NANOTEMPLATE ENGINEERING OF A STEALTH MRI CONTRAST AGENT

DESCRIPTION (provided by applicant): The increasing costs of therapy and the demonstrated benefits of improved treatment efficacy with early detection are important incentives to develop tumor diagnostic agents of greater specificity and sensitivity. Paramagnetic gadolinium complexes are widely used as MRI (magnetic resonance imaging) contrast agents to improve sensitivity and/or specificity during MRI examinations which enable the acquisition of high resolution images. Due to the inherent volume dilution effect, most current contrast agents are limited to targeting sites where they can be expected to accumulate in high concentration, such as in the blood stream. The next generation agents of MRI contrast agents need to have higher relaxivities and specific targeting properties to overcome the volume dilution effect. NanoMed Pharmaceuticals, Inc. and its collaborators at the University of Kentucky will prepare a nanoparticle contrast enhancement agent for use in MRI. A microemulsion precursor will be employed to manufacture these nanoparticles by a readily scalable process using materials already approved for use in humans by the FDA. Surface modification will be used to impart stealth and targeting properties so that the nanoparticles can avoid clearance and be taken up preferentially by tumors. The Specific Aims of this Phase I proposal are to prepare pegylated biodegradable nanoparticles composed of FDA-approved materials that have an average diameter of 100-150 nm using a Nanotemplate Engineering method, prepare nanoparticles coated with Transforming Growth Factor-a for tumor targeting, demonstrate that 60% of the administered dose of pegylated/targeted nanoparticles are retained in the blood at 8 hr, and 30% at 24 hr after i.v. administration, produce a scaled-up batch of pegylated/targeted nanoparticles, and demonstrate sufficient contrast in vivo tumor MR images following administration of pegylated/targeted Gd- nanoparticles to tumor-bearing mice. The physical and magnetic properties pegylated and targeted nanoparticles will be measured in various media by NMR spectroscopic techniques. These measurements will aid in assessing the dose of Gd-containing nanoparticles required to provide sufficient contrast in MR images. We will also prepare Gd nanoparticles that have paclitaxel entrapped within the nanoparticle matrix that would allow these nanoparticles to serve as dual therapeutic/imaging nanovectors. These may be used in preclinical models and in clinical studies to test the hypothesis that nanoparticle drug delivery correlates with tumor response. The ultimate goal is to introduce a new contrast agent that provides superior MR images that allow for the early diagnosis of tumors and rapid intervention in the treatment of the disease. The increasing costs of therapy and the demonstrated benefits of improved treatment efficacy with early detection are important incentives to develop tumor diagnostic agents of greater specificity and sensitivity. NanoMed Pharmaceuticals, Inc., in collaboration with investigators at the University of Kentucky, proposes to use a novel method to produce stealth nanoparticles that provide superior MRI images that allow for the early detection of cancer.