Immune cell-based drug delivery system with biodegradable fluorescent nanoparticles for brain cancer treatment

Abstract

Event Abstract Back to Event Immune cell-based drug delivery system with biodegradable fluorescent nanoparticles for brain cancer treatment Gloria Kim1, Virginia A. Sanabria1, Cheng Dong1 and Jian Yang1 1 Pennsylvania State University, Biomedical Engineering, United States Introduction: Brain cancer is a life-threatening disease due to its rapid development and the difficulty in its treatment. In 2006-2010, 7.27 malignant brain tumor incidents occurred per 100,000 people in the U.S alone[1]. Even after an aggressive resection followed by concurrent or sequential radiation and chemotherapies, the median survival time of patients with the most common primary brain tumor, glioblastoma, is less than 15 months. Unfortunately, the delivery of drugs to the brain is extremely challenging due to the presence of the blood-brain barrier (BBB). To overcome this obstacle, we developed an immune cell mediated nanoparticle (ICNP) delivery system using human monocytic cells as delivery vehicles and demonstrated its ability to transmigrate across the in vitro BBB and effectively deliver biodegradable photoluminescent polymer (BPLP) nanoparticles (Fig. 1). Materials and Methods: BPLP-Cys was synthesized based on our previous report with a simple polycondensation of reacting citric acid, 1,8-octanediol, and L-cysteine[2]. BPLP-poly (lactic acid) (BPLP-Cys-LA50) copolymer was synthesized according to a previously reported method[3]. BPLP-Cys-LA50 nanoparticles were prepared via a single emulsion method. To mimic the BBB, a static transwell has been developed with bovine brain microvascular endothelial cells (BBMVECs) cultured on the membrane filter. Two groups of human monocytic THP-1 cells (with and without BPLP-Cys-LA50 nanoparticles) were added to the top chamber and allowed to migrate across the BBMVEC monolayer in response to monocyte chemoattractant protein-1 in the basal chamber. Transmigration of THP-1 cells with and without BPLP-Cys-LA50 nanoparticles was studied by confocal microscopy and flow cytometry. Results and Discussion: We successfully established an in vitro BBB model using BBMVECs on a porous membrane with its barrier function confirmed. Our in vitro studies showed that the THP-1 cells carrying BPLP-Cys-LA50 nanoparticles transmigrated across the BBB and efficiently delivered BPLP-Cys-LA50 nanoparticles to the basal chamber under pseudo-inflammatory conditions created using MCP-1 as a chemoattractant. The intrinsic photoluminescence of BPLP-Cys-LA50 nanoparticles enabled facile quantification of the migrated THP-1 cells using flow cytometry and confocal microscopy (Fig. 2). The intrinsic photoluminescence of BPLP-Cys-LA50 nanoparticles enabled in vitro tracking of migrated THP-1 cells. These results suggest that our ICNP system can offer obvious advantages over traditional drug delivery system in overcoming the BBB. Conclusion: We demonstrated the feasibility of using immune cells as drug carriers for brain cancer using their innate targeting, penetrating, and therapeutic functions. THP-1 cells internalized BPLP-Cys-LA50 nanoparticles and carried them via the BBB successfully. In our future studies, BPLP-Cys-LA50 nanoparticles will be used to encapsulate an antitumor drug. The release mechanism of the antitumor drug will be tailored by changing the degradation of BPLP-Cys-LA50 carrier nanoparticles and the delivery of nanoparticle-drug complexes via the BBB will be monitored real-time using the photoluminescent property of nanoparticles. Our ICNP system based on BPLP-Cys-LA50 nanoparticles may open up a path to new transformative platform technology for brain drug delivery. This work was supported in part by the National Science Foundation awards (CBET-BME 1330663 and DMR 1313553).; The authors thank Dr. James Connor for providing BBMVECs.