Journal
ONCOTARGET
Volume 8, Issue 3, Pages 5371-5381Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14260
Keywords
combination therapy; dendritic cells; nanoparticle; TLR7/8 agonist; vasculature disruption
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Funding
- Korea Basic Science Institute [D36401]
- R&D Convergence Program of NST (National Research Council of Science & Technology) of Republic of Korea [CRC-15-02-KRIBB]
- National Research Foundation of Korea (NRF) grant - Korean government (MEST) [2014R1A2A1A10049960]
- National Research Council of Science & Technology (NST), Republic of Korea [CRC-15-02-KRIBB, D36400] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2014R1A2A1A10049960] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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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