Molecular and cellular imaging can provide important insight into the mechanisms and efficacy of novel therapeutics.    This  study involves  the  combined  use  of  Prof. Sessler’s  gadolinium  texaphyrin complex  (Gd-Tex; Xcytrin®)  at  the  5 mg/kg/day x 10 day level and radiation therapy  (3000  Gy  total).  The images  are  recorded  on day  1,  at  2  months,  and  at 6 months.  The white areas are cancerous regions whose visualization is made more facile by the presence of the highly paramagnetic gadolinium(III) cation contained in the texaphyrin core.  The black regions appearing  where  the  cancer  was  originally  present  are  ascribed  to  non-malignant,  but  not  completely regenerated tissue. 

Further  study  will  be  required  to  assess  the  utility  of  Gd-Tex  in  terms  of  effecting  prolonged survival,  improved  local  response, etc. for this  and  other  cancers. However, it is already clear that it localizes very selectively to solid tumors and  could  provide  the  basis  for  developing  new,  improved cancer-selective  imaging  agents.    Current work, therefore, involves generating new analogues of texaphyrin, including  ones  that  are  based  on  diflormylpyrroles  and dipyrrolylmethanes  and  thus  far simpler to make, and testing them as disease-selective markers.  This is being done using systems that both  contain  paramagnetic  metals  (for  MRI  detection)  and  ones  that  contain  either  light,  diamagnetic cations, or no metals at all (to permit fluorescence-based detection). Collaborations within the IGERT group have proved instrumental in terms of testing the properties of several of the new systems that have been prepared to date and will likely continue to prove essential for future success.

            Another  important  example  is  the  use  of  molecular  imaging  to  monitor  the  efficacy  of  gene therapy.  One of the fundamental limitations in the area of gene therapy has been the inability to monitor the pathway of DNA transport in tissues and inside subcellular compartments. The Roy lab, which is involved in polymer-controlled delivery of DNA vaccines, is interested in the development of effective labeling techniques for therapeutic genes and coupling them with highly sensitive microscopic and in vivo imaging techniques in order to monitor DNA transport.  This work will be performed both on the cellular and subcellular levels as well as in in vivo animal models following gene delivery via different routes.  For  example,  combining  the  fiber-optic  confocal microscope developed by the Richards-Kortum lab, polymeric microparticles, which  are  highly  scattering,  could  be  monitored  in  vivo  following transcutaneous delivery. Similarly high resolution microscopic techniques developed by several groups within the IGERT program, coupled with novel labeling techniques for DNA can answer fundamental questions about DNA transport in the cell. 

Other complementary imaging techniques are being explored to image gene expression in vivo.  Dr. Kundra recently established a lab at MD Anderson focused on imaging gene expression in vivo using radiologic and nuclear medicine techniques. Dr. Juri Gelovani will join MD Anderson as Chair of the Dept. of Experimental Diagnostic Imaging in July 2003. His research interests include quantifying gene transfer and expression in vivo using PET, magnetic resonance spectroscopy and optical methods.

Another  important  area  of  research  within  this  IGERT  program  is  monitoring  in-situ  cell differentiation and growth within tissue engineering scaffolds.  For example, the Roy lab is developing micro-fabricated polymer scaffolds with precise spatio-temporal distribution of biological factors to study stem cell differentiation into multiple lineages. Their goal is to create complex organ structures in vitro. It is imperative to be able to analyze the distribution patterns of bio-factors throughout these scaffolds in real time and with high resolution to ensure optimal distribution of differentiation factors. Furthermore, following  stem  cell  seeding,  the  efficacy  of  the  scaffolds  to  create  multiple  cell  lineages  in  a  spatio-temporal pattern needs to be evaluated using high resolution, multi-dimensional imaging techniques.  

Promoting  neovascularization  subsequent  to  spinal  cord  injury  can  markedly  accelerate endogenous repair of the spinal cord, thereby supporting functional recovery and improved patient quality of  life.  Currently,  angiogenic  therapy  of  the  spinal  cord  is  hindered  by  the  inability  to  noninvasively assess spinal cord vascularization and to deliver angiogenic agents to the injury effectively.  A focus of our IGERT  renewal  program  is  to  combine  advanced  in vivo magnetic  resonance  imaging (MRI)  with neurobehavioral assessment, quantitative histometric analysis, and novel angiogenic delivery vehicles to provide a unique opportunity to investigate endogenous spinal cord repair and use the knowledge base to develop a clinically translatable strategy. Through collaboration between Professors Narayana, Schmidt, and Patrick, we are mapping the kinetics of neovascularization during spinal cord injury repair using in vivo, longitudinal dynamic contrast-enhanced MRI and correlating the results with the gold standard of quantitative immunohistochemical analysis. The resultant new MRI diagnostic tool will provide high resolution, noninvasive visualization and assessment of the spatial and temporal kinetics of angiogenesis within the spinal cord. Through collaboration with Professors Schmidt and Patrick, we are developing synthetic polymer hydrogels that possess precisely tuned angiogenic potentials amenable to placement at sites of traumatic insult to the spinal cord.

This interdisciplinary interaction that marries a novel diagnostic imaging tool with an innovative angiogenic  delivery  vehicle  to  provide  a  clinically  translatable  repair  strategy  provides  a  unique  and exciting  opportunity  to  train  graduate  students.   We  bring together the state-of-the-art in MRI, tissue engineering, drug delivery,  angiogenesis,  and  regenerative  medicine  to  permit  the  enhancement  and assessment of spinal cord repair. The proposed activities of this interaction provide a training platform that directly exposes students to the cross-fertilization of engineering, life science, and clinical science.  Drug delivery applications require analogous techniques to assess the distribution and function of drugs.  Dr. Nicholas Peppas is developing novel biomaterials-based agents for drug delivery. Microscopy  can characterize  the  physical structure  of  biomaterials, probe  for  small  molecules, and  assess  the  ultimate success of these techniques.  In  the  areas  of  cellular  and tissue  engineering,  it  is imperative  that  cell-based constructs  and  therapies  be analyzed for their ability to integrate and  function  in the  body.  Charles Patrick and Christine Schmidt focus on tissue engineering therapies for improving tissue function. For example, IGERT trainee Jessica Winter is using novel imaging probes (i.e., fluorescent quantum dots)  developed  by the Korgel lab to label nerve tissue and modulate nerve properties via electric fields for nerve regeneration. 

Working with Drs. Hazle and Chao, we will expand the multi-modal imaging approaches to plan and monitor therapeutics.  Dr. Hazle’s primary research interest is in the development of new MRI-guided therapeutic procedures.  MRI is capable of generating temperature maps in a few seconds, making it possible to target and monitor thermal therapies such as focused ultrasound in real time. Dr. Hazle’s group is developing more robust MRI sequences for temperature imaging, as well as new techniques for estimating the extent of treatment.  Dr. Hazle has established a new  program  in  experimental imaging research  to  implement  and  develop  instrumentation  and  techniques  for  imaging  small  animals.  Instrumentation  includes  a  new  state-of-the-art 4.7 T, 40 cm horizontal-bore Bruker Biospec magnetic resonance  imager/spectrometer,  an  Enhanced  Vision  Systems  micro-CT,  an  animal-optimized  gamma camera with SPECT capability, a micro-PET camera, microradiography devices, and a novel new volume computed  tomography  system  being  developed  in  collaboration  with  the  General  Electric  Corporate Research and Development center. Much of the research supported by the facility is related to the in vivo molecular imaging of cancer research.   Dr. Chao  is  examining  how  serial  CT  examinations  of  pelvic tissue can be registered into a single anatomic frame of reference for cumulative dose calculations to treat cervical  cancer  with  intracavitary  brachytherapy.  Pelvic soft-tissue structures undergo large deformations and displacements during the external-beam and multiple-ICT course of radiation therapy for locally advanced cervix cancer. These changes cannot be modeled by the conventional rigid landmark transformation method.  Dr. Chao’s  group  has  developed  deformable  anatomic  template  registration method,  to  successfully  describe  these  large  anatomic  shape  changes  before  and  after  ICT.  These promising modeling  results  indicate  that  realistic  registration  of  the  cumulative  dose  distribution to the organs (or targets) of interest for radiation therapy of cervical cancers is achievable.