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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

Notes: (A) Untreated control (three mice), (B) PLGA-empty (four mice), and (C) PLGA-OP (four mice) 20 mg treated cohorts. Necropsy tumors, HE staining of tumors, and paraffin-embedded tumor sections (5 μm) on glass slides were processed for immunohistochemistry using primary DyLight 488 conjugated rat monoclonal anti-mouse CD31+ (PECAM-1) antibody, primary anti-E-cadherin, and N-cadherin antibodies followed with polyclonal goat anti-rabbit Alexa Fluor® 488 secondary antibody and Entellan® rapid mounting media. Background control (not shown) sections were prepared without the primary antibodies and relative staining density was 2–4×105. The bar on the stained tissue sections represents 200 μm. Images are representative of at least five fields of view from two tumor sections. (D) Quantitative analysis was done by assessing the density of tumor staining corrected for background in each panel using Corel Photo Paint 8.0 software. Each symbol in the figure represents the mean ± SEM corrected density of tumor staining within the respective images. Statistical analysis using unpaired t-test was carried out using GraphPad Prism and results were compared with the untreated cohort.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); SEM, standard error of the mean.
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f4-dddt-9-4573: Notes: (A) Untreated control (three mice), (B) PLGA-empty (four mice), and (C) PLGA-OP (four mice) 20 mg treated cohorts. Necropsy tumors, HE staining of tumors, and paraffin-embedded tumor sections (5 μm) on glass slides were processed for immunohistochemistry using primary DyLight 488 conjugated rat monoclonal anti-mouse CD31+ (PECAM-1) antibody, primary anti-E-cadherin, and N-cadherin antibodies followed with polyclonal goat anti-rabbit Alexa Fluor® 488 secondary antibody and Entellan® rapid mounting media. Background control (not shown) sections were prepared without the primary antibodies and relative staining density was 2–4×105. The bar on the stained tissue sections represents 200 μm. Images are representative of at least five fields of view from two tumor sections. (D) Quantitative analysis was done by assessing the density of tumor staining corrected for background in each panel using Corel Photo Paint 8.0 software. Each symbol in the figure represents the mean ± SEM corrected density of tumor staining within the respective images. Statistical analysis using unpaired t-test was carried out using GraphPad Prism and results were compared with the untreated cohort.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); SEM, standard error of the mean.

Mentions: At necropsy, it was observed that the treatment of tumor-bearing mice with PLGA-OP cylinders at day 35 attenuated the aggressive tumor vascularization (Figure 4C) compared with the untreated control cohort (Figure 4A). There is also indication that PLGA cylinder implants on their own attenuate tumor vascularization and potentially, tumor growth. There is some evidence of residual PLGA cylinder in proximity to the tumor, as seen for example in the image of the tumor in Figure 4C.


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)

Notes: (A) Untreated control (three mice), (B) PLGA-empty (four mice), and (C) PLGA-OP (four mice) 20 mg treated cohorts. Necropsy tumors, HE staining of tumors, and paraffin-embedded tumor sections (5 μm) on glass slides were processed for immunohistochemistry using primary DyLight 488 conjugated rat monoclonal anti-mouse CD31+ (PECAM-1) antibody, primary anti-E-cadherin, and N-cadherin antibodies followed with polyclonal goat anti-rabbit Alexa Fluor® 488 secondary antibody and Entellan® rapid mounting media. Background control (not shown) sections were prepared without the primary antibodies and relative staining density was 2–4×105. The bar on the stained tissue sections represents 200 μm. Images are representative of at least five fields of view from two tumor sections. (D) Quantitative analysis was done by assessing the density of tumor staining corrected for background in each panel using Corel Photo Paint 8.0 software. Each symbol in the figure represents the mean ± SEM corrected density of tumor staining within the respective images. Statistical analysis using unpaired t-test was carried out using GraphPad Prism and results were compared with the untreated cohort.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); SEM, standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

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

f4-dddt-9-4573: Notes: (A) Untreated control (three mice), (B) PLGA-empty (four mice), and (C) PLGA-OP (four mice) 20 mg treated cohorts. Necropsy tumors, HE staining of tumors, and paraffin-embedded tumor sections (5 μm) on glass slides were processed for immunohistochemistry using primary DyLight 488 conjugated rat monoclonal anti-mouse CD31+ (PECAM-1) antibody, primary anti-E-cadherin, and N-cadherin antibodies followed with polyclonal goat anti-rabbit Alexa Fluor® 488 secondary antibody and Entellan® rapid mounting media. Background control (not shown) sections were prepared without the primary antibodies and relative staining density was 2–4×105. The bar on the stained tissue sections represents 200 μm. Images are representative of at least five fields of view from two tumor sections. (D) Quantitative analysis was done by assessing the density of tumor staining corrected for background in each panel using Corel Photo Paint 8.0 software. Each symbol in the figure represents the mean ± SEM corrected density of tumor staining within the respective images. Statistical analysis using unpaired t-test was carried out using GraphPad Prism and results were compared with the untreated cohort.Abbreviations: OP, oseltamivir phosphate; PLGA, poly (lactic-co-glycolic acid); SEM, standard error of the mean.
Mentions: At necropsy, it was observed that the treatment of tumor-bearing mice with PLGA-OP cylinders at day 35 attenuated the aggressive tumor vascularization (Figure 4C) compared with the untreated control cohort (Figure 4A). There is also indication that PLGA cylinder implants on their own attenuate tumor vascularization and potentially, tumor growth. There is some evidence of residual PLGA cylinder in proximity to the tumor, as seen for example in the image of the tumor in Figure 4C.

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