title: Combining vasculature disrupting agent and Toll-like receptor 7/8 agonist for cancer therapy.
abstract: 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.
authors.affiliation: Bioimaging Research Team, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.|Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea.|Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
authors.forename: Anushree
authors.initials: A
authors.lastname: Seth
authors.affiliation: Bioimaging Research Team, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.|Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.affiliation: Bioimaging Research Team, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.|Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Cho
authors.affiliation: Bioimaging Research Team, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.
authors.forename: Cheongsoo
authors.initials: C
authors.lastname: Park
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea.
authors.forename: Sovannarith
authors.initials: S
authors.lastname: Korm
authors.affiliation: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
authors.forename: Inpyo
authors.initials: I
authors.lastname: Choi
authors.affiliation: SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Yong Taik
authors.initials: YT
authors.lastname: Lim
authors.affiliation: Bioimaging Research Team, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.|Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea.|Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Hong
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D007093:Imidazoles / Q000008:administration & dosage*; D007167:Immunotherapy / Q000379:methods; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*; D044004:Xanthones / Q000008:administration & dosage*
chemical_list: D000634:Aminoquinolines; D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D044004:Xanthones; C546771:gardiquimod; C066668:vadimezan
keywords: TLR7/8 agonist; combination therapy; dendritic cells; nanoparticle; vasculature disruption