title: CDC20siRNA and paclitaxel co-loaded nanometric liposomes of a nipecotic acid-derived cationic amphiphile inhibit xenografted neuroblastoma.
abstract: Despite significant recent progress in the area of translational genomics of neuroblastoma, the overall survival rates for children with high-risk NB continue to be not more than 5 years due to tumor relapse and/or drug-resistant tumors. Herein we report on the development of a neuroblastoma targeting nanometric (130-150 nm) circulation stable liposomal system prepared from a novel nipecotic acid-derived cationic amphiphile (NACA). The size ranges of liposomes (130-150 nm) were confirmed by both dynamic light scattering and transmission electron microscopy. The findings in the gel electrophoresis assay revealed that siRNAs encapsulated within the liposomes of NACA (with 90% entrapment efficiency) are protected from attack by RNase. Cellular uptake experiments using FAM-siRNA loaded liposomes of NACA showed the liposomal entry in human neuroblastoma cells (IMR-32) to be mediated via the GABAAreceptor. CDC20siRNA-loaded liposomes of NACA caused significantly higher CDC20 gene silencing efficiency in IMR-32 cells compared to CDC20 gene knockdown efficiency mediated by CDC20siRNA-loaded control non-targeting liposomes (NTL). The findings in the annexin-V binding based flow cytometric apoptosis assay and MTT-based cellular cytotoxicity assay support the notion that pronounced (80%) neuroblastoma cell death upon treatment with CDC20siRNA & PTX co-loaded liposomes of NACA presumably originates from enhanced apoptosis of cells. Importantly, intravenously administered CDC20siRNA & PTX co-loaded liposomes of NACA significantly inhibited growth of xenografted human neuroblastoma in athymic nude mice. The presently disclosed strategy of co-delivering potent anticancer siRNA and small molecule chemotherapeutics using liposomes of NACA opens a new door for combating the dreaded disease of neuroblastoma.
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad-500007, India. arabinda@iict.res.in and Academy of Scientific & Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India.
authors.forename: Sukanya
authors.identifier: http://orcid.org/0000-0002-1410-9715
authors.initials: S
authors.lastname: Bhunia
authors.affiliation: CSIR-Centre for Cellular & Molecular Biology, Hyderabad-500007, India.
authors.forename: Vegesna
authors.initials: V
authors.lastname: Radha
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad-500007, India. arabinda@iict.res.in and Academy of Scientific & Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India.
authors.forename: Arabinda
authors.initials: A
authors.lastname: Chaudhuri
mesh_terms: D000818:Animals; D064199:Cdc20 Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy*; D009557:Nipecotic Acids / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D064199:Cdc20 Proteins; D008081:Liposomes; D009557:Nipecotic Acids; D034741:RNA, Small Interfering; C577488:CDC20 protein, human; D017239:Paclitaxel