2010-2015 Initial PEN
Brigham and Women's Hospital
Massachusetts General Hospital
Massachusetts Institute of Technology
$16.8 Million ca.
Ralph Weissleder, MD, Ph.D.
Professor of Systems Biology and Radiology
Center for Systems Biology
Massachusetts General Hospital
Richard B. Simches Research Center
185 Cambridge Street
Boston, MA 02114
The overall goal of this NHLBI funded Program (PI: R. Weissleder) is to create and support a highly multidisciplinary team of expert chemists, biologists, engineers and physicians to develop and rapidly translate new nanotechnologies to better diagnose and treat heart, lung and blood disorders. The current team includes investigators from the Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH), Harvard Medical School (HMS), Harvard School of Engineering and Applied Sciences (SEAS), Massachusetts Institute of Technology (MIT) and the Broad Institute of Harvard and MIT. Specific applications of nanotechnology in this application include molecular imaging and sensing, drug delivery, targeted therapies and nanosensors. Powerful chemical biology approaches are being used to functionalize nanomaterials and to test their biosafety at unprecedented throughputs.
Specific aims for this program include:
Project 1: Novel nanomaterials
Nanomaterials have enjoyed widespread use as optical imaging agents because they can be synthesized and rapidly adapted in modular fashion, exploit multivalency of attached affinity ligands for improved avidity, designed as smart sensors, incorporate therapeutics (theranostics) and often be detected by multiple imaging techniques (multimodality imaging). Unfortunately, many available nanomaterials require excitation in the visible range or when labeled with organic fluorochromes exhibit narrow stokes shifts between excitation and emission. Ideally, fluorescent nanoparticles would be excitable in the infrared and exhibit very large Stokes shifts. The main focus of this project is twofold: a) investigation and development of novel materials with unique photophysical characteristics on the nanoscale to overcome current limitations of limited target-to-background of fluorescent nanoparticles and b) addressing how complex live systems such as mammalian cells interact with and process these novel materials. Both aims are highly relevant as they aim at creating new nanomaterials with improved sensing capabilities and better understanding how mammalian cells process these and other nanomaterials.
Project 2: Nanoparticle libraries for the discovery of cell-specific imaging probes for cardiovascular disease and therapy
The goal of this project is to extend powerful nanoparticle library approaches to the discovery of novel targeted nanoparticles for specific cell types important for cardiovascular disease studies, patient phenotyping and therapeutic discovery. Existing cell-specific nanoparticles largely image cells of the monocyte/macrophage lineage because of their phagocytic properties. To remedy this limitation and expand the repertoire of targetable agents to other cell types important for heart-lung-blood disease, we have developed an integrated, generalizable nanoparticle discovery pipeline that includes synthesis of libraries of small molecule-nanoparticle conjugates, high-throughput screening of these libraries for specific binding activity, detailed kinetic binding studies that elicit structure-activity relationships for nanoparticle design, and the discovery of agents that target specific cell types in vitro and in vivo. This Project seeks to apply this library-based technology to two discrimination problems of intense biologic and therapeutic interest in cardiovascular disease.
Project 3: Development of macrophage targeted 18F-PET nanoparticles for imaging of vascular inflammation
This project focuses on the synthesis of macrophage targeted, clinically viable nanoparticle preparations for 18F-PET imaging. The broader goal of the project is to develop targetable nanoparticle platforms for improved detection and imaging of a variety of molecular targets associated with cardiovascular and pulmonary diseases. We have previously labeled nanoparticles with 64Cu for in vivo PET imaging. While this is a reasonable strategy for imaging of long half-live synthetic materials and biologicals (such as nanoparticles or antibodies), 64Cu labeling has a number of disadvantages. Importantly, it is not as readily available as other PET isotopes, is not easily combinable with click chemistries for target attachment (using Cu(I) catalysts) and organ exposure can be dose limiting. For this and other reasons (cost, ease of use, clinical translation), we have investigated 18F nanoparticle labeling techniques, in particular “click chemistries”. While our proof-of-principle experiments are highly encouraging, there is considerable room for improvement. First, we wish to further improve the specific activity of 18F labeled nanoagents to drastically decrease the injected dose (microdosing). Second, we wish to improve the 18F labeling yield while decreasing the conjugation time, minimizing the number of steps required for purification and automating the whole procedure with a view towards clinical scale-up. Third, to account for the faster decay of 18F compared to 64Cu, we wish to modulate the in vivo pharmacokinetics of nanomaterials to allow for earlier imaging following injection than is currently possible.
Project 4: Theranostic nanotechnology approach to the management of cardiac transplantation complications
Cardiac transplantation remains the ultimate intervention for treatment of advanced heart failure, a disease of increasing prevalence worldwide. Two major complications limit the long-term survival of cardiac allografts. Acute rejection, characterized by an aggressive immune response, causes myocardial necrosis that can impair severely the contractile function of the allograft and lead to graft failure. Repetitive episodes of non-fatal parenchymal rejection can set the stage for a second major complication that limits the longevity of cardiac allografts: transplantation arteriopathy or graft vascular disease. This more chronic process also involves an inflammatory response, but one of a more prolonged and smoldering nature. We propose to explore a theranostic approach that will not only permit visualization of the rejection process but also use targeted nanoparticles to deliver therapeutics that may quell parenchymal rejection by acting locally. Such an approach may limit systemic toxicity of immunosuppressive or anti-inflammatory therapies. Moreover, we propose to adapt this concept to the use of targeted nanoparticle–mediated delivery of therapeutics to intervene on the development of chronic graft arterial disease.
Project 5: Rapid detection of infection using nanosensors
We have developed a handheld, diagnostic magnetic resonance (DMR) system that can perform rapid, quantitative and multi-channeled detection of biological targets including bacteria, cells, protein and DNA. The DMR system consists of a chip-based NMR (nuclear magnetic resonance) system arranged in an array format, microfluidics, an integrated CMOS (complementary metal oxide semiconductor) integrated circuit (IC) for signal processing, and a portable magnet. The system utilizes magnetic nanoparticles as molecular sensors that enhance the spin-spin relaxation of surrounding water protons, to achieve an inherent amplification of molecular interactions. Given this, the main objective of this project is to further advance the next generation DMR platform for the rapid detection of clinically relevant pulmonary infections, namely tuberculosis (MTB) and ventilator acquired pneumonia (VAP). These diseases were chosen because they pose considerable clinical challenges, because good/fast (“immediate results”) diagnostic tests are lacking, because the diseases are highly prevalent and/or expensive to society and because the availability of novel point-of-care (POC) technology could change the current clinical practice.