title: Therapeutic designed poly (lactic-co-glycolic acid) cylindrical oseltamivir phosphate-loaded implants impede tumor neovascularization, growth and metastasis in mouse model of human pancreatic carcinoma.
abstract: Poly (lactic-co-glycolic acid) (PLGA) copolymers have been extensively used in cancer research. PLGA can be chemically engineered for conjugation or encapsulation of drugs in a particle formulation. We reported that oseltamivir phosphate (OP) treatment of human pancreatic tumor-bearing mice disrupted the tumor vasculature with daily injections. Here, the controlled release of OP from a biodegradable PLGA cylinder (PLGA-OP) implanted at tumor site was investigated for its role in limiting tumor neovascularization, growth, and metastasis. PLGA-OP cylinders over 30 days in vitro indicated 20%-25% release profiles within 48 hours followed by a continuous metronomic low dose release of 30%-50% OP for an additional 16 days. All OP was released by day 30. Surgically implanted PLGA-OP containing 20 mg OP and blank PLGA cylinders at the tumor site of heterotopic xenografts of human pancreatic PANC1 tumors in RAGxCγ double mutant mice impeded tumor neovascularization, growth rate, and spread to the liver and lungs compared with the untreated cohort. Xenograft tumors from PLGA and PLGA-OP-treated cohorts expressed significant higher levels of human E-cadherin with concomitant reduced N-cadherin and host CD31(+) endothelial cells compared with the untreated cohort. These results clearly indicate that OP delivered from PLGA cylinders surgically implanted at the site of the solid tumor show promise as an effective treatment therapy for cancer.
authors: Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.
authors: Michael
authors: M
authors: Hrynyk
authors: Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.
authors: Jordon P
authors: JP
authors: Ellis
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors: Fiona
authors: F
authors: Haxho
authors: Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.
authors: Stephanie
authors: S
authors: Allison
authors: Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.
authors: Joseph Am
authors: JA
authors: Steele
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors: Samar
authors: S
authors: Abdulkhalek
authors: Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.
authors: Ronald J
authors: RJ
authors: Neufeld
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors: Myron R
authors: MR
authors: Szewczuk
mesh_terms: D020341:Absorbable Implants; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004343:Drug Implants; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D053139:Oseltamivir / Q000008:administration & dosage* / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; C513384:CDH1 protein, human; C050361:CDH2 protein, human; D015820:Cadherins; D004337:Drug Carriers; D004343:Drug Implants; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D053139:Oseltamivir; D011092:Polyethylene Glycols
keywords: PLGA; metastasis; oseltamivir phosphate; pancreatic cancer; tumor neovascularization