Abstract 4536: Biomimetic carriers modulate tumor vascular barrier function

Abstract

Abstract Introduction We showed that nanoporous silicon (NPS) particles coated with leukocyte cellular membranes -Leukolike Vectors (LLV) - possess cell-like properties. These biomimetic carriers can escape macrophage uptake, delay sequestration by the reticulo-endothelial system, target tumor inflamed vasculature and accumulate within the cancer parenchyma. We characterized the content and function of the leukocyte's proteins transferred onto the LLV coating and evaluated their interaction with inflamed cancer vasculature. Experimental Procedures The leukocyte membrane coating was analyzed with several biochemistry techniques. In vitro experiments were performed using reconstructed inflamed endothelia. Flow chamber systems were used to simulate vessel flow dynamics and study LLV docking, firm adhesion and transcytosis. In vivo experiments were performed with Intra Vital Microscopy (IVM) to image in real time LLV behavior in BALB/c mice carrying syngeneic breast cancers. Results LLV were studied using dynamic light scattering and scanning electron microscopy to characterize particles size (1 μm), pore sizes (60 nm) and surface properties (positive charge and uniform coating). Biochemical analyses revealed that we successfully transferred on the surface of the LLV critical protein among which LFA-1, MAC1, and CD45. Upon interaction of the LLV with inflamed endothelia we found that VE-cadherin expression was substantially reduced. We also described the differential process of cell internalization and showed that LLV escaped the endo-lysosomal compartment during intracellular trafficking. IVM showed delayed sequestration by spleen and liver macrophages, increased circulation half-life and increased targeting of tumor associated inflamed vasculature. To further demonstrate the ability of our biomimetic carrier to affect the biology of tumor endothelia, we evaluated the extravasation of an intravascular 70 kDa FITC dextran reporter. We measured the increase in vessel permeability and tissue diffusion over time and confirmed that LLV were able to favor the extravasation of the reporter molecule in the cancer parenchyma. Conclusion Our work showed for the first time that is possible to transfer biologically active leukocyte membrane proteins onto synthetic particles. Our biomimetic carriers retain favorable cell-like functions that can enhance the kinetics of oncotransport by decreasing endothelial cellular junctions and increasing diffusion of a therapeutic payload within the tumor tissue. We envision that biomimetic drug delivery systems derived from the infiltrating immune cells of a cancer patient could represent the next generation of personalized treatments. Note: This abstract was not presented at the meeting. Citation Format: Alessandro Parodi, Roberto Palomba, Michael Evangelopoulos, Claudia Corbo, Ennio Tasciotti. Biomimetic carriers modulate tumor vascular barrier function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4536. doi:10.1158/1538-7445.AM2015-4536