Contact angle, a potential screening tool for anticancer drug delivery systems and breast cancer tumor tissues.

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2024-03-21

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Purpose: Breast cancer is one the most commonly diagnosed cancers in the United States and the second leading cause of cancer death among women. Despite progress in treatments and early detection reducing mortality, there is a continuous increase in annual cases, particularly among certain patient populations, causing persistent health disparities. The tumor extracellular matrix (ECM), which provides mechanical support, modulates the microenvironment, and supplies signaling molecules for cancer growth, has been linked to breast cancer health disparities. In this study, we propose an innovative approach to characterize and quantify the physiochemical properties of breast cancer ECM. Additionally, we hypothesize that drug delivery nano-therapies' interactions with tumor ECM can be quantified using this method. We aim to understand how drug delivery systems, such as liposomal doxorubicin (Doxil®), interact with ECM and affect breast cancer therapy outcomes.

Methods: Liposomes with different Doxil-like compositions (varying PEG content, molecular weight, and end-cap group) were prepared using the thin-film layer hydration method followed by sonication for particle size reduction. De-identified breast cancer fixed tissue sections (with demographic data) purchased from US Biomax Inc. were deparaffinized in xylene, ethanol, and water in consecutive washing cycles. Tissues were decellularized by up to three freeze-thaw cycles in water. Water contact angles were measured on decellularized tissue sections using a customized optical goniometer. Tissue sections were treated with liposomes by incubating them for 2 min in liposomal suspensions and rinsed with DI water 3 times.

Results: Liposomes reduce the water contact angle on glass slides and tissue sections in a concentration-dependent and composition-dependent manner. Doxil-like liposomes decrease the water contact angle for concentrations higher than 0.5 mg/ml. This reduction increases proportionally as the concentration rises, reaching a plateau for concentrations higher than 1.5 mg/ml. Peg-free liposomes exhibit the lowest activity in contact angle reduction, suggesting PEG's central role in the surfactant-like activity of liposomes. Changes in PEG end-cap and molecular weight, influence both liposome surface activity and tissue retention. The contact angle varies among different tissues, with a notable tendency for fibrotic tissues, such as metastatic tumor tissue, to have a higher contact angle and therefore higher hydrophobicity. PEGylated liposomes are more retained by metastatic tissues and highly hydrophobic tissues, indicating that PEG enhances liposome adsorption in more hydrophobic environments.

Conclusion: The contact angle method for tumor ECM characterization developed in our laboratory enables the quantification of tumor ECM features through a liquid-solid dynamic interaction approach. Our data highlight and quantify the importance of PEG as a surface molecule on contact angle-measured interactions between anti-cancer liposomes and breast cancer tumors, consistent with clinical testing of Doxil® where the inclusion of PEG was crucial for therapeutic efficacy. In addition to liposome composition, tumor type (grade or metastatic) can be quantified with this method, permitting an increased understanding of the role tissue surface properties play in the efficacy of anti-cancer nano-therapies. The described method can serve as a preclinical tool to screen drug delivery systems and predict their efficacy by quantifying their target tissue interactions.

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Research Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Pharmaceutical & Pharmacotherapy Award - 1st Place

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