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| Content Provider | PubMed Central |
|---|---|
| Author | Crisp, Jessica L. Savariar, Elamprakash N. Glasgow, Heather L. Ellies, Lesley G. Whitney, Michael A. Tsien, Roger Y. |
| Abstract | Activatable cell penetrating peptides (ACPPs) provide a general strategy for molecular targeting by exploiting the extracellular protease activities associated with disease. Previous work used a matrix metalloproteinase (MMP-2 and 9) cleavable sequence in the ACPP to target contrast agents for tumor imaging and fluorescence guided surgery. To improve specificity and sensitivity for MMP-2, an integrin αvβ3 binding domain, cyclic-RGD, was covalently linked to the ACPP. This co-targeting strategy relies on the interaction of MMP-2 with integrin αvβ3, which are known to associate via MMP-2’s hemopexin domain. In U87MG glioblastoma cells in culture, dual targeting greatly improved ACPP uptake compared to either MMP or integrin αvβ3 targeting alone. In vivo, dual-targeted ACPP treatment resulted in tumor contrast of 7.8±1.6, a 10 fold higher tumor fluorescence compared to the negative control peptide, and increased probe penetration into the core of MDA-MB-231 tumors. This platform also significantly improved efficacy of the chemotherapeutic monomethylauristatin E (MMAE) in both MDA-MB-231 orthotopic human and syngeneic Py230 murine breast tumors. Treatment with cyclic-RGD-PLGC(Me)AG-MMAE-ACPP resulted in complete tumor regression in one quarter of MDA-MB-231 tumor bearing mice, compared to no survival in the control groups. This rational mechanism for amplified delivery of imaging and potent chemotherapeutic agents avoids the use of antibodies and may be of considerable generality. |
| Related Links | http://dx.doi.org/10.1158/1535-7163.mct-13-1067 |
| Ending Page | 1525 |
| Page Count | 12 |
| Starting Page | 1514 |
| File Format | |
| ISSN | 15357163 |
| e-ISSN | 15388514 |
| Journal | Molecular cancer therapeutics |
| Issue Number | 6 |
| Volume Number | 13 |
| Language | English |
| Publisher Date | 2014-06-01 |
| Access Restriction | Open |
| Subject Keyword | Cancer Research Oncology Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Oncology |
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