Aims

There are six specific aims for this project:

Specific Aim #1: Preparation and assembly of programmed, integrated nanosystems.
We will develop nanoscale building blocks and assemblies (with varying structures, compositions and dimensions) that can serve as platforms from which ligands can be presented to achieve tissue selective targeting, and within which elements can be packaged for therapy or for molecular detection. Nanostructures will be synthesized and characterized as single function agents, as programmable multi- function agents, and as integrated systems. Mechanisms for controlled release of therapeutic agents and safe disposal of the carrier components will also be developed.

Specific Aim #2: Application of nanostructures for imaging at increased levels of sensitivity.
The nanostructures will be labeled with large numbers of detectable elements and targeting moieties that provide for increased optical, MR or radiolabel imaging. The increased sensitivity will be studied for nanostructures constructed to undergo selective interactions with cell surface receptors and also those that utilize intracellular targeting.

Specific Aim #3: Direct imaging of gene expression by recognition of mRNA transcription products.
We propose to develop antisense gene expression imaging agents for COX2 and iNOS as markers of inflammation and for therapeutic transgenes. The imaging/delivery agents will be constructed by linking a high affinity antisense PNA (peptide nucleic acid) to a nanoparticle that is adorned with a permeation peptide, such as TAT (HIV-1 Tat protein transduction domain), and an optical, MR or radiolabel imaging agent. The high affinity antisense PNA will be identified and verified by binding experiments in vitro and in vivo.

Specific Aim #4: Application of the nanostructures for therapy.
We will develop nanostructures for controlled delivery and triggered release of molecular therapeutics, including therapeutic transgenes. The nanoscale materials will be crafted to package therapeutic agents into selective domains within the host (nanostructure) and to possess release mechanisms that can be triggered by in vivo events and by external stimulation. The versatile nanostructures envisioned in this application will serve as non-viral alternatives for therapeutic gene transfer. We propose to develop nanoparticle-based gene transfer agents and to monitor their effectiveness through separate nanostructures targeting transgene mRNA and/or protein for imaging.

Specific Aim #5: Cross disciplinary education and training of medical and materials scientists.
We plan to develop a formal curriculum in the areas of nanotechnology and imaging sciences. Through new and existing courses, together with cross-disciplinary research experiences, we will mentor and train the next generation of scientists and clinicians to use nanotechnology in the treatment of disease. These individuals will be taught to integrate nanoscience, nanotechnology, biology and medicine creatively and proficiently.

Specific Aim #6: Serve a leadership role in the dissemination and translation of nanotechnology developments to unmet medical needs.
In addition to state-of-the-art research activities being conducted by leading researchers in each of the major disciplines, this PEN will disseminate techniques and applications broadly via publications, workshops, talks and web-based formats. The PEN will also actively promote cross-disciplinary research activities in the general areas of nanotechnology and HBL diseases at the host institutions and in the broader scientific and clinical communities.

The overall goal is to increase the interest and research activity in these critical areas far beyond the original PEN.