title: Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasis.
abstract: Poor prognosis in mammary carcinoma is associated with a certain expression profile of a defined set of genes including osteopontin and bone sialoprotein. Efficient and specific delivery of antisenses (AS) and a protection of the sequences from degradation are the crucial conditions for AS therapeutic efficiency. We hypothesized that effective and safe AS delivery direceted against these genes could be achieved by polymeric nanoparticles (NP) fabricated from a biocompatible polymer. Due to their nano-size range and small negative charge, AS-NP can overcome the absorption barrier offering increased resistance to nuclease degradation, sustained duration of AS administration, and consequently, prolonged antisense action. The ASs designed against OPN and BSP-II were successfully encapsulated in NP composed of the biodegradable and biocompatible polylactide-co-glycolide polymer (PLGA), exhibiting sustained release and stability of the ASs. The therapeutic efficacy of the AS-NP delivery system was examined in vitro, and in a breast cancer bone metastasis animal model of MDA-MB-231 human breast cancer cells in nude rats. Treatment with OPN-AS or BSP-AS loaded NP in comparison with osmotic mini-pumps (locoregional injection and SC implants, respectively) resulted in a significant decrease in both, tumor bone metastasis incidence and in the size of the lesions in rats with metastases. Despite its smaller dose, AS-NP exhibited a better therapeutic efficacy than osmotic mini-pumps in terms of lesion ratio at later time periods (8-12 weeks). It may be concluded that AS delivery by NP is a promising therapeutic modality providing stability of the encapsulated AS and a sustained release.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Elazar
authors.forename: Hassan
authors.initials: H
authors.lastname: Adwan
authors.forename: Tobias
authors.initials: T
authors.lastname: Bäuerle
authors.forename: Keren
authors.initials: K
authors.lastname: Rohekar
authors.forename: Gershon
authors.initials: G
authors.lastname: Golomb
authors.forename: Martin R
authors.initials: MR
authors.lastname: Berger
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D058574:Integrin-Binding Sialoprotein; D019344:Lactic Acid; D053758:Nanoparticles; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D011923:Rats, Nude; D012795:Sialoglycoproteins / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C546871:IBSP protein, human; D058574:Integrin-Binding Sialoprotein; D016376:Oligonucleotides, Antisense; D012795:Sialoglycoproteins; D053495:Osteopontin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid