Abstract 2207: Using AFM to predict the specificity of tumor targeting nanomedicine in vivo

Abstract

Abstract Most cancer target and biomarker studies focus on the identification of overexpressed genes or proteins of cancer cells. However, their potential feasibility as tumor-specific antigens targeted by antibody-guided nanomedicine has not consistently been based on quantitative assessments of tumor specificity and binding strength. Cancer cell membrane surfaces possess hundreds of different functionally versatile proteins (receptors and ligands) which are heterogeneously upregulated or downregulated to promote cancer development and progression. Selection of appropriate drug targets is pivotal to the successful development of tumor-targeted therapeutics because tumor-specific affinity of potential cancer targets is a key factor modulating cellular binding and uptake, and has the potential to translate to therapeutic bioactivity. To date, the quantitative measurements of cancer target antibody-antigen interactions are often limited by dynamic biophysical and biomechanical methods for probing such interactions. To address this challenge, we used flow cytometric analyses to compare 40 potential cancer cell surface target candidates for triple negative breast cancer (TNBC), an aggressive malignancy with limited treatment options. We selected intercellular adhesion molecule-1 (ICAM-1) as the “optimized” TNBC target for nanomedicine. Reasoning that adhesion forces between the ICAM-1 antibody and live human breast cancer cells could be used to guide nanomedicine delivery to TNBC tumors, we used atomic force microscopy (AFM) to evaluate the binding strength between the ICAM-1 antibody and antigen on live human TNBC cells and non-neoplastic cells. Adhesion forces between the ICAM-1 antibody and live human TNBC MDA-MB-231 cells (523 ± 113 pN) were significantly higher than those of non-neoplastic MCF10A cells (336 ± 33 pN). We next validated these findings by engineering ICAM-1-targeted immunoliposomes and then tested their TNBC-specific binding affinity and cytotoxicity on three TNBC cell lines. In vivo imaging experiments further confirmed that the ICAM-1-targeted immunoliposomes preferentially accumulated in orthotopic TNBC tumors, in comparison with nonspecific, IgG-conjugated liposomes. These data support the conclusion that ICAM-1 antibody-conjugated immunoliposomes containing chemotherapeutic drugs have the potential to preferentially target and destroy TNBC cells, and may also be applicable to a range of metastatic cancers that demonstrate an overexpression of ICAM-1. These findings also support the use of AFM as a valuable tool in the characterization of surface antigen-antibody interactions that predict in vitro and in vivo binding affinity. Acknowledgements: D. Auguste acknowledges the support of NIH 1DP2CA174495. M. Moses acknowledges the support of NIH R01CA185530 and the Breast Cancer Research Foundation. Citation Format: Peng Guo, Biran Wang, Daxing Liu, Jiang Yang, Marsha Moses, Debra Auguste. Using AFM to predict the specificity of tumor targeting nanomedicine in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2207.