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Aims: The activity of the transcription factor c-Myc is dependent upon heterodimerization with Max to control target gene transcription. Small-molecule inhibitors of c-Myc-Max have exhibited low potency and poor water solubility and are therefore unsuitable for in vivo application. We hypothesized that a nanomedicine approach incorporating a cryptic c-Myc inhibitor prodrug could be delivered and enzymatically released in order to effectively inhibit melanoma., Materials & Methods: An Sn-2 lipase-labile Myc inhibitor prodrug was synthesized and included in two αvβ3-targeted nanoparticle platforms (20 and 200 nm). The inherent antiproliferate potency was compared with the lipid-free compound using human and mouse melanoma cell lines., Results & Conclusion: These data demonstrate for the first time a successful nanodelivery of c-Myc inhibitors and their potential use to prevent melanoma.

As atherosclerosis remains one of the most prevalent causes of patient mortality, the ability to diagnose early signs of plaque rupture and thrombosis represents a significant clinical need. With recent advances in nanotechnology, it is now possible to image specific molecular processes noninvasively with MRI, using various types of nanoparticles as contrast agents. In the context of cardiovascular disease, it is possible to specifically deliver contrast agents to an epitope of interest for detecting vascular inflammatory processes, which serve as predecessors to atherosclerotic plaque development. Herein, we review various applications of nanotechnology in detecting atherosclerosis using MRI, with an emphasis on perfluorocarbon nanoparticles and fluorine imaging, along with theranostic prospects of nanotechnology in cardiovascular disease.

Background: The chemical instability of antiangiogenic fumagillin, combined with its poor retention during intravascular transit, requires an innovative solution for clinical translation. We hypothesized that an Sn-2 lipase-labile fumagillin prodrug, in combination with a contact-facilitated drug delivery mechanism, could be used to address these problems., Methods: α(v)β(3)-targeted and nontargeted nanoparticles with and without fumagillin in the prodrug or native forms were evaluated in vitro and in vivo in the Matrigel™ (BD Biosciences, CA, USA) plug model of angiogenesis in mice., Results: In vitro experiments demonstrated that the new fumagillin prodrug decreased viability at least as efficacious as the parent compound, on an equimolar basis. In the Matrigel mouse angiogenesis model, α(v)β(3)-fumagillin prodrug decreased angiogenesis as measured by MRI (3T), while the neovasculature was unaffected with the control nanoparticles., Conclusion: The present approach resolved the previously intractable problems of drug instability and premature release in transit to target sites.

Aim: To develop a fibrin-specific urokinase nanomedicine thrombolytic agent., Materials & Methods: In vitro fibrin-clot dissolution studies were utilized to develop and characterize simultaneous coupling and loading of anti-fibrin monoclonal antibody and urokinase onto perfluorocarbon nanoparticle (NP) surface. In vivo pharmacokinetics and fibrin-specific targeting of the nanolytic agent was studied in dogs., Results: Simultaneous coupling of up to 40 anti-fibrin antibodies and 400 urokinase enzymes per perfluorocarbon NP produced an effective targeted nanolytic agent with no significant surface protein-protein interference. Fibrin clot dissolution was not improved by increasing homing capacity from 10 to 40 antibodies/NP, but increasing enzymatic payload from 100 to 400/NP resulted in maximized lytic effect. Fluorescent microscopy showed that rhodamine-labeled urokinase nanoparticles densely decorated the intraluminal thrombus in canine clots in vivo analogous to the fibrin pattern, while an irrelevant-targeted agent had negligible binding., Conclusion: This agent offers a vascularly constrained, simple to administer, low-dose nanomedicine approach that may present an attractive alternative for treating acute stroke victims.

Aim: This study examines the effect of combining the antiangiogenic effect of αvß₃-targeted fumagillin nanoparticles with the conventional antirheumatic drug methotrexate for the treatment of inflammatory arthritis., Method: Arthritis was induced in mice by K/BxN serum transfer, and disease activity was monitored by clinical score and change in ankle thickness. Groups of mice received nanoparticles or methotrexate as single therapy or nanoparticles and methotrexate as combination therapy., Results: We found that animals treated with a pulse dose of fumagillin nanoparticles followed by methotrexate had significantly improved and sustained clinical response compared with those treated with either agent alone. Histological analysis confirmed a significant decrease in inflammatory cell influx, bone erosions, cartilage damage and angiogenesis with the combination therapy., Conclusion: Analysis of plasma cytokine levels suggests that fumagillin nanoparticles enhanced the systemic anti-inflammatory effects of methotrexate. Antiangiogenic nanotherapy may represent a promising approach for the treatment of inflammatory arthritis when combined with a conventional antirheumatic drug.

Aim: Receptor-specific small molecules and nanoparticles are widely used in molecular imaging of tumors. Although some studies have described the relative strengths and weaknesses of the two approaches, reports of a direct comparison and analysis of the two strategies are lacking. Herein, we compared the tumor-targeting characteristics of a small near-infrared fluorescent compound (cypate-peptide conjugate) and relatively large perfluorocarbon-based nanoparticles (250 nm diameter) for imaging alpha(nu)beta(3)-integrin receptor expression in tumors., Materials & Methods: Near-infrared fluorescent small molecules and nanoparticles were administered to living mice bearing subcutaneous or intradermal syngeneic tumors and imaged with whole-body and high-resolution optical imaging systems., Results: The nanoparticles, designed for vascular constraint, remained within the tumor vasculature while the small integrin-avid ligands diffused into the tissue to target integrin expression on tumor and endothelial cells. Targeted small-molecule and nanoparticle contrast agents preferentially accumulated in tumor tissue with tumor-to-muscle ratios of 8 and 7, respectively, compared with 3 for nontargeted nanoparticles., Conclusion: Fluorescent small molecular probes demonstrate greater overall early tumor contrast and rapid visualization of tumors, but the vascular-constrained nanoparticles are more selective for detecting cancer-induced angiogenesis. A combination of both imaging agents provides a strategy to image and quantify integrin expression in tumor tissue and tumor-induced neovascular systems.

Nanomedicine promises to enhance the ability of clinicians to address some of the serious challenges responsible for cardiovascular mortality, morbidity and numerous societal consequences. Targeted imaging and therapy applications with perfluorocarbon nanoparticles are relevant to a broad spectrum of cardiovascular diseases, ranging from asymptomatic atherosclerotic disease to acute myocardial infarction or stroke. As illustrated in this article, perfluorocarbon nanoparticles offer new tools to recognize and characterize pathology, to identify and segment high-risk patients and to treat chronic and acute disease.