ReviewNanomedicine for the prevention, treatment and imaging of atherosclerosis
Introduction
Cardiovascular diseases (CVD) are considered to be the pandemic of the 21st century. The spectrum of CVD includes coronary artery, cerebrovascular and peripheral vascular disease [1]. These impose a significant healthcare burden globally, particularly in the industrialized countries. The World Health Organization (WHO) estimates that 18 million people die each year from CVD. By 2030, CVD will account for 24 million deaths annually worldwide despite advances in cardiovascular and drug research [1].
Atherosclerosis is induced by a low-grade inflammatory process in the vascular wall, leading through various steps to the eventual formation of atheromatous plaque (Fig. 1) [2], [3]. It predominantly affects the vessel intima (the innermost vessel layer) and is associated with cholesterol and lipid deposition with infiltration of inflammatory cells. With improved understanding of its pathophysiology, the theory to account for atherogenesis has evolved overtime. Endothelial injury triggers a compensatory response, which leads to inflammatory cell infiltration. In addition, low density lipoprotein (LDL) retention and matrix interaction in the subendothelial space is the inciting event in atherogenesis. Oxidized LDL (oxLDL) is the central element to atherosclerosis. It acts as a potent chemo-attractant for circulating monocytes. These inflammatory cells penetrate the subendothelial space, acquire phenotypical characteristics of macrophages and, by up-taking oxLDL via scavenger receptor pathways, produce cholesterol-ester laden foam cells [3]. Over time mature lesions accumulate and form atherosclerotic plaques which may manifest clinically due to plaque related complications.
Expansion of atherosclerotic plaques may lead to gradual narrowing of the lumen and eventually occlusion of the vessel. Clinical symptoms related to such chronic progression are due to the oxygen supply–demand mismatch to the organs affected by restricted blood circulation. For example, patients with stable CAD typically complain of angina triggered by physical exertion. Atherosclerotic plaques may also become progressively unstable due to local reaction to pro-inflammatory cytokines and proteinases, leading to plaque ulceration or rupture. The exposed lipid core is highly pro-coagulant and predispose to acute thrombosis of the vessel lumen. This manifests clinically as acute vascular syndromes, such as acute myocardial infarction (AMI) or stroke, depending on the vascular territory affected by the disease [4].
Atherosclerosis is a multi-factorial disease and many different approaches have been attempted for its prevention and treatment. There is an expanding demand for the development of novel drug delivery systems (DDSs) with the ability to target specific tissues or cell types. Recent advances in nanotechnology has provided novel insights to disease prevention and made possible different approaches to the treatment of atherosclerosis.
Nanoparticles are particles with diameter from 1 to 100 nm although the dynamic range can cover the whole nm scale. The ideal size for a DDS ranges from 10 to 100 nm [5]. They can be classified into several categories, according to their shape (nanospheres, nanotubes, dendrimers, linear, block, graft – Fig. 2), physicochemical properties (pH sensitive, magnetic, stealth nanoparticles) and the materials used for its synthesis (natural, synthetic, hybrid, or gold nanoparticles) [6]. Their small size confers several intriguing physical, optical, mechanical and chemical properties that are completely different to materials of the macrocosmic realm. One such example is their ability to freely traverse through the body and target a desired location without being recognized as “intruders” from the immune system. For example, they are able to interact and affect cell and tissue physiology by subsequently undergoing surface chemical modification.
DDS allows for safe delivery of drug product by combining nanomaterials to bioactive molecules or drugs, which may otherwise have poor pharmacokinetics or are toxic to living cells. Such techniques can be used in order to precisely control different aspects of drug efficacy such as pharmacokinetics, bioavailability, targeted delivery, non-specific toxicity and immunogenicity. DDS demonstrate several advantages over conventional treatments of disease and have been increasingly applied in a multimodal approach [7].
An effective DDS should ideally be constructed in a pattern, which mimics an in vivo physiological equivalent and can be used for local or systemic administration. Depending on the specific application, adjustments can be further made to the hydrophilicity, lipophilicity, DDS to drug binding, bioavailability, biocompatibility and shape [8].
Section snippets
Nanodevices for the treatment of atherosclerosis
Recent advances in nanodevices for nanomedicine have been largely achieved by either combining older treatment methods with newer nanoparticle technology, or by implementing entirely novel techniques that have shown significant promise in the field (Table 1).
Nanoparticles for imaging and therapeutic applications
Nanomedicine has also contributed to the field of atherosclerotic plaque imaging and help diagnosis of the disease. A range of molecular and cellular imaging techniques have been applied to imaging techniques, such as ultrasound (US), MRI, positron emission tomography (PET), computed tomography (CT), and single photon emission computed tomography (SPECT) [59]. The materials used to enhance imaging of inflammation and atherosclerotic plaques including liposomes [60], polyamidoamine (PAMAM) and
Nanotechnology for ex vivo and in vivo biomarker detection
Biomarkers include circulating molecules that can provide diagnostic or prognostic value to a disease state. Biomarkers have become progressively powerful tools for the early detection of several disorders, enabling early and effective treatment of diseases [68]. The ideal biomarker should have high sensitivity and specificity and can be performed at a relatively low cost [68]. Several biomarkers have been used to identify high risk populations in CVD. These include C-reactive protein (CRP) [69]
Nanotoxicology
The unique advantages of nanoparticles also account for some of their limitations. Nanoparticles demonstrate distinct differences compared to larger particles due to their miniscule size. Nanotoxicology is an emerging field of science aimed to assess safety risks of the materials involved in nanotechnology. The potential toxicity of the nanomaterials can be hard to assess since it requires thorough examination of each material individually and their combinations as well. Nanoparticle toxicity
Conclusion
Over the last few years there have been tremendous advances in the field of nanomedicine, mainly driven by the promising results from pilot studies. Given the infancy status in its development, new breakthroughs in the field may appear in the near future. New nanomaterials and techniques are becoming available to improve bioavailability, drug loading capacity and specific tissue targeting efficiency, as well as to limit biodegradation product toxicity. The range of possible applications of
Contributors
Costas Psarros: drafted the manuscript; Regent Lee: contributed to the writing of the manuscript; Marios Margaritis: contributed to the writing of the manuscript; and Charalambos Antoniades: made critical revisions to the manuscript/supervision.
Competing interests
No competing interests.
Provenance and peer review
Commissioned and externally peer reviewed.
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