In the past four years, we have succeeded in developing cyclic peptide LXY3 that binds to a3b1 integrin of many ovarian cancer cell lines with high affinity (Kd = 50nM). In addition, we have also developed a RGD-containing cyclic peptide that target avb3 integrin of several epithelial cancer and tumor blood vessels. The RGD ligand, LXW7, is unique, because unlike other head-to-tail cyclic RGD peptide, which does not have a built-in handle, LXW7 has two handles to which the imaging tag can be readily attached. We have demonstrated with optical imaging that LXW7, compared to published RGD ligands, has better in vivo targeting potential for cancer. We have developed a new class of micelle-based nanoparticle drug and we were able to demonstrate that such nanocarrier, loaded with paclitaxel, (i) could target subcutaneously implanted ovarian cancer xenograft with high specificity, and (ii) exhibited superior therapeutic efficacy when compared to Taxol(R) and Abraxane(R). Irinotecan, a topoisomerase inhibitor, has been shown clinically to be an active drug against ovarian cancer. We therefore have recently explored the formulation of SN-38, the active drug metablite of the parent prodrug Irinotecan. Preliminary data indicated that SN-38 can be formulated with our telodendrimer. It is important to note that the in vitro anti-tumor activity of SN-38 is 1000 times more potent than its prodrug, Irinotecan. Since the mechanism of action of paclitaxel (tubulin stabilizer), and SN-38 (topoisomerase inhibitor) are very different, we believe concurrent treatment of xenograft-bearing mice with both paclitaxel-nanoparticle and SN-38 nanoparticle will be particularly effective. In this Competitive Renewal Proposal, we plan to pursue the following specific aims: 1. To use [14C]-labeled paclitaxel to determine the in vivo biodistribution and ovarian cancer targeting properties of paclitaxel-loaded nanocarriers, with or without tumor targeting ligands. 2. To study the in vivo intratumoral distribution of various formulations of nanocarriers with high resolution fluorescent microscopy, transmission electron microscopy and cryoelectron microscopy. 3. To optimize the novel nano-formulations of SN-38 and to determine their in vivo therapeutic efficacies in both subcutaneous and intraperitoneal ovarian cancer xenograft models. 4. Based on the results of aims 1, 2 and 3, to develop optimized paclitaxel-loaded and SN-38-loaded tumor targeting-nanocarriers;and to compare their efficacies as single or combination therapy in both subcutaneous and intra-peritoneal ovarian cancer xenograft models.

Public Health Relevance

In the past four years, we have succeeded in developing cyclic peptide LXY3 that binds to a3b1 integrin of many ovarian cancer cell lines with high affinity a RGD-containing cyclic peptide that target avb3 integrin of several epithelial cancer and tumor blood vessels. The RGD ligand, LXW7, is unique, because unlike other head-to-tail cyclic RGD peptide, which does not have a built-in handle, LXW7 has two handles to which the imaging tag can be readily attached. We have demonstrated with optical imaging that LXW7, compared to published RGD ligands, has better in vivo targeting potential for cancer. We have developed a new class of micelle-based nanoparticle drug and we were able to demonstrate that such nanocarrier, loaded with paclitaxel, (i) could target subcutaneously implanted ovarian cancer xenograft with high specificity, and (ii) exhibited superior therapeutic efficacy when compared to Taxol(R) and Abraxane(R). In this proposed research, we plan to develop therapeutic drug- loaded nanoparticles decorated with LXY3 and/or LXW7 as an effective and less toxic therapy for ovarian cancer. Xenograft model will be used in this research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115483-10
Application #
8657829
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2005-07-25
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
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