Abstract 3727: Dual acidic pH targeted mesoporous silica nanoparticles for noninvasive detection of triple negative breast cancer
Authors: Hayes Joshua T. , Samykutty Abhilash , McNally Molly , Thomas Alexandra , Chiba Akiko , Grizzle William , Winkfield Karen M. , McNally Lacey R. 
Published: August 2018

Abstract
Purpose: Current screening methods for triple negative breast cancer suggest the presence and size of tumor, but do not identify the tumor microenvironment. The inability to determine precise tumor location and position following diagnosis impedes medical confidence in surgical resection and radiation therapy. Theranostic nanoparticles can be targeted for dye and drug delivery to facilitate non-invasive characterization and treatment of malignancies. Combinational use of nanomedicine and Multispectral Optoacoustic Tomography (MSOT) renders high resolution images through ultrasonic detection of thermoelastic dye expansion (the optoacoustic effect). Approaches in nanomedicine are steadily growing, but clinical evaluation relies on minimizing off-target accumulation and controlling cargo release. We evaluated a mesoporous silica nanoparticles with pH-sensitive chitosan gatekeeper and tumor targeting V3 pH low-insertion peptide (V3 pHLIP) conjugation (V3-CMSN-780) for dual acidic pH targeted delivery to triple negative breast cancer. Methods: Mesoporous silica nanoparticles were synthesized around a structural skeleton of hexadecyltrimethylammonium bromide (CTAB). CTAB was removed from the particles through repeated dialysis. Subsequent particles were characterized with digital light scattering (DLS) and zetasizer to confirm particle size and zeta potential. Mesoporous nanoparticles were then coated with chitosan for extracellular acidic pH selectivity and functionalized with variant 3 pH low-insertion peptide (V3 pHLIP) to promote anchoring of the particle to tumor cells. Functionalized nanoparticles (V3-CMSN) were loaded with NIR 780 (5 mg/mL) and delivered to MDA-MB-231 and MDA-MB-468 malignant cell lines at pH 7.4, 6.8, and 6.6 to confirm pH-sensitive dye release into the cells with Near Infrared fluorescent imaging. V3-CMSN treated cells were inserted into tissue mimicking phantoms which were evaluated using MSOT. Results: The size of V3-CMSN-780 was 35 d. nm with a zeta potential of 25 mV. V3-CMSN were loaded with 780 dye with a dye loading efficiency of 77%. Cellular uptake of V3-CMSN-780 within MDA-MB-231 cells was 2152 a.u., 5242 a.u., and 3639 a.u. at pHs 7.4, 6.8, and 6.6, respectively, based NIR fluorescent imaging. Treatment of MDA-MB-231 cells with V3-CMSN-780 within tissue mimicking phantoms also confirmed acidic pH selectivity of the particles with a 6X and 4X accumulation of particles at pH 6.8 and 6.6 as compared to pH 7.4. While similar results were observed in MDA-MB-468 cells with NIR fluorescent imaging, MSOT imaging indicated that MDA-MB-468 cells treated at pH 6.8 and 6.6 had increased 780 signal, 110X and 16X, incomparison to pH 7.4. Conclusion: Successful dual targeting of breast tumor cells provides a foundation for later in vivo and ex vivo studies using V3-780-CMSNs to deliver diagnostic and therapeutic cargo to malignant breast tissue.
Citation Format: Joshua T. Hayes, Abhilash Samykutty, Molly McNally, Alexandra Thomas, Akiko Chiba, William Grizzle, Karen M. Winkfield, Lacey R. McNally. Dual acidic pH targeted mesoporous silica nanoparticles for noninvasive detection of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3727.