Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasis.
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.
Elazar
Victoria
V
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Adwan
Hassan
H
Bäuerle
Tobias
T
Rohekar
Keren
K
Golomb
Gershon
G
Berger
Martin R
MR
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
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