Protein L Functionalized Microparticles For Early Detection Of Surface Markers In Heterogeneous Colorectal Lesions

Author

Saleh Ramezani, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0002-7872-9454

Date of Graduation

8-2023

Document Type

Dissertation (PhD)

Program Affiliation

Medical Physics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Mary C. Farach Carson, PhD

Committee Member

Daniel Harrington, PhD

Committee Member

Pratip Bhattacharya, PhD

Committee Member

Daniel Carson, PhD

Committee Member

Richard Wendt, PhD

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths among both men and women worldwide, a statistic that can be improved with early detection. Increased understanding of the tumor landscape has identified surface antigens that can be utilized to distinguish normal and cancerous tissue lining the colonic lumen. Use of antibodies conjugated to nano/micromaterials offers a means to detect these antigens, however, the heterogeneous nature of tumors makes it unlikely that antibodies against a single antigen will have sufficient sensitivity and specificity to detect all tumors. A versatile micromaterial able to be functionalized with more than one targeting antibody presents an opportunity to improve detection reliability. Here, we demonstrate the utility of a “universal” surface functionalization approach using Antibody-Protein L functionalized microparticles (MPs) that enable simultaneous incorporation of antibodies recognizing different surface targets. Using CRC cell heterogeneous tumoroids (HET-tumoroids) and orthotopic animal models expressing different surface antigens, we demonstrated that 1) Antibody-Protein L functionalized MPs identify Mucin 1 (MUC1) and epithelial cell adhesion molecule EpCAM positive tumoroids proportionally to antigen expression, 2) Antibody-Protein L MPs detect CRC surface antigens on the luminal colon surface in vivo, and 3) concurrent targeting of multiple surface antigens enhance sensitivity of detection of heterogeneous colorectal lesions. We also examined a variety of colon tumor subtypes in a standard tissue array to demonstrate the usefulness of targeting MUC1 and EpCAM for early-stage heterogeneous lesions.

Keywords

colorectal cancer, tumor heterogeneity, Protein L microparticles, CRC biomarkers, early detection, colonoscopy, cell surface protein, adenocarcinoma