Integrated Nanosystem for Diagnosis and Therapy


Project Number

HL080729

Active Period

Current PEN          2005-2010

Web Site

http://www.nhlbi-pen.info/

Budget

$12 Million ca.

Consortuim

Washington University in Saint Louis
University of California, Santa Barbara
University of California, Berkley

Principal Investigators

Karen L. Wooley, Ph.D.
James S. McDonnell Distinguished University Professor in Arts & Sciences
Department of Chemistry
Washington University in St. Louis
One Brookings Drive, CB 1134
St. Louis, MO 63130-4899
phone: 314-935-7136
fax: 314-935-9844
klwooley@wustl.edu


Aims

The central mission of this project is to develop a group of well-characterized and versatile nanoscale agents that can be assembled, labeled, targeted, filled, and activated as needed for the diagnosis and treatment of various diseases of relevance to the National Heart Lung and Blood Institute (NHLBI).

The overall experimental strategy is focus on biological models of acute pulmonary and systemic vascular injury (in vitro and in vivo) to demonstrate the effectiveness of these agents. Acute vascular injury and inflammation have been chosen as general targets since they affect tissues broadly, including those of the lung and cardiovascular system.

Specific aims for this project include:

Project 1:

  1. Optimize our existing nanomaterials for degradability, scalability and translation for IND submission;
  2. Optimize targeting ligand and nanomaterial carrier to achieve highest (pM) binding affinity and specificity;
  3. Design responsive, transformative nanostructures for targeted therapeutic delivery;
  4. Construct hierarchically-assembled, multi-functional nanoscale objects;
  5. Demonstrate unique triggering mechanisms for milieu-selective therapeutic release.

Project 2:

  1. Optimize antimicrobial efficacy;
  2. Achieve targeted delivery to the infectious organisms directly.

Project 3:

  1. Characterize and optimize NPs for efficient, non-toxic, intracellular delivery of PNA and siRNA;
  2. Use NPs to deliver PNAs and siRNAs in vivo to image and modulate transcription of iNOS in models of lung injury.

Project 4:

  1. Assess the in vitro binding and biodistribution of nanoconstructs targeting NPR-C synthesized in Project 1 and the Nanomaterials Production Core;
  2. Validate these nanoconstructs for imaging in rabbit and mouse models of atherosclerosis, angiogenesis and neo-intimal proliferation;
  3. Perform full toxicity testing and xIND submission with the CANF-comb, or the most promising compound targeting NPR-C;
  4. Perform two human study feasibility trials with the selected CANF nanoconstruct.

Developmental Project 1:

  1. Validate comb-vMIP-2 as a novel nanoagent to specifically target chemokine receptors;
  2. Utilize comb-vMIP-2 as a novel NP to image vascular inflammation related to de novo atherosclerosis and in response to acute vascular injury.

Developmental Project 2:

  1. Synthesize and characterize activatable NIR fluorescent dyes for ROS and NO in a degradable NP;
  2. Test NIR fluorescent NPs in vitro and for in vivo imaging.

Nanomaterials Production Core:

  1. Provide cost-effective, state-of-the-art instrumentation and facilities for the large-scale preparation of functionalized nanomaterials leading to increased availability;
  2. Develop standard procedures for the purification of nanomaterials suitable for in vivo studies;
  3. Act as a central repository for all nanomaterial samples and data;
  4. Facilitate research opportunities in nanomaterial research through coordinated access and visitations to the Core by PEN researchers.

Skills Development Core:

  1. Formulate science curricula for enhanced learning;
  2. Expand the scope and impact of outreach activities;
  3. Cross-train PEN personnel to create interdisciplinary scientists who are experts in their primary discipline (chemistry, biology, medicine, etc.), yet well-versed in other areas of nanoscience;
  4. Disseminate nanotechnology results and expertise through publications, patents, workshops and seminars.

Administrative Core:

  1. Provide strong leadership through an active and effective management structure;
  2. Facilitate communication via an innovative combination of in-person and web-based meetings and tools;
  3. Solicit and oversee institutional support and infrastructure.

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