oxide nanoparticles (CuO) show promise as antineoplastic agents and have been shown to induce cell death in cancer cell lines. The CuO particle will cause a buildup of ROS resulting in a double stranded DNA break. Characterization of the CuO Particles showed rod like shape, particle sizes less than 50 nm, and a surface charge of -18mV. Cell response was investigated through viability, apoptosis, and ROS production studies. The HEC 1A cells were the most sensitive to CuO NPs with the lowest IC₅₀ value of 3.606 µg/mL, the highest percentage of cells in stages of apoptosis, and the most ROS production shown in confocal images. Ishikawa and KLE cells had similar IC₅₀ values, but less than 10% of the KLE cells were in apoptosis compared to Ishikawa’s 62% and HEC 1A’s 70%.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.355

Recommended Citation

Rowlands, Claire E., "Sustained Release Systems For Endometrial Cancer" (2024). Theses and Dissertations--Chemical and Materials Engineering. 167.
https://uknowledge.uky.edu/cme_etds/167