Document Type

Thesis - Open Access

Award Date

2024

Degree Name

Master of Science (MS)

Department / School

Pharmaceutical Sciences

First Advisor

Hemachand Tummala

Abstract

Breast cancer, particularly the estrogen receptor-positive (ER+) subtype, remains a formidable challenge in oncology. Traditional oral therapies for ER-positive breast cancer, such as selective estrogen receptor modulators (SERMs) like Tamoxifen (TAM) and Toremifene (TOR), often encounter issues related to limited bioavailability, metabolic complications, and significant systemic side effects. These side effects include the risk of blood clots, hot flashes, vaginal dryness, menstrual cycle disruptions, and uterus cancer, which can hinder long-term adherence to preventive therapy. The exploration of local drug delivery into breast tissue presents a promising alternative to tackle these challenges. In this study, we explored the feasibility of utilizing breast tissue as a local reservoir to carry Toremifene (TOR) or other SERMs by delivering directly into the breast tissue. This approach would present several advantages for the use of SERMs for the treatment and prevention of breast cancer, including reduced systemic off-target effects, improved anticancer efficacy with high local drug concentration, suitability for long-term treatment with lower applied doses, improved patient compliance, ease of self-administration, and avoidance of first-pass metabolism. In this study, TOR was selected as a model drug based on a) its growing use in ER-positive breast cancer therapy, b) it doesn’t require activation by the liver enzymes, unlike Tamoxifen, which is a prodrug, c) its lipophilic nature, and d) like other SERMs, its high potency is accompanied by severe side effects, often resulting in patients discontinuing preventive therapy. The goal of the study was to deliver TOR across the breast skin to diffuse and equilibrate with fat tissue of the breast. To achieve the goal, Toremifene was encapsulated into solid lipid nanoparticles (SLNs) and subsequently incorporated into fast-dissolving microneedle patches (MNPs) to deliver them across the breast skin. In Chapter II the encapsulation of TOR in SLNs was optimized by altering various formulation parameters using Box-Behnken Design (BBD) of the experimental design model. The ability of SLNs to retain the drug in aqueous medium was established through release kinetics studies. The ability of MNPs to penetrate human breast skin and deliver the cargo (SLNs) was established using confocal microscopy and skin histochemistry. The diffusion rate of the SLNs in excised human breast showed that the SLN’s diffused at the rate of 2 mm/hr. This study for the first time established the feasibility of using breast tissue as a reservoir for delivering anti-cancer drugs. In summary, this research is significant as it offers a novel approach to breast cancer treatment by utilizing breast tissue as a drug reservoir. The development of SLN-loaded microneedles for transdermal delivery could potentially improve the therapeutic outcomes and quality of life for breast cancer patients by minimizing systemic drug exposure and reducing the dosage frequency.

Publisher

South Dakota State University

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Rights Statement

In Copyright