Aminosilanized flower-structured superparamagnetic iron oxide nanoparticles coupled to 131I-labeled CC49 antibody for combined radionuclide and hyperthermia therapy of cancer

Q2 · MEDICINE

Article

Author: Janković, Drina ; Prijović, Željko ; Ognjanović, Miloš ; Vranješ-Đurić, Sanja ; Mijović, Milica ; Antić, Bratislav ; Stanković, Aljoša ; Mihailović, Jasna ; Mirković, Marija ; Milanović, Zorana ; Radović, Magdalena

Combined radionuclide therapy with magnetic nanoparticles-mediated hyperthermia has been under research focus as a promising tumor therapy approach. The objective of this study was to investigate the potential of ¹³¹I-radiolabeled superparamagnetic iron oxide nanoparticles (SPIONs) prepared as the ~40 nm flower-shaped structures with excellent heating efficiency (specific absorption rate at H₀ = 15.9 kA∙m^-1 and resonant frequency of 252 kHz was 123.1 W∙g^-1) for nano-brachytherapy of tumors. ¹³¹I-radiolabeled CC49 antibody attached to SPIONs via reactive groups of 3-aminopropyltriethoxysilane (APTES) provided specificity and long-lasting localized retention after their intratumoral application into LS174T human colon adenocarcinoma xenografts in NOD-SCID mice. The results demonstrate feasibility and effectiveness of magnetic hyperthermia (HT), radionuclide therapy (RT) and their combination (HT + RT) in treating cancer in xenograft models. Combined therapy approach induced a significant (p < 0.01) tumor growth suppression in comparison to untreated groups presented by the tumor volume inhibitory rate (TVIR): 54.38%, 68.77%, 73.00% for HT, RT and HT + RT, respectively in comparison to untreated group and 48.31%, 64,62% and 69,41%, respectively, for the SPIONs-only injected group. Histopathology analysis proved the necrosis and apoptosis in treated tumors without general toxicity. Obtained data support the idea that nano-brachytherapy combined with hyperthermia is a promising approach for effective cancer treatment.

01 Mar 2008·International ImmunopharmacologyQ2 · MEDICINE

A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs

Q2 · MEDICINE

Article

Author: Dennis H. Robinson ; Peter R. Gwilt ; Jasmine P. Davda ; Surinder K. Batra ; Maneesh Jain

Optimization of the use of monoclonal antibodies (MAbs) as diagnostic tools and therapeutic agents in the treatment of cancer is aided by quantitative characterization of the transport and tissue disposition of these agents in whole animals. This characterization may be effectively achieved by the application of physiologically based pharmacokinetic (PBPK) models. The purpose of this study was to develop a PBPK model to characterize the biodistribution of the pancarcinoma MAb CC49 IgG in normal and neoplastic tissues of nude mice, and to further apply the model to predict the disposition of multivalent single chain Fv (scFv) constructs in mice. Since MAbs are macromolecules, their transport is membrane-limited and a two-pore formalism is employed to describe their extravasation. The influence of binding of IgG to the protective neonatal Fc receptor (FcRn) on its disposition is also accounted for in the model. The model successfully described (131)I-CC49 IgG concentrations in blood, tumor and various organs/tissues in mice. Sensitivity analysis revealed the rate of transcapillary transport to be a critical determinant of antibody penetration and localization in the tumor. The applicability of the model was tested by predicting the disposition of di- and tetravalent scFv constructs of CC49 in mice. The model gave reasonably good predictions of the disposition of the scFv constructs. Since the model employs physiological parameters, it can be used to scale-up mouse biodistribution data to predict antibody distribution in humans. Therefore, the clinical utility of the model was tested with data for (131)I-CC49 obtained in patients, by scaling up murine parameter values according to known empirical relationships. The model gave satisfactory predictions of CC49 disposition and tumor uptake in man.

01 Jun 2003·Cancer Biotherapy and RadiopharmaceuticalsQ4 · MEDICINE

Comparison of Biodistribution, Dosimetry, and Outcome from Clinical Trials of Radionuclide-CC49 Antibody Therapy

Q4 · MEDICINE

Article

Author: LoBuglio, Albert ; Shen, Sui ; Meredith, Ruby ; Carey, Delicia ; Robert, Francisco ; Macey, Daniel ; Khazaeli, M.B.

CC49 is a second-generation murine antibody with anti-TAG-72 (tumor-associated antigen) reactivity. For cancer therapy, it has the advantage of being expressed on adenocarcinomas but not on most normal tissues. CC49 has been utilized in phase I and II clinical trials at multiple institutions. Therapeutic applications to date have included (131)I-, (90)Y-, and (177)Lu-CC49, with tracer amounts of (111)In-CC49 as a dosimetry surrogate for (90)Y-CC49 therapy. Dosimetry methods and details of their description vary between studies. Biodistribution to normal organs and the effective plasma T(1/2) for various radionuclides were relatively consistent among patients with different diseases and treatment at several institutions. As expected with marrow suppression being the dose-limiting toxicity, higher doses of (177)Lu-CC49 were tolerated via intraperitoneal than IV administration. The biologic response modifier interferon enhanced TAG-72 expression and resulted in a trend of increased uptake of (131)I-CC49 by tumors. Tumor dose estimates were more variable than that of normal organs. Standardization and improved dosimetry may be helpful for comparison among patients in various studies and for establishing dose/toxicity relationships that are useful for predicting safe levels of radioimmunoconjugates.

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Neoplasms	Preclinical	US	Corixa Corp.	-

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