A variety of novel nanomaterials have recently been developed with primary in vivo distribution to macrophages and macrophage subtypes. These materials have been used for the diagnosis of diseases where macrophages play a critical role in pathogenesis. For example, we have developed fluorescently labeled dextran-based superparamagnetic iron oxide (magnetofluorescent) nanoparticles detectable by magnetic resonance and optical imaging and have used them for macrophage targeting in lymph nodes, atherosclerosis, rheumatoid arthritis, diabetes and other diseases. Clinical trials with some of these materials are currently ongoing. Macrophages, in particular activated macrophages, are a key component of atherosclerotic vessels and can constitute up to 10-20% of the cells present within the culprit lesions. Macrophages secrete proteolytic enzymes which cause degradation of fibrous caps, promote atherothrombosis, and/or play other key roles in the progressive inflammatory cascade. We originally hypothesized that selective """"""""silencing"""""""" of activated macrophages could lead to long lasting therapeutic effects. Thus, we have conjugated light-activatable therapeutic moieties to the nanoparticles. In one specific design we conjugated a novel, highly phototoxic chlorin (& = 0.6), and a near-infrared fluorophore (AlexaFluor 750, ex/em 749/775 nm) to the nanoparticle. When activated by laser irradiation at 650 nm, the nanoagent displays exquisite phototoxicity, with an LC50 of 14 nM. Preliminary results demonstrate superb accumulation and therapeutic efficacy of this nanoparticle in atherosclerotic lesions in apolipoprotein E knockout (ApoE-/-) mice following systemic injection and light treatment. The challenge now is to develop a clinically viable, next-generation nanoplatform and ascertain its potential utility in the detection and treatment of atherosclerotic vascular disease. Prior screens have identified polyvinyl alcohol (PVA) as a highly promising coating material, and results in nanoparticle preparations that are both biostable and biocompatible. The overall goal of the proposed research is to synthesize and fully characterize a novel theranostic (therapeutic and diagnostic) nanomaterial based upon PVA coated iron oxide nanoparticles. The in vitro and in vivo efficacy of the nanomaterial will be elucidated with respect to both the imaging and therapeutic functionalities. Within these studies, we will also explore the role of focal macrophage ablation on the stasis of the atherosclerotic lesions at the cellular level, and possible modulatory effects on circulating monocytes. The impetus for these studies is the belief that the combination of diagnostic and therapeutic functionalities within one multifunctional nanoparticle has the potential to revolutionize the prevention of coronary syndromes.

Public Health Relevance

The overall goal of this research is to build upon our preliminary data with respect to the therapeutic efficacy of a theranostic agent in the diagnosis and treatment of atherosclerotic vasculature. In particular, we will: 1) synthesize and characterize a novel therapeutic nanoagent, 2) determine its in vivo efficacy in a murine model of atherosclerosis, and 3) investigate the local and systemic effects of focal macrophage ablation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL093607-02
Application #
7844969
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Danthi, Narasimhan
Project Start
2009-07-01
Project End
2011-12-30
Budget Start
2010-07-01
Budget End
2011-12-30
Support Year
2
Fiscal Year
2010
Total Cost
$221,250
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
McCarthy, Jason R; Sazonova, Irina Y; Erdem, S Sibel et al. (2012) Multifunctional nanoagent for thrombus-targeted fibrinolytic therapy. Nanomedicine (Lond) 7:1017-28
McCarthy, Jason R; Jaffer, Farouc A (2011) The role of nanomedicine in the imaging and therapy of thrombosis. Nanomedicine (Lond) 6:1291-3
McCarthy, Jason R (2010) Nanomedicine and Cardiovascular Disease. Curr Cardiovasc Imaging Rep 3:42-49
McCarthy, Jason R (2010) Multifunctional agents for concurrent imaging and therapy in cardiovascular disease. Adv Drug Deliv Rev 62:1023-30
McCarthy, Jason R; Bhaumik, Jayeeta; Karver, Mark R et al. (2010) Targeted nanoagents for the detection of cancers. Mol Oncol 4:511-28
McCarthy, Jason R; Korngold, Ethan; Weissleder, Ralph et al. (2010) A light-activated theranostic nanoagent for targeted macrophage ablation in inflammatory atherosclerosis. Small 6:2041-9