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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.

Hrynyk M, Ellis JP, Haxho F, Allison S, Steele JA, Abdulkhalek S, Neufeld RJ, Szewczuk MR - Drug Des Devel Ther (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.

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.

No MeSH data available.


Related in: MedlinePlus

Therapeutic design of PLGA-OP cylindrical implants.Notes: (A) Fabrication of PLGA-OP; (a, b) dissolved suspension of PLGA in acetone containing Span 80 with OP or without as a blank was transferred using a 1 mL glass syringe from a height of 4 cm onto a smooth Teflon sheet to form a flat, circular disk, in a fume hood for 1 hour followed by refrigeration at 5°C overnight; (c) PLGA-OP disk was lifted from the teflon sheet using a razor blade, and (d) rolled onto a glycerol lubricated precision glide 18 gauge syringe tip to form a cylinder; (e) fabricated PLGA-OP cylinders were extracted from the syringe needle and stored at −80°C; (f) surgical implantation of blank PLGA and PLGA-OP at tumor site (image showing PLGA-OP near necropsied live tumor at end point of experiment. (B) Photograph of PLGA-empty and PLGA-OP cylinders. (C) SEM micrographs of PLGA-OP cylinder; (a) micrograph of a single layer cross-section with hollow continuous center throughout the entire PLGA-OP structure, (b) top surface, (c) magnified porous surface structure, (d) magnified surface structure, and (e) magnified internal structure of PLGA-OP showing crystals of OP.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); SEM, scanning electron microscope.
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f1-dddt-9-4573: Therapeutic design of PLGA-OP cylindrical implants.Notes: (A) Fabrication of PLGA-OP; (a, b) dissolved suspension of PLGA in acetone containing Span 80 with OP or without as a blank was transferred using a 1 mL glass syringe from a height of 4 cm onto a smooth Teflon sheet to form a flat, circular disk, in a fume hood for 1 hour followed by refrigeration at 5°C overnight; (c) PLGA-OP disk was lifted from the teflon sheet using a razor blade, and (d) rolled onto a glycerol lubricated precision glide 18 gauge syringe tip to form a cylinder; (e) fabricated PLGA-OP cylinders were extracted from the syringe needle and stored at −80°C; (f) surgical implantation of blank PLGA and PLGA-OP at tumor site (image showing PLGA-OP near necropsied live tumor at end point of experiment. (B) Photograph of PLGA-empty and PLGA-OP cylinders. (C) SEM micrographs of PLGA-OP cylinder; (a) micrograph of a single layer cross-section with hollow continuous center throughout the entire PLGA-OP structure, (b) top surface, (c) magnified porous surface structure, (d) magnified surface structure, and (e) magnified internal structure of PLGA-OP showing crystals of OP.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); SEM, scanning electron microscope.

Mentions: Poly (D,L-lactic-co-glycolic) acid cylinders loaded with OP at different doses were fabricated using a novel method as depicted in Figure 1A. There is no loss of OP during the formulation, and granular OP was uniformly distributed throughout the polymer matrix. The procedure involves drop-wise extrusion of the PLGA solution containing insoluble OP crystals dispersed by a surfactant. Extruded droplets form circular disks on a smooth Teflon surface, enabling rapid evaporation and thus removal of the solvent. The disks were readily removed from Teflon with a sharp blade, and sufficiently flexible to be wrapped around a lubricated syringe needle forming a cylinder. The advantage in the use of a syringe needle to form cylinders is that different needle diameters allow flexibility in the fabrication of cylinders of different diameters. PLGA was selected as matrix polymer for its sustained, controlled release properties resulting from bulk hydrolysis of the polymer.17 As well, various medical devices and pharmaceutical products formulated from PLGA have US Food and Drug Administration approval.18,19


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.

Hrynyk M, Ellis JP, Haxho F, Allison S, Steele JA, Abdulkhalek S, Neufeld RJ, Szewczuk MR - Drug Des Devel Ther (2015)

Therapeutic design of PLGA-OP cylindrical implants.Notes: (A) Fabrication of PLGA-OP; (a, b) dissolved suspension of PLGA in acetone containing Span 80 with OP or without as a blank was transferred using a 1 mL glass syringe from a height of 4 cm onto a smooth Teflon sheet to form a flat, circular disk, in a fume hood for 1 hour followed by refrigeration at 5°C overnight; (c) PLGA-OP disk was lifted from the teflon sheet using a razor blade, and (d) rolled onto a glycerol lubricated precision glide 18 gauge syringe tip to form a cylinder; (e) fabricated PLGA-OP cylinders were extracted from the syringe needle and stored at −80°C; (f) surgical implantation of blank PLGA and PLGA-OP at tumor site (image showing PLGA-OP near necropsied live tumor at end point of experiment. (B) Photograph of PLGA-empty and PLGA-OP cylinders. (C) SEM micrographs of PLGA-OP cylinder; (a) micrograph of a single layer cross-section with hollow continuous center throughout the entire PLGA-OP structure, (b) top surface, (c) magnified porous surface structure, (d) magnified surface structure, and (e) magnified internal structure of PLGA-OP showing crystals of OP.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); SEM, scanning electron microscope.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539083&req=5

f1-dddt-9-4573: Therapeutic design of PLGA-OP cylindrical implants.Notes: (A) Fabrication of PLGA-OP; (a, b) dissolved suspension of PLGA in acetone containing Span 80 with OP or without as a blank was transferred using a 1 mL glass syringe from a height of 4 cm onto a smooth Teflon sheet to form a flat, circular disk, in a fume hood for 1 hour followed by refrigeration at 5°C overnight; (c) PLGA-OP disk was lifted from the teflon sheet using a razor blade, and (d) rolled onto a glycerol lubricated precision glide 18 gauge syringe tip to form a cylinder; (e) fabricated PLGA-OP cylinders were extracted from the syringe needle and stored at −80°C; (f) surgical implantation of blank PLGA and PLGA-OP at tumor site (image showing PLGA-OP near necropsied live tumor at end point of experiment. (B) Photograph of PLGA-empty and PLGA-OP cylinders. (C) SEM micrographs of PLGA-OP cylinder; (a) micrograph of a single layer cross-section with hollow continuous center throughout the entire PLGA-OP structure, (b) top surface, (c) magnified porous surface structure, (d) magnified surface structure, and (e) magnified internal structure of PLGA-OP showing crystals of OP.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); SEM, scanning electron microscope.
Mentions: Poly (D,L-lactic-co-glycolic) acid cylinders loaded with OP at different doses were fabricated using a novel method as depicted in Figure 1A. There is no loss of OP during the formulation, and granular OP was uniformly distributed throughout the polymer matrix. The procedure involves drop-wise extrusion of the PLGA solution containing insoluble OP crystals dispersed by a surfactant. Extruded droplets form circular disks on a smooth Teflon surface, enabling rapid evaporation and thus removal of the solvent. The disks were readily removed from Teflon with a sharp blade, and sufficiently flexible to be wrapped around a lubricated syringe needle forming a cylinder. The advantage in the use of a syringe needle to form cylinders is that different needle diameters allow flexibility in the fabrication of cylinders of different diameters. PLGA was selected as matrix polymer for its sustained, controlled release properties resulting from bulk hydrolysis of the polymer.17 As well, various medical devices and pharmaceutical products formulated from PLGA have US Food and Drug Administration approval.18,19

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.

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.

No MeSH data available.


Related in: MedlinePlus