• Georgia Tech, Emory, UCD
• Mt. Sinai, MIT, BWH, Columbia, NYU
• MGH, Harvard, BWH, MIT, Broad
• WUSTL, TAMU, UCB, UCSB, UTSW

Integrated Nanosystem for Diagnosis and Therapy

Aims

This PEN will produce integrated nanosystems for the diagnosis and treatment of pulmonary and cardiovascular diseases. The nanomaterials are tailored with specific sizes, shapes and compositions, identified from years of developmental work experience, to provide for enhanced imaging and treatment of lung infectious diseases, acute lung injury, and atherosclerosis. A balance of fundamental and translational research studies and skills development activities are proposed through collaborative interactions among a diverse team of investigators working on four Projects, two Developmental Projects and three Cores, as outlined here and detailed throughout this proposal.

Specific aims for this project include:

Project 1 Aims:

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

Project 2 Aims:

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

Project 3 Aims:

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

Project 4 Aims:

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

Developmental Project 1 Aims:

• Validate comb-vMIP-2 as a novel nanoagent to specifically target chemokine receptors;
• 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 Aims:

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

Nanomaterials Production Core Aims:

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

Skills Development Core Aims:

• Formulate science curricula for enhanced learning;
• Expand the scope and impact of outreach activities;
• 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;
• Disseminate nanotechnology results and expertise through publications, patents, workshops and seminars.

Administrative Core Aims:

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