Alpha(V)Beta(3)-Targeted Nanoprobes for In Vivo Imaging of Tumor Angiogenesis
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Lung cancer is the leading cause of cancer-related deaths in the US and abroad (WHO, 2010). Early detection of the disease has increased patients’ five-year survival rates from 4% to over 50% (NCI SEER, 2010). Angiogenesis plays a critical role in the carcinogenesis and cancer metastasis of solid tumors. Integrin αvβ3 is a well-established overexpressed biomarker of angiogenesis and has recently been exploited in the clinical stratification of different types of cancer. Although magnetic resonance imaging (MRI) is not a first-line clinical imaging modality for the detection and diagnosis of lung cancer, recent advances in theranostic polymeric nanoplatforms and the development of ultrasensitive contrast agents, such as superparamagnetic iron oxide (SPIO) nanoparticles, has greatly broadened the application of MRI in cancer detection and molecular imaging. The objective of this work is to develop superparamagnetic polymeric micelle (SPPM) nanoprobes that can noninvasively image tumor angiogenesis in vivo using conventional T2/T2*-weighted and off-resonance saturation (ORS) MRI methods. Therefore, we hypothesized that the inclusion of an αvβ3-specific ligand, cRGD (cyclic Arg-Gly-Asp) peptide and encapsulation of a cluster of SPIO in the SPPM nanoprobe formulation would allow the specific imaging of tumor angiogenesis. SPPM nanoprobes are small (50-70 nm), and contain a cluster of SPIO in the core while maintaining the micelle core-shell architecture. In vitro examination of αvβ3-targeted cRGD-SPPM demonstrate an increase cellular uptake in αvβ3 overexpressing cells over control SPPM formulations. Upon translation to in vivo subcutaneous lung tumor models in mice, cRGD-SPPM is able to noninvasively image and quantitate tumor angiogenesis and demonstrate in vivo colocalization with αvβ3 integrin. In parallel with SPPM characterization, the ORS imaging method was validated in vitro and was successfully applied in vivo for imaging tumor angiogenesis and demonstrated an increased sensitivity and specificity for SPPM over conventional T2*-weighted MR imaging. Application of high temporal resolution (HTR) - MRI, combined with the ultrasensitivity of the SPPM nanoprobe, allows for the kinetic analysis of cRGD-SPPM targeting to angiogenic regions in vivo. Finally, SPPM shows the ability to detect small lung cancer nodules (<700 μm - 3 mm) in tail-vein induced orthotopic lung cancer models using convention T2-weighted and ORS MRI. The results presented herein, provide the characterization and proof-of-principle experiments that point towards the diagnostic potential of SPPM nanoprobes for the early detection of lung cancer.