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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

Necropsy liver (A) and lung (B). RAGxCγ double mutant mice were implanted with 0.5×106 PANC1 pancreatic cancer cells subcutaneously on the rear flank and PLGA-empty and PLGA-OP 20 mg cylinders were surgically implanted at day 35 post-implantation when tumors reached 100–120 mm3. Paraffin-embedded tissue sections (5 μm) on glass slides were processed for HE staining for each mouse necropsied at end point of the study. Stained tissue sections were photographed using a Zeiss Imager M2 fluorescence microscope at 400× magnification. Images are representative of at least five fields of view from two tissue sections. Metastatic tissue clusters were microscopically counted per tissue sections (5 μm) and plotted in the graph.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); RAG, recombinase activating gene.
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f6-dddt-9-4573: Necropsy liver (A) and lung (B). RAGxCγ double mutant mice were implanted with 0.5×106 PANC1 pancreatic cancer cells subcutaneously on the rear flank and PLGA-empty and PLGA-OP 20 mg cylinders were surgically implanted at day 35 post-implantation when tumors reached 100–120 mm3. Paraffin-embedded tissue sections (5 μm) on glass slides were processed for HE staining for each mouse necropsied at end point of the study. Stained tissue sections were photographed using a Zeiss Imager M2 fluorescence microscope at 400× magnification. Images are representative of at least five fields of view from two tissue sections. Metastatic tissue clusters were microscopically counted per tissue sections (5 μm) and plotted in the graph.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); RAG, recombinase activating gene.

Mentions: Necropsy live livers (Figure 6A) and lungs (Figure 6B) were lacking visible tumor nodules for the blank PLGA and PLGA-OP treated cohorts compared with extensive visible tumors for the untreated controls. There were neither tumor nodules nor metastatic clusters of cancer cells in the liver or lung for the PLGA-OP treated cohort. Both blank PLGA and PLGA-OP treatments markedly attenuated the metastatic spread of PANC1 cancer cells to the lungs and liver (Figure 6A and B) compared with extensive evidence of metastatic spread in the untreated cohort. Lack of metastatic spread to the lung and liver following PLGA treatment may be due in part to a disrupted tumor vasculature development and reduced host CD31+ endothelial cell migration, or result from a decreased expression of the cell surface mesenchymal marker, N-cadherin, and an increased expression of the cell surface epithelial marker, E-cadherin as previously reported by us for pancreatic cancer.15


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)

Necropsy liver (A) and lung (B). RAGxCγ double mutant mice were implanted with 0.5×106 PANC1 pancreatic cancer cells subcutaneously on the rear flank and PLGA-empty and PLGA-OP 20 mg cylinders were surgically implanted at day 35 post-implantation when tumors reached 100–120 mm3. Paraffin-embedded tissue sections (5 μm) on glass slides were processed for HE staining for each mouse necropsied at end point of the study. Stained tissue sections were photographed using a Zeiss Imager M2 fluorescence microscope at 400× magnification. Images are representative of at least five fields of view from two tissue sections. Metastatic tissue clusters were microscopically counted per tissue sections (5 μm) and plotted in the graph.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); RAG, recombinase activating gene.
© Copyright Policy
Related In: Results  -  Collection

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

f6-dddt-9-4573: Necropsy liver (A) and lung (B). RAGxCγ double mutant mice were implanted with 0.5×106 PANC1 pancreatic cancer cells subcutaneously on the rear flank and PLGA-empty and PLGA-OP 20 mg cylinders were surgically implanted at day 35 post-implantation when tumors reached 100–120 mm3. Paraffin-embedded tissue sections (5 μm) on glass slides were processed for HE staining for each mouse necropsied at end point of the study. Stained tissue sections were photographed using a Zeiss Imager M2 fluorescence microscope at 400× magnification. Images are representative of at least five fields of view from two tissue sections. Metastatic tissue clusters were microscopically counted per tissue sections (5 μm) and plotted in the graph.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); RAG, recombinase activating gene.
Mentions: Necropsy live livers (Figure 6A) and lungs (Figure 6B) were lacking visible tumor nodules for the blank PLGA and PLGA-OP treated cohorts compared with extensive visible tumors for the untreated controls. There were neither tumor nodules nor metastatic clusters of cancer cells in the liver or lung for the PLGA-OP treated cohort. Both blank PLGA and PLGA-OP treatments markedly attenuated the metastatic spread of PANC1 cancer cells to the lungs and liver (Figure 6A and B) compared with extensive evidence of metastatic spread in the untreated cohort. Lack of metastatic spread to the lung and liver following PLGA treatment may be due in part to a disrupted tumor vasculature development and reduced host CD31+ endothelial cell migration, or result from a decreased expression of the cell surface mesenchymal marker, N-cadherin, and an increased expression of the cell surface epithelial marker, E-cadherin as previously reported by us for pancreatic cancer.15

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