Integrin αvβ3-targeted gold nanoshells augment tumor vasculature-specific imaging and therapy

Huan Xie1, Parmeswaran Diagaradjane2, Amit A Deorukhkar2, Beth Goins3, Ande Bao3, William T Phillips3, Zheng Wang4, Jon Schwartz5, Sunil Krishnan21Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA; 2Department of Radiation Oncology, Division of Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Radiology, the University of Texas Health Science Center at San Antonio (UTHSC-San Antonio), San Antonio, TX, USA; 4MPI Research, Inc., Mattawan, MI, USA; 5Nanospectra Biosciences, Inc., Houston, TX, USAPurpose: Gold nanoshells (NSs) have already shown great promise as photothermal actuators for cancer therapy. Integrin αvβ3 is a marker that is specifically and preferentially overexpressed on multiple tumor types and on angiogenic tumor neovasculature. Active targeting of NSs to integrin αvβ3 offers the potential to increase accumulation preferentially in tumors and thereby enhance therapy efficacy.Methods: Enzyme-linked immunosorbent assay (ELISA) and cell binding assay were used to study the in vitro binding affinities of the targeted nanoconjugate NS–RGDfK. In vivo biodistribution and tumor specificity were analyzed using 64Cu-radiolabeled untargeted and targeted NSs in live nude rats bearing head and neck squamous cell carcinoma (HNSCC) xenografts. The potential thermal therapy applications of NS–RGDfK were evaluated by subablative thermal therapy of tumor xenografts using untargeted and targeted NSs.Results: ELISA and cell binding assay confirmed the binding affinity of NS–RGDfK to integrin αvβ3. Positron emission tomography/computed tomography imaging suggested that tumor targeting is improved by conjugation of NSs to cyclo(RGDfK) and peaks at ~20 hours postinjection. In the subablative thermal therapy study, greater biological effectiveness of targeted NSs was implied by the greater degree of tumor necrosis.Conclusion: The results presented in this paper set the stage for the advancement of integrin αvβ3-targeted NSs as therapeutic nanoconstructs for effective cancer therapy.Keywords: nanoparticle, cyclo(RGDfK), cancer, thermal ablatio

Near-infrared narrow-band imaging of gold/silica nanoshells in tumors

textGold nanoshells (GNS) are a new class of nanoparticles that can be optically tuned to scatter or absorb light from the near-ultraviolet to near-infrared (NIR) region by varying the core (dielectric silica) /shell (gold) ratio. In addition to spectral tunability, GNS are inert and bioconjugatable making them potential labels for in vivo imaging and therapy of tumors. We report the use of GNS as exogenous contrast agents for enhanced visualization of tumors using narrow band imaging (NBI). NBI takes advantage of the strong NIR absorption of GNS to distinguish between blood and nanoshells in the tumor by imaging in narrow wavelength bands in the visible and NIR, respectively. Using tissue-simulating phantoms, we determined the optimum wavelengths to enhance contrast between blood and GNS. We then used the optimum wavelengths for ex-vivo imaging of tumors extracted from human colon cancer xenograft bearing mice injected with GNS. Systemically delivered GNS accumulated passively in tumor xenografts by enhanced permeability and retention (EPR) effect. Ex-Vivo NBI of tumor xenografts demonstrated tumor specific heterogeneous distribution of GNS with a clear distinction from the tumor vasculature. The results of the present study demonstrate the feasibility of using GNS as contrast agents to visualize tumor tissues using NBI technique.Biomedical Engineerin