title: Improvement of doxorubicin efficacy using liposomal anti-polo-like kinase 1 siRNA in human renal cell carcinomas.
abstract: It is well-known that renal cell carcinomas (RCCs) are resistant to classical cytotoxic anticancer drugs. Therefore, facilitating the impact of anticancer drugs by altering the cell phenotype should be a useful strategy for circumventing this. We developed a multifunctional envelope-type nanodevice (MEND) as an in vivo carrier of siRNA to tumor tissues. We previously reported that a MEND containing YSK05 (YSK-MEND) efficiently delivered siRNA in RCC-bearing mice. We herein report on a combination therapy involving the use of siRNA-mediated specific gene knockdown and cytotoxic drug doxorubicin (DOX), and an advantage of YSK-MEND as an investigation tool for in vivo function of a gene. si-PLK1 encapsulated within YSK-MEND was prepared using the tertiary butanol dilution method. The in vitro cellular viability under the exposure of DOX was compared between OS-RC-2 cells with and without si-PLK1 transfection. In an in vivo study, tumor-bearing mice were systemically injected with YSK-MEND and DOX-loaded liposomes. The combination of DOX and si-PLK1 drastically reduced tumor growth rate, and apoptotic cells were observed. In an in vitro study, PLK1 knockdown increased G2/M cell population and reduced the expression of cyclin B1 (CCNB1) mRNA. CCNB1 suppression by si-PLK1 encapsulated in YSK-MEND was also observed in the in vivo experiments. A combination of DOX and anti-polo-like kinase 1 siRNA (si-PLK1) resulted in a measurable delay in OS-RC-2 tumor growth. This result suggests that the combination of si-PLK1 delivery and doxorubicin by YSK-MEND holds potential for RCC therapy via cell CCNB1 regulation.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University , Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002470:Cell Survival; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D036103:Nanotechnology / Q000379:methods; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004317:Doxorubicin; D008081:Liposomes; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1