Anticancer Nanomedicine

Robert Griffin, Ph.D.
Professor, Department of Radiation Oncology
Co-leader, Experimental Cancer Therapeutic program

View Griffin’s published research.

The primary research focus of our radiation biology research group is on nanomedicine-based approaches with anti-angiogenic or anti-vascular treatment strategies for imaging and therapy and the relationship of these agents to the success of other cancer treatments.

We have found that anginex has potent anti-angiogenic effects, preferentially binds to and radiosensitizes tumor endothelium, extends radiation-induced tumor growth delay and acts synergistically in combination with radiotherapy against murine and human xenografted tumors with no side effects.

Secondly, the application of heat (hyperthermia) as a cancer primary or adjuvant treatment continues to prove itself as a clinically viable and successful modality.

The number of positive clinical trial outcomes has steadily accumulated over the last decade. There is also a growing list of improved technology platforms for delivery of higher temperature ablative procedures with minimal to low invasiveness.

The central hypotheses of this area of investigation is that the reoxygenation pattern of sublethally heated tumor can be exploited to improve subsequent radiation therapy and that heat-induced tumor destruction can be significantly improved and controlled with novel anti-vascular agents (arsenic trioxide and cytokine-coated gold nanoparticles) at low and high thermal doses.

We have recently developed a system to study the interaction of stromal cells and tumor cells in a 3-D culture environment and the role of this interaction on sensitivity of each cell type to therapy.

The receptor for the anginex peptide is galectin-1, a protein that is expressed in the membrane of cells as well as secreted into the tumor stroma and therefore is an extremely useful system to understand more about the stromal contribution to anti-tumor therapies.

We have also done a significant amount of work characterizing the FDA approved leukemia agent Arsenic Trioxide as an anti-vascular agent alone and in combination with radiotherapy and/or thermal therapy against solid tumor models and are currently focusing on strategies to use nanomedicine vehicles to increase delivery of arsenic to models of multiple myeloma and various solid tumor types.

We are working on characterizing a novel anti-angiogenic peptide, anginex, against solid tumors.

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Above: Two commercially available small-animal radiation research platforms. On the left is a system developed at Princess Margaret Hospital (Courtesy of PXI). On the right is a system engineered at Johns Hopkins University (Courtesy of Xstrahl; also Wong et al.). Both systems have precision animal positioning systems, an onboard X-ray imager and stable X-ray tubes with precision collimators for irradiation fields which could be smaller than 1 mm.

Molecular Cancer Therapeutics

Tumor perfusion in the SCK murine mammary carcinoma, grown in the hindlimb of A/J mice, after treatment with 250 µg/kg TNF-conjugated gold nanoparticles, hyperthermia (42.5 ºC, 60 min) and combination of nanoparticles and heat was non-invasively imaged using contrast enhanced ultrasonography. The orange-red color represents vascularity, or the blood flow index. A markedly defective tumor perfusion persisted in tumors receiving combined treatment. The nanoparticles (PT-cAu-TNF) are 33nm pegylated colloidal gold particles coated with TNF. For details see Visaria et al. in this issue.

Other Publications

• Apana SM, Griffin RJ,  Koonce NA, Webber JS, Dings RPM, Mayo KH, Berridge MS:  Synthesis of [18F]anginex with high specific activity [18F]fluorobenzaldehyde for targeting angiogenic activity in solid tumors.  J.  Label.  Compd.  Radiopharm. 54 (11), 708-713 (2011). 
• Asur RS, Sharma SS, Chang CW, Penagaricano J, Kommuru IM, Moros EG, Corry PM, Griffin RJ:  Spatially fractionated radiation induces cytotoxicity and changes in gene expression in bystander and radiation adjacent murine carcinoma cells.  Radiation Res Jun;177(6):751-65, 2012.
• Bischof JC, Griffin RJ et al.  Nanoparticle Pre-Conditioning for Enhanced Thermal Therapies in Cancer; Nanomedicine, 6(3):545-63, 2011.
• Chen D, Xia R, Chen X, Shafirstein G, Griffin RJ, Corry P, Moros EG:  SonoKnife: Feasibility of a Line-Focused Ultrasound Device for Thermal Ablation Therapy.  Med Phys. Jul;38(7):4372-85, 2011.
• Chen X, Moros E, Corry P, Webber JS, Griffin RJ:   An Alternating Focused Ultrasound System for Thermal Therapy Studies Using Small Animals.  Med Phys Apr;38(4):1877-87, 2011.
• Dings RPMD, Loren M, Mikkelson S, Corry PM, Griffin RJ:  Tumor thermotolerance, a physiological phenomenon involving vessel normalization. Int J Hyperthermia, 27(1):42-52, 2011.
• Griffin, RJ, Koonce NA, Dings RPM, Siegel E, Moros EG, Bräuer-Krisch E, Corry PM:  Microbeam radiation therapy alters microvascular architecture and tumor oxygenation and is enhanced by a galectin-1 targeted anti-angiogenic peptide.  Radiation Res, Jun;177(6):804-12, 2012.
• Griffin RJ, Williams BW, Koonce NA, Bischof JC, Song CW, Srinath R, Upreti M:  Vascular disrupting agent arsenic trioxide enhances thermoradiotherapy of solid tumors.  Journal of Oncology, vol. 2012, Article ID 934918, 2012.
• Park H-J, Griffin RJ, Hui S, Song CW:  Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypo-fractionated radiotherapy (SBRT and SRS). Radiation Res, 177: 311-327, 2012.
• Przybyla B, Shafirstein G, Koonce NA, Webber JS, Griffin RJ:  Conductive thermal ablation of 4T1 murine breast carcinoma reduces severe hypoxia in surviving tumor.  Int J Hyperthermia, 28(2): 156-162, 2012.
• Shafirstein G, Baumler W, Hennings L, Siegel E, Friedman R, Moreno MA, Webber JS,Jackson C, Griffin RJ:  Indocyanine Green Enhanced Near Infrared Laser Treatment of SCK Tumors in a Mouse Model. Int J Cancer, 130(5):1208-15, 2011.
• Suva LJ, Washam C, Nicholas R, and Griffin RJ:  Bone Metastasis: Mechanisms and Therapeutic Opportunities. Nature Reviews Endocrinology, 7(4):208-18, 2011.
• Upreti M, Jamshidi-ParsianA, KoonceNA, WebberJS, Sharma SK, Asea AA, Mader MJ, GriffinRJ:  Tumor-endothelial cell 3D spheroids: New aspects to enhance radiation and drug therapeutics.  Translational Oncology, 4(6):365-76, 2011.
• Upreti M, Koonce NA, Hennings L, Chambers T, Griffin RJ:  IRF-1 mediates melanoma sensitivity to chemotherapy and induces senescence in endothelial cells.   Cell Death and Disease, (8):e67 2010.
• Upreti M, Jamshidi-Parsian A, Apana S, Berridge MS, Fologea D , Koonce N A, Henry RL, Griffin RJ: “Radiation-induced Galectin-1 by endothelial cells: A promising molecular target for preferential drug delivery to the tumor vasculature.”  Journal of Molecular Medicine, in press 2012. Ms. No. JMME-D-12-00194R1

• National Institutes of Health / National Cancer Institute
• Focused Ultrasound Foundation (Research Award)
• Arkansas Breast Cancer Research Program

University of Arkansas for Medical Sciences, College of Medicine
Biomedical Research Center, # 824
Little Rock, AR 72205
Email: rjgriffin@uams.edu
Phone:(501) 526-7873