title: Tumor-penetrating codelivery of siRNA and paclitaxel with ultrasound-responsive nanobubbles hetero-assembled from polymeric micelles and liposomes.
abstract: Drug resistance is a big problem in systemic chemotherapy of hepatocellular carcinoma (HCC), and nanomedicines loaded with both chemotherapeutic agents (e.g. paclitaxel, PTX) and siRNA's targeting antiapoptosis genes (e.g. BCL-2) possess the advantages to simultaneously overcome the efflux pump-mediated drug resistance and antiapoptosis-related drug resistance. However, tumor-penetrating drug delivery with this type of nanomedicines is extremely difficult due to their relatively big size compared to the single drug-loaded nanomedicines. Aiming at address this problem, US-responsive nanobubbles encapsulating both anti-cancer drug paclitaxel (PTX) and siRNA (PTX-NBs/siRNA) for HCC treatment were developed by hetero-assembly of polymeric micelles and liposomes in the present study. Utilizing an external low-frequency US force imposed to the tumor site, effective tumor-penetrating codelivery of siRNA and PTX was achieved via tail vein injection of PTX-NBs/siRNA into nude mice bearing human HepG2 xerografts. Consequently, the PTX treatment-inducible antiapoptosis in HepG2 cells was effectively suppressed by the codelivered siRNA targeting an antiapoptosis gene (BCL-2 siRNA) during chemotherapy. Owing to the synergistic anti-cancer effect of two therapeutic agents, tumor growth was completely inhibited using low-dose PTX in animal study. Our results highlight the great potential of this type of US-responsive hetero-assemblies carrying both anti-cancer drug and siRNA as an effective nanomedicinal system for HCC therapy.
authors.affiliation: Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Tinghui
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Jingguo
authors.initials: J
authors.lastname: Li
authors.affiliation: PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China. Electronic address: zhengrq@mail.sysu.edu.cn.
authors.forename: Rongqin
authors.initials: R
authors.lastname: Zheng
authors.affiliation: PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Du
authors.initials: D
authors.lastname: Cheng
authors.affiliation: PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China; Center of Biomedical Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: shuaixt@mail.sysu.edu.cn.
authors.forename: Xintao
authors.initials: X
authors.lastname: Shuai
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016503:Drug Delivery Systems / Q000379:methods*; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D049329:Nanostructures / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D014162:Transfection; D014465:Ultrasonics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D008823:Micelles; D034741:RNA, Small Interfering; D017239:Paclitaxel
keywords: Chemotherapy; Codelivery; Drug resistance; Nanobubbles; RNA interfering; Ultrasound