title: Nanoparticle-mediated delivery of siRNA targeting Parp1 extends survival of mice bearing tumors derived from Brca1-deficient ovarian cancer cells.
abstract: Inhibition of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) with small molecules has been shown to be an effective treatment for ovarian cancer with BRCA mutations. Here, we report the in vivo administration of siRNA to Parp1 in mouse models of ovarian cancer. A unique member of the lipid-like materials known as lipidoids is shown to deliver siRNA to disseminated murine ovarian carcinoma allograft tumors following intraperitoneal (i.p.) injection. siParp1 inhibits cell growth, primarily by induction of apoptosis, in Brca1-deficient cells both in vitro and in vivo. Additionally, the treatment extends the survival of mice bearing tumors derived from Brca1-deficient ovarian cancer cells but not from Brca1 wild-type cells, confirming the proposed mechanism of synthetic lethality. Because there are 17 members of the Parp family, the inherent complementarity of RNA affords a high level of specificity for therapeutically addressing Parp1 in the context of impaired homologous recombination.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Deyin
authors.initials: D
authors.lastname: Xing
authors.forename: Yin
authors.initials: Y
authors.lastname: Ren
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
authors.forename: Sangeeta N
authors.initials: SN
authors.lastname: Bhatia
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Sharp
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000628:therapy*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004337:Drug Carriers; D034741:RNA, Small Interfering; D011065:Poly(ADP-ribose) Polymerases