There is an ever-increasing knowledgebase concerning the molecular signatures of specific diseases and their potential in personalized medicine, however, the translation of this information into clinical applications lags significantly behind. To bridge this gap, so-called "theranostic" materials are sought after to combine diagnostic and therapeutic agents within single systems. Nanomaterials provide a powerful platform for combining such functions. Indeed, the intense interest in nanoscale vehicles designed for targeted delivery and detection in vivo is predicated on the idea that such materials may infer their pharmacokinetic, bioavailability and targeting properties on small molecules and other cargo. Therefore, nanoscale packaging strategies aim to alleviate dose-limiting side effects associated with many otherwise clinically effective chemotherapeutic drugs presenting a major hurdle in the treatment of cancer. In addition, targeting diagnostics efficiently and selectively to given tissues while avoiding non-specific accumulation greatly enhances signal to noise in vivo imaging applications leading to more effective and accurate diagnoses. The naturally efficient targeting and infectious properties of biological disease vectors, in particular viruses, has made them models in efforts to design and develop synthetic and semi synthetic nanoscale vectors for targeted drug delivery. Therefore, research has focused on the development of appropriately decorated spherical particles of various sizes, degradability profiles, surface chemistry and material constitution. More recently, an increasing ability to synthesize complex nanoscale structures has inspired investigations into how shape can affect synthetic nanoscale particle interactions with cells and their behavior in vivo. The intriguing shape and size dependence of these key properties of delivery vectors inspires our proposal to develop polymeric materials capable of assembling into nanoscale objects in response to specific disease associated biochemical stimuli. These materials seek to combine the blood circulation and rapid clearance profiles of relatively low molecular weight polymers from normal tissues, with rapid accumulation and slow clearance rates of nanomaterials in tumor tissue. This approach utilizing switchable, transformable morphologies of smart polymeric materials is proposed as a new design paradigm in targeted diagnostic and therapeutic delivery. Therefore, we propose the development of a novel class of materials capable of switchable, programmed pharmacokinetic and targeting profiles in vivo.
We aim to study differential uptake into particular tissue types via MRI-based imaging together with fluorescence-based imaging for materials optimization and in vivo analysis. Our long-term goal is to develop programmable stimuli-responsive nanomaterials for detecting and treating disease. The objective herein is to develop an approach for the selective in vivo assembly of nanoscale objects with detectable properties unique to the assemblies;we term this approach Enzyme- directed Assembly of Particle Theranostics - EDAPT.

Public Health Relevance

The ability to accurately target diseased tissue to diagnose and treat patients remains a key challenge. This proposal aims to develop agents that use enzymes generated in diseased tissues to assemble within the tissue, to serve as nanoscale indicators for imaging and for targeting toxic anticancer drugs. This is a novel approach with broad implications for programmed;smart theranostics for tackling as yet unsolved problems in the treatment of human disease.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Nanotechnology Study Section (NANO)
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Krosnick, Steven
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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