Combining vasculature disrupting agent and toll-like receptor 7/8 agonist for cancer therapy
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Anushree Seth1,2,3, Hyunseung Lee1,3, Mi Young Cho1,3, Cheongsoo Park1, Sovannarith Korm2, Joo-Yong Lee2, Inpyo Choi3, Yong Taik Lim4, Kwan Soo Hong1,2,3
1Bioimaging Research Team, Korea Basic Science Institute, Cheongju 28119, Republic of Korea
2Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea
3Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
4SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon 16419, Republic of Korea
Kwan Soo Hong, email: [email protected]
Yong Taik Lim, email: [email protected]
Keywords: combination therapy, dendritic cells, nanoparticle, TLR7/8 agonist, vasculature disruption
Received: August 19, 2016 Accepted: December 07, 2016 Published: December 27, 2016
This study evaluates the effect of combination of two different treatment regimens for solid tumor therapy: vasculature targeting agent and immune-stimulation. Poly lactide-co-glycolide (PLGA) nanoparticles were synthesized for intracellular delivery of toll-like receptor (TLR) 7/8 agonist—gardiquimod. Spherical and mono-disperse gardiquimod encapsulated PLGA nanoparticles (Gardi-PLGA), approximately 194 nm in size were formulated. Gardi-PLGA induced immune-stimulation, and vasculature disrupting agent (VDA)—5,6-Dimethylxanthenone-4-acetic acid (DMXAA) was used in combination to assessing the influence on bone marrow derived dendritic cells (BMDCs) and B16-F10 melanoma cells. The combination treatment significantly increased the levels of pro-inflammatory cytokines, indicating their activation in BMDCs, while melanoma cells remained viable. Further, mice melanoma model was established, and DMXAA was administered intraperitoneally and Gardi-PLGA was administered via an intra-tumoral injection. The combination treatments strategy significantly inhibited tumor growth as shown by tumor volume analysis, and the survival rate of the mice was found to be 63.6% (n = 11), after 54 days of tumor inoculation. Immunohistochemical findings of tumor sections treated with DMXAA confirmed the in vivo vasculature disruption. Thus, the inhibition of tumor growth can be attributed to the synergistic effect of immune stimulation caused by DC activation and vasculature disruption.
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