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作者 Kuesters, Geoffrey M
書名 Development and evaluation of bevacizumab-modified pegylated cationic liposomes using cellular and in vivo models of human pancreatic cancer
國際標準書號 9781109732153
book jacket
說明 119 p
附註 Source: Dissertation Abstracts International, Volume: 71-05, Section: B, page: 3332
Adviser: Robert B. Campbell
Thesis (Ph.D.)--Northeastern University, 2010
Targeting the tumor vascular supply in a homogenous manner is a difficult task to achieve with the use of pegylated cationic liposomes (PCLs) alone. Our formulation consisting of bevacizumab conjugated to the distal end of PEG on PCLs was thus developed in an effort to eliminate some of this heterogeneity as well as to increase tumor targeting overall. This study focuses on pancreatic cancer, which has the poorest five-year survival rate of all cancers because of its late diagnosis. The addition of bevacizumab will target tumor areas because it binds to VEGF which is secreted by tumors in high levels. In vitro, we showed that pancreatic cancer cells (Capan-1, HPAF-II and PANC-1) all secrete VEGF into media at different levels, with Capan-1 producing the most and HPAF-II producing the least. A murine endothelial cell line, MS1-VEGF, produces and secretes the most VEGF. A human microvascular endothelial cell line (HMEC-1) was grown in two different conditions, with and without VEGF in the media. Modifying PCLs with bevacizumab enhanced the binding and uptake of PCLs by some pancreatic and endothelial cells in vitro, particularly the cells that had or secreted the most significant amount of VEGF in the media. This translated into enhanced tumor targeting in a biodistribution study using a Capan-1 subcutaneous pancreatic tumor model. This also showed enhanced blood retention compared to the unmodified PCLs while it diminished uptake by the spleen and increased uptake by the kidney. To test the therapeutic benefit of this enhanced uptake and targeting, an anti-angiogenic agent, 2-methoxyestradiol was incorporated into the formulation with 20% incorporation efficiency. Both the unmodified and modified drug-loaded PCLs were the least efficacious against Capan-1, moderately effective against HPAF-II, PANC-1, MS1-VEGF and HMEC-1 grown without VEGF in the media and most efficacious against HMEC-1 grown with VEGF which had the most VEGF present in the media. Multiple in vivo experiments were performed using two different pancreatic cancer models, one with HPAF-II and the other with Capan-1. The HPAF-II study showed that bevacizumab-modified PCLs significantly enhanced the therapeutic effect over unmodified PCLs, which were ineffective when compared to the untreated control. However, bevacizumab alone was just as efficacious as the bevacizumab-modified PCLs. In the Capan-1 study, both the modified and unmodified PCLs were efficacious but the bevacizumab-modified PCLs were the most efficacious. The addition of bevacizumab not only increased the tumor targeting but also the therapeutic efficacy of 2-methoxyestradiol. Attaching bevacizumab to the distal end of PEG on 2-methoxyestradiol-loaded PCLs was effective at limiting tumor growth. The potential for this formulation is not limited to therapy but also for imaging tumors as well as monitoring the therapeutic response
School code: 0160
Host Item Dissertation Abstracts International 71-05B
主題 Nanotechnology
Health Sciences, Oncology
0652
0992
Alt Author Northeastern University. Pharmaceutics and Drug Delivery Systems
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