title: Poly (γ-glutamic acid) based combination of water-insoluble paclitaxel and TLR7 agonist for chemo-immunotherapy.
abstract: Advanced anti-cancer regimens are being introduced for more effective cancer treatment with improved life expectancy. In this research, immuno-stimulating agent toll-like receptor-7 (TLR-7) agonist-imiquimod and low dose chemotherapeutic agent-paclitaxel were synergized to demonstrate tumor therapy along with anti-tumor memory effect. Both therapeutic agents being water insoluble were dispersed in water with the help of water soluble polymer: poly (γ-glutamic acid) (γ-PGA) using a co-solvent systems leading to formation of micro-dispersions of drugs. Paclitaxel and imiquimod formed crystalline microstructures in the size range of 2-3 μm and were stably dispersed in γ-PGA matrix for more than 6 months. Paclitaxel and combination of paclitaxel and imiquimod had significant tumor killing effect in-vitro on various tumor cell lines, while antigen presenting cells (dendritic cells-DCs) treated with the same concentration of imiquimod along with the combination led to enhanced proliferation (250%). In DCs, enhanced secretion of pro-inflammatory and Th1 cytokines was observed in cells co-treated with paclitaxel and imiquimod dispersed in γ-PGA. When administered by intra-tumoral injection in mouse melanoma tumor model, the treatment with combination exemplified drastic inhibition of tumor growth leading to 70% survival as compared to individual components with 0% survival at day 41. The anti-tumor response generated was also found to have systemic memory response since the vaccinated mice significantly deferred secondary tumor development at distant site 6 weeks after treatment. The relative number and activation status of DCs in-vivo was found to be dramatically increased in case of mice treated with combination. The dramatic inhibition of tumor treated with combination is expected to be mediated by both chemotherapeutic killing of tumor cells followed by uptake of released antigen by the DCs and due to enhanced proliferation and activation of the DCs.
authors: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors: Anushree
authors: A
authors: Seth
authors: Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors: Min Beom
authors: MB
authors: Heo
authors: SKKU Advanced Institute of Nanotechnology (SAINT), School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: yongtaik@skku.edu.
authors: Yong Taik
authors: YT
authors: Lim
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D000077271:Imiquimod; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D017239:Paclitaxel / Q000494:pharmacology*; D010316:Particle Size; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D012995:Solubility; D016019:Survival Analysis; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014867:Water / Q000737:chemistry*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D051199:Toll-Like Receptor 7; C511775:poly(gamma-glutamic acid); D014867:Water; D011099:Polyglutamic Acid; D000077271:Imiquimod; D017239:Paclitaxel
keywords: Chemotherapy; Combination therapy; Drug delivery; Immuno-stimulation; Poly(γ-glutamic acid)