Abstract A169: Macrophage targeted zoledronic acid conjugated biomineral nanoparticles for γδT-cell-based cancer immunotherapy

Nanoparticle platforms can be engineered to deliver immune-stimulatory molecules to specific immune cell populations, thereby evoke desired response. Here, we present a novel biomineral nanoparticle system for macrophage specific delivery of bisphosphonate molecules to evoke activation of γδ T-cells for cancer immunotherapy. Generally, γδ T-cells therapy is implemented either by ex vivo expansion followed by adoptive transfer or by in vivo activation using intravenous injection of bisphosphonates. One of the major limitations of intravenously injection of bisphosphonates such as zoledronic acid is its unfavorable biodistribution in the skeletal system due to covalent binding with calcium in the bone. In the present work, we have pre-conjugated zoledronic acid in a calcium-containing biomineral nanoparticle (Zol-BM) that has spontaneous specificity towards macrophages in the liver, spleen and lymph nodes. This enabled targeted expression of γδT-cell stimulating ligand, isopentyl pyrophosphate, in macrophages, leading to enhanced activation of γδT-cells. Optimized Zol-BM showed a drug conjugation efficiency of ~95% with particle size ~ 100 nm and zeta potential, -15mV. The compatibility of Zol-BM was tested in primary human peripheral blood mononuclear cells and macrophages cell lines. The biodistribution analysis of Zol-BM in healthy rat models showed accumulation in liver, spleen and lymph nodes which was confirmed by MRI and Prussian-blue analysis. Flow cytometry based γδT-cell proliferation analysis gave ~18% enhancement in γδ T-cell subset compared to untreated control. Thus, we show that by rational design of engineered nanoparticles, specific immuno-stimulatory molecules like zolendronate can be delivered to desired immune cells of interest (macrophages) for activating another sub-population of immune cells such as γδ T-cells, for cancer-immunotherapy applications. Citation Format: Anusha Ashokan, Minu Anoop, Siju Surendran, Aparna Balakrishnan, Ida M. Anna, Anjana Ramkumar, Girish Chundayil Madathil, Vijay Harish, Manzoor Koyakutty. Macrophage targeted zoledronic acid conjugated biomineral nanoparticles for γδT-cell-based cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A169.