title: Dual targeting of integrin αvβ3 and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery.
abstract: Activatable cell-penetrating peptides (ACPP) 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 α(v)β(3)-binding domain, cyclic-RGD, was covalently linked to the ACPP. This co-targeting strategy relies on the interaction of MMP-2 with integrin α(v)β(3), which are known to associate via the hemopexin domain of MMP-2. In U87MG glioblastoma cells in culture, dual targeting greatly improved ACPP uptake compared with either MMP or integrin α(v)β(3) targeting alone. In vivo, dual-targeted ACPP treatment resulted in tumor contrast of 7.8 ± 1.6, a 10-fold higher tumor fluorescence compared with 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 with 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.
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, Maryland.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Crisp
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, Maryland.
authors.forename: Elamprakash N
authors.initials: EN
authors.lastname: Savariar
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, MarylandAuthors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, Maryland.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Glasgow
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, Maryland.
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Whitney
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, MarylandAuthors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, MarylandAuthors' Affiliations: Departments of Pharmacology, Pathology, and Chemistry and Biochemistry, Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; and Howard Hughes Medical Institute, Bethesda, Maryland rtsien@ucsd.edu.
authors.forename: Roger Y
authors.initials: RY
authors.lastname: Tsien
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000473:pathology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D049268:Positron-Emission Tomography; D011859:Radiography
chemical_list: D057846:Cell-Penetrating Peptides; D003287:Contrast Media; D039302:Integrin alphaVbeta3; D020778:Matrix Metalloproteinase 2
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