title: Targeted nanomedicine for suppression of CD44 and simultaneous cell death induction in ovarian cancer: an optimal delivery of siRNA and anticancer drug.
abstract: OBJECTIVE
  The proposed project is aimed at enhancing the efficiency of epithelial ovarian cancer treatment and reducing adverse side effects of chemotherapy using nanotechnology. Overexpression of the CD44 membrane receptor results in tumor initiation, growth, cancer stem cells' specific behavior, development of drug resistance, and metastases. We hypothesize that a developed cancer-targeted delivery system that combines CD44 siRNA with paclitaxel would successfully deliver its payload inside cancer cells, effectively induce cell death, and prevent metastases.
  
  
  METHODS
  We synthesized, characterized, and tested a nanoscale-based drug delivery system (DDS) containing a modified polypropylenimine (PPI) dendrimer as a carrier; anticancer drug paclitaxel as a cell death inducer; a synthetic analog of luteinizing hormone-releasing hormone (LHRH) peptide as a tumor-targeting moiety; and siRNA targeted to CD44 mRNA. The proposed DDS was tested in vitro and in vivo using metastatic ovarian cancer cells isolated from patients with malignant ascites.
  
  
  RESULTS
  We found that in contrast with cells isolated from primary tumors, CD44 was highly overexpressed in metastatic cancer cells. Treatment with the proposed tumor-targeted nanoscale-based nucleic acid and DDS led to the suppression of CD44 mRNA and protein, efficient induction of cell death, effective tumor shrinkage, and prevention of adverse side effects on healthy organs.
  
  
  CONCLUSIONS
  We show a high therapeutic potential for combinatorial treatment of ovarian carcinoma with a novel DDS that effectively transports siRNA targeting to CD44 mRNA simultaneously with cytotoxic agents. Clin Cancer Res; 19(22); 6193-204. ©2013 AACR.
authors.affiliation: Authors' Affiliations: Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway; Rutgers Cancer Institute of New Jersey and Department of Obstetrics and Gynecology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon.
authors.forename: Vatsal
authors.initials: V
authors.lastname: Shah
authors.forename: Oleh
authors.initials: O
authors.lastname: Taratula
authors.forename: Olga B
authors.initials: OB
authors.lastname: Garbuzenko
authors.forename: Olena R
authors.initials: OR
authors.lastname: Taratula
authors.forename: Lorna
authors.initials: L
authors.lastname: Rodriguez-Rodriguez
authors.forename: Tamara
authors.initials: T
authors.lastname: Minko
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001202:Ascitic Fluid / Q000166:cytology*; D001692:Biological Transport; D050091:Dendrimers / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010865:Pilot Projects; D011126:Polypropylenes; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology*; D011966:Receptors, LHRH / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D050091:Dendrimers; D018960:Hyaluronan Receptors; D011126:Polypropylenes; D034741:RNA, Small Interfering; D011966:Receptors, LHRH; C443641:poly(propyleneimine); D007987:Gonadotropin-Releasing Hormone; D017239:Paclitaxel
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