Document Type

Dissertation - Open Access

Award Date

2019

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Omathanu Perumal

Abstract

Breast cancer is the second leading cause of cancer death in women. About 1 in 8 women will develop breast cancer in their lifetime. The current systemic approaches are associated with significant side effects including some life-threatening toxicity, leading to poor patient compliance. To overcome this limitation, localized transdermal drug delivery system was investigated in the current study. In addition, majority of breast cancers originate from the ducts and lobules in the breast. Therefore, localized transdermal drug delivery system can maximize drug concentration in the breast and minimize systemic adverse effects, resulting in a potential approach for preventing and/or treating early stage breast cancer. In the current work, three different chemopreventive agents with different mechanisms of action and physicochemical properties were used. This includes aspirin, endoxifen and fenretinide. Due to the systemic side effects and/or poor oral bioavailability of these chemopreventive agents, they were selected in the current work. To explore the feasibility of localized transdermal delivery of these agents to the breast through breast skin and mammary papilla (nipple), four different penetration enhancement approaches were evaluated. In the first approach, the influence of hydroalcoholic vehicles (0, 33, 50 and 66% ethanol, v/v) on drug permeation through breast skin and mammary papilla was tested. In the second approach, the effect of different chemical penetration enhancers (sandalwood oil, limonene and eugenol) on drug permeation through breast skin and mammary papilla was studied. The third approach focused on the influence of different vesicular carrier systems (ethosomes and liposomes) on drug permeation through breast skin and mammary papilla. The fourth approach focused on the use of microneedles on drug permeation through breast skin. The first goal was to investigate the feasibility of localized transdermal delivery of aspirin to the breast through breast skin and mammary papilla (nipple). Aspirin has been shown to have breast cancer prevention effects. Oral aspirin is associated with gastrointestinal (GI) side effects. Also, a large oral daily dose of aspirin is needed for its activity against breast cancer. To this end, the localized transdermal delivery of aspirin to the breast can enhance the drug concentration in the breast and minimize its GI side effects. The results demonstrated that aspirin permeated through the breast skin and through the mammary papilla. However, the permeation of aspirin through the breast skin was much higher than the permeation through mammary papilla. Among the hydroalcoholic vehicles tested, 33% ethanol showed the highest permeation through the breast skin, while 66% ethanol showed the highest permeation through mammary papilla. Among the chemical penetration enhancers, 5% sandalwood oil in 50% ethanol showed the highest aspirin permeation through the breast skin and mammary papilla. Compared to 50% ethanol, 5% sandalwood oil increased the aspirin permeation by 3.8-fold and 3.2- fold through the breast skin and mammary papilla, respectively. Ethosomes showed similar skin permeation to 33% ethanol, while liposomes showed less permeation in comparison to 33% ethanol. On the other hand, liposomes showed the highest permeation through the mammary papilla in comparison to ethosomes and 33% ethanol. Microneedles significantly increased the aspirin permeation through breast skin in comparison to 33% hydroalcoholic vehicle. The second goal was to investigate the feasibility of localized transdermal delivery of endoxifen to the breast through breast skin and mammary papilla. Endoxifen, an active metabolite of tamoxifen, has been shown to have a strong activity against breast cancer. Endoxifen has 100-fold greater binding affinity for estrogen receptors in the breast compared to tamoxifen. However, tamoxifen and its metabolites act as an antagonist estrogen receptor in breast tissue and an agonist estrogen receptor in other organs including liver, bone and uterus, leading to severe side effects. To this end, the localized transdermal delivery of endoxifen to the breast can enhance the drug concentration in the breast and minimize the systemic exposure of the drug. The results demonstrate that endoxifen permeated through breast skin but not through the mammary papilla. Among the different hydroalcoholic vehicles (0-66% ethanol, v/v) tested, 33% ethanol showed the highest endoxifen permeation through the breast skin. Among the different chemical penetration enhancers, 5% sandalwood oil co-treated with 50% ethanol showed the highest endoxifen permeation through the breast skin. Liposomes and ethosomes systems showed less permeation through the breast skin in comparison to 33% ethanol. Also, microneedles increased the endoxifen permeation through breast skin in comparison to 33% hydroalcoholic vehicle. The final goal of the current work was to investigate the feasibility of localized transdermal delivery of fenretinide to the breast through breast skin and mammary papilla. Fenretinide has been shown to have a strong activity against breast cancer in pre-clinical and clinical studies. However, fenretinide has poor oral bioavailability due to its poor water solubility and poor permeability, which limits its clinical therapeutic benefits. Taken together, the localized transdermal delivery of fenretinide to the breast can increase the drug concentration in the breast and overcome its oral delivery limitations. The findings demonstrated that fenretinide permeated through the breast skin but did not show any permeation through the mammary papilla. From the hydroalcoholic vehicles studies, an increase in the alcohol concentration in the vehicle increased the fenretinide permeation through the breast skin. Liposomes increased fenretinide permeation through the breast skin in comparison to ethosomes and 33% hydroalcoholic vehicle. Among the different chemical penetration enhancers tested, 5% sandalwood in 66% alcohol showed the highest fenretinide permeation through the breast skin. On the other hand, microneedles pre-treatment significantly increased the fenretinide permeation through the breast skin in comparison to 66% hydroalcoholic vehicle. Compared to 66% ethanol, microneedles enhanced the fenretinide permeation through the breast skin by 3.2-fold. In addition, the results from in vivo studies demonstrated that the localized transdermal delivery of fenretinide to the breast can achieve high fenretinide concentration in the breast with minimal fenretinide concentration in other organs. The in vivo results suggest that the localized transdermal delivery of fenretinide to the breast might lead to a safe strategy and an effective localized therapy approach for breast cancer. Overall, the findings from the current work demonstrate the feasibility of localized transdermal delivery of three chemopreventive agents with different physicochemical properties (aspirin, endoxifen and fenretinide) to the breast using penetration enhancement methods. Among the four penetration enhancement methods, microneedles-assisted system was found to be the best enhancement permeation approach for the three drugs. The results from this study can be utilized to develop localized therapeutic approaches for prevention and treatment of early stages of breast cancer.

Format

application/pdf

Number of Pages

211

Publisher

South Dakota State University

Rights

In Copyright - Educational Use Permitted
http://rightsstatements.org/vocab/InC-EDU/1.0/

Available for download on Sunday, February 23, 2020

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