Integrated Nanostructured Systems

Nanotechnology; Tumor Angiogenesis; Radiation Therapy; Biochemistry and Molecular Biology.

Dr. Khan's research focuses on tumor angiogenesis, nanotechnology, and radiotherapy.

A) Dendrimer Nanocomposites in Radiotherapy and Imaging of the Tumor Microvasculature:
Nanotechnology is by its nature very multidisciplinary. Dr. Khan (biology) and Dr. Lajos Balogh (materials sciences, engineering) are the Co-Directors of the NanoBiotechnology Center at RPCI, where research is done involving several collaborative researchers. In the nanotechnology research, Dr. Khan and Balogh focus on both tumor imaging and therapy using composite nanodevices (CNDs) that exploit differences between the normal and tumor microvasculature. The composite nanodevices have a dendrimer 3-D polymer component with an external surface that can be use for targeting or placement of agents to attack cancer, and the "inner" region traps inorganic materials again that can be used for imaging and therapy (for example the CNDs can deliver radiation dose at level at least a log fold more that that seen with radioactive antibody therapies). One set of experiments in the laboratory attempts to send nanocomposites through the leaky tumor microvasculature and into cancer tissue in mouse tumor model systems, and examines important effects produced by small changes in nanodevice size or charge. The second major area is attempting to design and test nanocomposites targeted directly at the leaky tumor microvasculature, and to utilize this for multi-level imaging (whole animal, intra-tumoral, intracellular) using the same nanodevice. These are also being developed for therapy, as the metal (or Isotopes) carried by the nanodevices can be used for the delivery of radiation dose to the tumor microvasculature.

B) Tetrathiomolybdate (TM) and Radiotherapy:
His laboratory has also completed preclinical experiments demonstrating that the combination of a novel anti-angiogenic agent (tetrathiomolybdate or TM) with radiation therapy will slow tumor growth better than either therapy used alone in mouse model systems. TM is an orally administered agent that was shown to reduce copper levels in patients safely by Dr. George Brewer. Copper reduction has been shown to block angiogenesis, by affecting multiple pro-angiogenic molecules (bFGF, VEGF, IL-6, IL-8, angiogenic), making it a "multi-hit" anti-angiogenic agent. It has also been shown to slow tumor growth (in the laboratories of Dr. Khan, Dr. Merajver, and others). His research will now enter the clinic, with a recently NIH approved and funded phase I clinical trial to combine TM with radiotherapy in non-small cell lung carcinoma patients. As part of this research, markers linked with TM's anti-angiogenic action will be monitored, and an imaging study will be carried out to examine whether non-invasive means of demonstrating the anti-angiogenic action of the drug in patients can be found, and assist in future trials.

C) Multi-gene Molecular Analysis (Microarray) of Angiogenic Human Endothelial Cells:
Dr. Khan's laboratory continues to develop systems to permit the molecular analysis of angiogenesis in specifically engineered tumor microenvironments. This is done in an angiogenesis system developed by Drs. Nor, Polverini, Mooney, and Khan, where human endothelial cells are seeded onto a bioengineered matrix, implanted in SCID mice, and then undergo angiogenesis. His laboratory has developed techniques to extract the human endothelial cells from the scaffold for Microarray (multi-gene) analysis. Tumor cells can be added with the human endothelial cells, permitting the formation of multiple tumor microenvironments. The concept is to create any tumor microenvironment desired in vivo, permit human endothelial cells to undergo angiogenesis in these microenvironments, and examine the message patterns during the process of tumor angiogenesis with or without various therapies (chemotherapy, radiation, etc.).

Selected Publications:

A) Nanotechnology

Mohamed K. Khan, Leah D. Minc, Shraddha S. Nigavekar, Andrew C. Cook, Matthew Schipper, Wojciech G. Lesniak, Muhammed S. T. Kariapper, and Lajos P. Balogh. Fabrication of {198-Au} Radioactive Composite Nanodevices and their use for Nanobrachytherapy. NanoMedicine, In Press. (Nanomedicine: NBM 2008; x:1-13, doi:10.1016/j.nano.2007.11.005).

Lajos Balogh, Shraddha S. Nigavekar, Bindu M. Nair, Wojciech Lesniak, Chunxin Zhang, Lok Yun Sung, Muhammed S. T. Kariapper, Areej El-Jawahri, Mikel Llanes, Brian Bolton, Fatema Mamou, Wei Tan, Alan Hutson, Leah Minc, and Mohamed K. Khan. Significant Effect of Size on the in vivo Biodistribution of Gold Composite Nanodevices in a Mouse Tumor Models. Nanomedicine 2007; 3: 281-296.

Mohamed K. Khan, Shraddha S. Nigavekar, Leah D. Minc, Muhammed S. T. Kariapper, Bindu M. Nair, Wojciech G. Lesniak, Lajos P. Balogh. In Vivo Biodistribution of Dendrimers and Dendrimer Nanocomposites - Implications for Cancer Imaging and Therapy, Technology in Cancer Research and Treatment 2005; 4 (6): 603-613.

Kukowska-Latallo JF, Candido KA, Cao Z, Nigavekar SS, Marjoros IJ, Keszler B, Thomas TP, Balogh LP, Khan MK and Baker JR. Nanoparticle Targeting of Anticancer Drug Improves Therapeutic Response in Animal Model of Human Epithelial Cancer, Cancer Research 2005; 65 (12): 5317-24.

Nigavekar SS, Sung LY, Llanes M, El-Jawahri A, Lawrence TS, Becker CW, Balogh L, Khan MK. 3H dendrimer nanoparticle organ/tumor distribution. Pharm Res. 2004 Mar; 21(3):476-83

Lajos P. Balogh, Shraddha S. Nigavekar, Andrew C. Cook, Leah Minc, and Mohamed K. Khan. Development of Dendrimer-Gold Radioactive Nanocomposites to Treat Cancer Microvasculature. PharmaChem 2003; 2(4), 94-99.

Balogh L, Bielinska A, Eichman JD, Valluzzi R, Lee I, Baker JR, Lawrence TS and Khan MK. Dendrimer Nanocomposites in Medicine. Chimica Oggi (Chemistry Today) 2002; 20 (5): 35-40.

B) Anti-angiogenic Therapy and Radiotherapy - TM and RT

Mohamed K. Khan, Fatema Mamou, Matthew J. Schipper, Kerstin S. May, Alla Kwitny, Amber Warnat, Brian Bolton, Bindu M. Nair, Muhammed S. T. Kariapper, Meredith Miller, George Brewer, Daniel Normolle, Sofia Merajver and Theodoros Teknos. Combination of Tetrathiomolybdate and Radiation in a Mouse Model of HNSCC. Arch Otolaryngol Head Neck Surg. 2006; 132 (3): 333-338

Fatema Mamou, Kerstin S. May, Matthew J. Schipper, Navkiranjit Gill, Muhammed S. T. Kariapper, Bindu M. Nair, George Brewer, Daniel Normolle and Mohamed K. Khan. Tetrathiomolybdate Blocks bFGF- but not VEGF- Induced Incipient Angiogenesis in vitro. Anticancer Research 2006; 26: 1753-1758.

Khan MK, Miller MW, Taylor J, Gill NK, Dick RD, Van Golen K, Brewer GJ, Merajver SD. Radiotherapy and antiangiogenic TM in lung cancer. Neoplasia. 2002 Mar-Apr; 4(2):164-70.

C) Angiogenesis and Microarray - Scaffold Model Development

Nor JE, Peters MC, Christensen JB, Sutorik MM, Linn S, Khan MK, Addison CL, Mooney DJ, Polverini PJ. Engineering and characterization of functional human microvessels in immunodeficient mice. Lab Invest. 2001 Apr; 81(4):453-63.

D) Other

Yu Y, Moulton KS, Khan MK, Vineberg S, Boye E, Davis VM, O'Donnell PE, Bischoff J, Milstone DS. E-selectin is required for the antiangiogenic activity of endostatin. Proc Natl Acad Sci USA. 2004 May 25; 101(21):8005-10. Epub 2004 May 17.

Camphausen K, Moses MA, Beecken WD, Khan MK, Folkman J, O'Reilly MS. Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res. 2001 Mar 1; 61(5):2207-11.