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Inhibition of tumor angiogenesis and growth by nanoparticle-mediated p53 gene therapy in mice.

Prabha S, Sharma B, Labhasetwar V - Cancer Gene Ther. (2012)

Bottom Line: Overall, this led to significantly improved survival in p53NP-treated animals.NP-mediated p53 gene delivery slowed cancer progression and improved survival in an in vivo cancer model.We conclude that the NP-mediated sustained tumor p53 gene therapy can effectively be used for tumor growth inhibition.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, USA.

ABSTRACT
Mutation of the p53 tumor suppressor gene, the most common genetic alteration in human cancers, results in more aggressive disease and increased resistance to conventional therapies. Aggressiveness may be related to the increased angiogenic activity of cancer cells containing mutant p53. To restore wild-type p53 function in cancer cells, we developed polymeric nanoparticles (NPs) for p53 gene delivery. Previous in vitro and in vivo studies demonstrated the ability of these NPs to provide sustained intracellular release of DNA, thus sustained gene transfection and decreased tumor cell proliferation. We investigated in vivo mechanisms involved in NP-mediated p53 tumor inhibition, with focus on angiogenesis. We hypothesize that sustained p53 gene delivery will help decrease tumor angiogenic activity and thus reduce tumor growth and improve animal survival. Xenografts of p53 mutant tumors were treated with a single intratumoral injection of p53 gene-loaded NPs (p53NPs). We observed intratumoral p53 gene expression corresponding to tumor growth inhibition, over 5 weeks. Treated tumors showed upregulation of thrombospondin-1, a potent antiangiogenic factor, and a decrease in microvessel density vs controls (saline, p53 DNA alone, and control NPs). Greater levels of apoptosis were also observed in p53NP-treated tumors. Overall, this led to significantly improved survival in p53NP-treated animals. NP-mediated p53 gene delivery slowed cancer progression and improved survival in an in vivo cancer model. One mechanism by which this was accomplished was disruption of tumor angiogenesis. We conclude that the NP-mediated sustained tumor p53 gene therapy can effectively be used for tumor growth inhibition.

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Intratumoral expression of angiogenesis marker CD31Immunohistochemical analysis for CD31 (marker of angiogenesis) after 1, 3, and 5 weeks post treatment with saline (A-C), p53(-)NP (D-F), p53DNA (G-I), and p53NP (J-L). Arrows indicate blood vessels (positive stain for CD31).
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Figure 5: Intratumoral expression of angiogenesis marker CD31Immunohistochemical analysis for CD31 (marker of angiogenesis) after 1, 3, and 5 weeks post treatment with saline (A-C), p53(-)NP (D-F), p53DNA (G-I), and p53NP (J-L). Arrows indicate blood vessels (positive stain for CD31).

Mentions: CD31 staining for endothelial cells was notably lower in the p53NP group compared to controls (Figure 5), indicating less angiogenic activity, which is consistent with the presence of TSP-1. With time, there was an increase in CD31 expression in the control groups, especially at 5 weeks; however, the low level of CD31 staining in the p53NP group was sustained.


Inhibition of tumor angiogenesis and growth by nanoparticle-mediated p53 gene therapy in mice.

Prabha S, Sharma B, Labhasetwar V - Cancer Gene Ther. (2012)

Intratumoral expression of angiogenesis marker CD31Immunohistochemical analysis for CD31 (marker of angiogenesis) after 1, 3, and 5 weeks post treatment with saline (A-C), p53(-)NP (D-F), p53DNA (G-I), and p53NP (J-L). Arrows indicate blood vessels (positive stain for CD31).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3400709&req=5

Figure 5: Intratumoral expression of angiogenesis marker CD31Immunohistochemical analysis for CD31 (marker of angiogenesis) after 1, 3, and 5 weeks post treatment with saline (A-C), p53(-)NP (D-F), p53DNA (G-I), and p53NP (J-L). Arrows indicate blood vessels (positive stain for CD31).
Mentions: CD31 staining for endothelial cells was notably lower in the p53NP group compared to controls (Figure 5), indicating less angiogenic activity, which is consistent with the presence of TSP-1. With time, there was an increase in CD31 expression in the control groups, especially at 5 weeks; however, the low level of CD31 staining in the p53NP group was sustained.

Bottom Line: Overall, this led to significantly improved survival in p53NP-treated animals.NP-mediated p53 gene delivery slowed cancer progression and improved survival in an in vivo cancer model.We conclude that the NP-mediated sustained tumor p53 gene therapy can effectively be used for tumor growth inhibition.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, USA.

ABSTRACT
Mutation of the p53 tumor suppressor gene, the most common genetic alteration in human cancers, results in more aggressive disease and increased resistance to conventional therapies. Aggressiveness may be related to the increased angiogenic activity of cancer cells containing mutant p53. To restore wild-type p53 function in cancer cells, we developed polymeric nanoparticles (NPs) for p53 gene delivery. Previous in vitro and in vivo studies demonstrated the ability of these NPs to provide sustained intracellular release of DNA, thus sustained gene transfection and decreased tumor cell proliferation. We investigated in vivo mechanisms involved in NP-mediated p53 tumor inhibition, with focus on angiogenesis. We hypothesize that sustained p53 gene delivery will help decrease tumor angiogenic activity and thus reduce tumor growth and improve animal survival. Xenografts of p53 mutant tumors were treated with a single intratumoral injection of p53 gene-loaded NPs (p53NPs). We observed intratumoral p53 gene expression corresponding to tumor growth inhibition, over 5 weeks. Treated tumors showed upregulation of thrombospondin-1, a potent antiangiogenic factor, and a decrease in microvessel density vs controls (saline, p53 DNA alone, and control NPs). Greater levels of apoptosis were also observed in p53NP-treated tumors. Overall, this led to significantly improved survival in p53NP-treated animals. NP-mediated p53 gene delivery slowed cancer progression and improved survival in an in vivo cancer model. One mechanism by which this was accomplished was disruption of tumor angiogenesis. We conclude that the NP-mediated sustained tumor p53 gene therapy can effectively be used for tumor growth inhibition.

Show MeSH
Related in: MedlinePlus