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Nanoparticles in endothelial theranostics
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PHAREP-350; No. of Pages 5 Pharmacological Reports xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep
Review article
Nanoparticles in endothelial theranostics Szczepan Zapotoczny, Krzysztof Szczubiałka, Maria Nowakowska * Faculty of Chemistry, Jagiellonian University, Krako´w, Poland
A R T I C L E I N F O
Article history: Received 9 February 2015 Received in revised form 18 May 2015 Accepted 20 May 2015 Available online xxx
A B S T R A C T
The paper presents the recent advances in the development and studies of multifunctional nanoparticles which can be used to prevent/cure the cardiovascular diseases by detecting, treating and monitoring the early stages of atherosclerotic and thrombotic changes in endothelium. ß 2015 Published by Elsevier Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.
Keywords: Nanoparticles Theranostics Cardiovascular diseases Atherosclerosis Thrombosis
Contents Introduction . . . . . . . . . . . . . . Nanotheranostic strategies in Atherosclerosis . . . . . . . . . . . . Thrombosis. . . . . . . . . . . . . . . Toxicity/safety . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . Funding . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . .
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Introduction Development of nanotechnology affected many areas of human activity, including medicine. Application of nanotechnology in medicine resulted in the advent of nanomedicine which revolutionized both diagnostics and therapy. Nanomedicine utilizes materials and devices of nanometric dimensions, often prepared via operations carried out on the molecular level. The properties of such systems are quite different than these characteristics of the macroscopic ones and can be adjusted to the specific needs [1]. Nanoparticles are the most popular nanostructures utilized in
* Corresponding author. E-mail address: [email protected] (M. Nowakowska).
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nanomedicine. They have tunable electronic, optical, magnetic and biological properties. Nanoparticles can be manufactured as the objects of various chemical composition, surface characteristics, size and shape. They can be prepared from various materials such as metals, metal oxides, silica, natural and synthetic polymers, carbon, lipids and biomolecules. They can exist as hollow, porous or solid structures of different morphologies such as spheres, cylinders, tubes or platelets [2]. Nanoparticles can be loaded with various substances, e.g. drug molecules. These objects have large surface area per unit of volume what is particularly important for their interactions with other objects/(bio)surfaces. The nanoparticle surface can be tailor-made or designed to address specific needs. The modification can involve attaching the specific ligands/ antibodies/peptides allowing active drug delivery to the targeted tissue as well as the prolonged circulation in the blood, thus
http://dx.doi.org/10.1016/j.pharep.2015.05.018 1734-1140/ß 2015 Published by Elsevier Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.
Please cite this article in press as: Zapotoczny S, et al. Nanoparticles in endothelial theranostics. Pharmacol Rep (2015), http:// dx.doi.org/10.1016/j.pharep.2015.05.018
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increasing the probability of the passive drug delivery, e.g. by the Enhanced Permeability and Retention (EPR) effect in the abnormal vasculature of the cancer tissue. Recently, there has been a considerable effort to use the same nanoparticles for multimodal diagnosis and therapy, which include targeted drug delivery and its sustained and/or controlled release (Fig. 1). Such integration of both of these medical procedures was named ‘‘theranostics’’. The most often used nano-sized materials for theranostic purposes include: polymeric, lipid-based or metal oxide nanoparticles, dendrimers and cage proteins [3–6]. These nanoparticles are attractive for the theranostic applications, mainly because of their ability to be located in pathological lesions rather than in normal tissues, particularly in the case of cancer or in dysfunctional endothelium [7,8]. It is believed that theranostic approach can improve the outcome and increase the safety of medical procedures. It should allow identification and treatment of the diseases at their earliest stage when the chances for patient’s recovery are relatively high and to monitor/correct the treatment. In that regard, theranostics can be very helpful in the development of personalized medicine which replaces the standard diagnostic and therapeutic strategies by individualized approach taking into account the inter-individual variability in therapeutic response. Recently, there has been a growing interest in the potential application of the personalized treatment for widely spread and difficult to cure degenerative diseases such as cancer, neurodegenerative disorders and cardiovascular diseases. To develop that person-oriented and disease-oriented theranostic treatment for all these diseases, one has to design and synthesize the multifunctional nanoparticles and study their interactions with endothelium, the thin continuous layer of cells lining the luminal surface of blood vessels which is the interface between circulating blood and the vessel wall. Thus, endothelium is the first contact point for nanoparticles, especially when introduced via injection, but also serves as a barrier protecting extravascular sites. It is a main target in the treatment of inflammation, neurological, cardiovascular (ischemia, thrombosis and stroke), pulmonary and oncological diseases. In the current paper, we discuss the recent advances in nanotheranostics of early stages of cardiovascular diseases.
Fig. 1. Schematic structure of nanoparticles/nanocapsules for biomedical applications.
Nanotheranostic strategies in cardiovascular diseases Cardiovascular diseases (CVD) are the leading cause of morbidity/mortality worldwide. Each year CVD account for over 4 million deaths in Europe and over 1.9 million deaths in the EU. It is predicted that in 2030, the number of CVD-related deaths will increase to 23.6 million world-wide [9]. There is a number of identified causes, both biological and environmental, for the development of these diseases. Although the medical procedures were considerably improved in the last decades, their general therapeutic results are not satisfactory. That is mostly due to the fact that the therapy is implemented when the disease is already advanced, or quite often even after it has been manifested in cardiovascular events (such as myocardial infarction (MI) or stroke). It should be also noted that some patients do not respond positively to the currently used treatment. Thus, there is a need for the sensitive and possibly noninvasive procedures allowing detection of these diseases at the early stage and for novel drugs/therapeutic methods [10]. Atherosclerosis As the majority of CVD start from the atherosclerosis, which has been recognized as an inflammatory-type disease, the tools for its detection and inhibition are necessary [11,12]. Currently, atherosclerosis is diagnosed at the advanced stages by direct measurements of degree of stenosis, or indirectly, by the determination of the effect of arterial stenosis on organ perfusion. However, even at the early stages of atherosclerosis, there are considerable changes in endothelium structure and chemistry– the gaps between endothelial cells are formed leading to increased endothelial permeability and the level of the expressed adhesion molecules is growing. Those changes induce accumulation of low-density lipoproteins and activated macrophages followed by adhesion of extracellular proteinases, apoptotic cells and free radicals, resulting in building of atherosclerosis plaques. The progression of the plaque formation induces the hypoxiadriven angiogenesis leading to the formation of new blood vessels. In the final stage of atherosclerosis, the components of plaques are exposed to blood and induce thrombosis manifested by the clinical symptoms, such as MI or stroke. Surprisingly, there have been only very few studies on atherosclerosis detection based on monitoring the level of inflammatory biomarkers. There is, however, much more activity on improvement of the sensitivity and efficiency of various molecular imaging techniques, such as magnetic resonance imaging (MRI), optical fluorescence imaging (OFI) or positron emission tomography (PET). Recent progress in MRI was possible due to the application of properly designed and synthesized contrast agents. There are so-called positive and negative MRI contrast agents. The former ones reduce proton longitudinal relaxation time, T1, providing the positive contrast (bright signal), while the latter ones are T2 agents that shorten proton transverse relaxation time causing negative contrast (dark signal) [13]. Positive contrast agents are typically paramagnetic compounds, usually gadolinium complexes or manganese ions, while superparamagnetic materials, mainly these based on iron oxide nanoparticles, act as the negative contrasts [14,15]. It is believed that dual-mode T1–T2 contrast agents, combining the advantages of positive and negative contrasts, may improve diagnosis [16,17]. Nanostructural materials were shown to have clear advantages over conventional MRI agents. Nanometer dimensions of these materials have considerable impact on magnetic properties and ability to operate on cellular level [18–21]. Originally, single functional superparamagnetic iron oxide nanoparticles (SPION) with size of 100 180 nm and ultrasmall superparamagnetic iron
Please cite this article in press as: Zapotoczny S, et al. Nanoparticles in endothelial theranostics. Pharmacol Rep (2015), http:// dx.doi.org/10.1016/j.pharep.2015.05.018
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oxide nanoparticles (USPIO) with size of 40 60 nm were synthesized and shown to be the effective MRI contrast agents. That was followed by the development of multifunctional nanoparticles both holding various diagnostic functionalities, targeting ligands and carrying drug agents. That allows simultaneous application of several imaging techniques, application of a drug and facilitates following the progress of therapy and its respective correction. It has been shown that USPIO conjugated to the ligands targeting endothelial cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) or selectins can be used for noninvasive identification of expression of these compounds indicating early stages of atherosclerosis [22–25]. They have been also used for in vivo MRI detection of vulnerable atherosclerosis plaques in humans and animals (rabbits) [26–29]. That was effective because plaques contain various inflammatory cells, in particular macrophages, which can take up (via phagocytosis) USPIO. These nanoparticles can also interact with deposits of other types such as lipids and these formed as a result of endothelial inflammation. As the macrophages can lead to inflammatory atherosclerotic plaques destabilization and disruption, resulting in MI and stroke [30], their monitoring is essential for identifying and treating the vulnerable plaques, the immediate cause of these life-threatening complications [31,32]. The multifunctional, characterized by low systemic toxicity, imaging liposomal formulations containing glucocorticoids (L-PLP) have been developed and used to deliver the drugs to the atherosclerotic plaques and to follow up the delivery and track anti-inflammatory effects of these drugs in atherosclerotic lesions [33–35]. The in vivo experiments performed using the rabbit model with pronounced atherosclerotic lesions have shown significant and fast decrease in inflammation by a single injection of liposomeencapsulated glucocorticoids. The changes were visible already in 2 days after administration of that system and could be followed up for at least 7 days. The USPIO g Fe2O3 nanoparticles (with a mean hydrodynamic diameter of 21 nm) were used to detect and monitor the change in plaque inflammation induced by statin (atorvastatin) and dietary change in a rabbit model of atherosclerosis. A significant decrease of activated macrophage content within the atherosclerotic plaques of the group treated with atorvastatin compared with the untreated one was observed [36]. That corresponded well with the earlier observation on the role of atorvastatin on high-cholesterol-diet-induced atherosclerosis in humans and monitored using histological procedures [37]. The therapeutic approach proposed for high-risk patients is to stabilize atherosclerotic lesions by inducing regression. Stabilization of plaques was manifested with lowered density of intraplaque macrophages and increased interstitial collagen content [38]. The high-density lipoprotein (HDL) nanoparticles (10 2 nm) labeled with amphiphilic gadolinium chelates and functionalized with collagen-specific peptides were developed and used to monitor in vivo plaque compositional changes from high macrophage/low collagen to low macrophage/high collagen on plaque regression, in a Reversa mouse model of atherosclerosis regression. The results of these studies can facilitate the search for therapeutics and the methods of their application [39]. By using the iron oxide nanoparticles covered with protein and functionalized with LyP-1 peptide or receptor-targeted nanoparticles, one can image the endothelium lesions [39–42]. The polyclonal antibodies OxLDL conjugated to iron oxide nanoparticles have been demonstrated to be useful for in vivo MRI detection of perivascular carotid-collar-induced atherosclerotic lesions in ApoE-deficient mice [43]. The vulnerable plaques can be also detected by imaging the apoptotic cells. That was done using iron oxide nanoparticles decorated with annexin A5 [44]. Development of atherosclerotic plaque and progression of the disease is accompanied by neovascularization of the vessel wall accompanied with intraplaque hemorrhage, which increases the rate of plaque growth and
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induces destabilization [45–48]. Therefore, the inhibition of angiogenesis is considered as a potential therapeutic approach to plaque stabilization. Synthetic analogs of fumagillin have been demonstrated to inhibit angiogenesis [49]. Fumagillin was delivered to the aortic wall of rabbit using avb3-integrin-targeted paramagnetic nanoparticles and shown to inhibit neovascularization. The therapeutic process can be noninvasively assessed by MRI [50,51]. Thrombosis Advanced atherosclerosis can result in the formation around atherosclerotic plaques, in the lumen of the blood vessel, the thrombus (blood clot) which hinders the blood flow leading to hypoxia, or even anoxia and infarction. These can be manifested in a number of ways, the most common life-threatening events being stroke and MI (heart attack). The early diagnosis and treatment of thrombosis can reduce the probability of occurrence of these conditions [52]. Although the thrombosis is a quite complex phenomenon, it has been recognized that the specific binding of activated platelets and fibrinogen are essential steps in its pathway. That finding was crucial for the development of detecting tools, e.g. nanoparticles conjugated to fibrin targeting peptides have been demonstrated to be useful for that purpose [53,54]. The currently available thrombolytic therapy is not satisfactory. Intravenous therapy is the treatment of choice in thrombosis. The intravenous tissue plasminogen activator (IV tPA) was approved as the thrombolytic agent by FDA for use in acute ischemic stroke patients. It is recommended for up to 3 h from the symptom onset [55,56]. The European Cooperative Acute Stroke Study III (ECASS III) has shown that alteplase administered for up to 3 4.5 h after the onset of stroke symptoms resulted in significant benefits for the patients [57]. Although there are various clinically used antithrombotics (thrombolytics, anticoagulants and antiplatelet drugs), they suffer from a short half-life in plasma, a low targeting ability, and the tendency to induce hemorrhage. Thus, there is a search for targeted local thrombolytic therapy and for the systems allowing for targeted detection of thrombi, local drug supply and the dynamic monitoring of its thrombolytic efficiency. The in vitro studies have shown that tPA encapsulated in liposomes [58,59] or in poly(lactide-co-glycolide) (PLGA) nanoparticles coated with chitosan was more efficient in dissolving the blood clots than tPA in solution [60,61]. For magnetically targeted detection of thrombi and dynamic in vivo monitoring of the thrombolytic drug efficiency using MRI, the SPION conjugated with tPA have been synthesized [62,63]. To take advantage from the biochemical targeting, the surfaces of tPA containing nanoparticles were modified with cyclic arginine glycine aspartic acid (RGD) tripeptide. RGD is a receptor antagonist of platelet membrane glycoprotein GP IIb/IIIa that restrains the platelets from accumulation at the thrombus [64]. It has been shown that RGD conjugated to the surface of liposomes or PLGA nanoparticles loaded with tPA enhanced in vitro thrombolysis [59,65–67]. The thrombus-targeting nanoparticles with a dual function of early detection and treatment of a thrombus were also prepared. The systems were constructed from Fe3O4-based PLGA nanoparticles carrying recombinant tissue plasminogen activator (rtPA), coated with a film made of chitosan grafted with RGD. They showed good affinity to thrombi and exhibited strong thrombolytic and contrast-enhancing effects as seen using in vitro and in vivo experiments [68]. Toxicity/safety Before considering the clinical applications of nanoparticles, the studies on their toxicity are necessary. In that regard, the effect of
Please cite this article in press as: Zapotoczny S, et al. Nanoparticles in endothelial theranostics. Pharmacol Rep (2015), http:// dx.doi.org/10.1016/j.pharep.2015.05.018
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nanoparticles on the targeted tissue but also on other tissues/ organs exposed to the interactions with them during their circulation and clearance should be evaluated. Also, the cytotoxicity and immunogenicity of the possible products of nanoparticle biodegradation have to be determined [69]. Although these issues are not fully understood, it has been recognized that the parameters such as chemical composition, size, geometry, charge and type of surface affect the toxicity. Gadolinium-containing nanoparticles were shown to induce nephrogenic systemic fibrosis, which is particularly dangerous in patients with kidney problems [70]. SPION were demonstrated as being much safer [71]. They were shown to be non-cytotoxic for endothelial cells in vitro at concentrations below 0.1 mg/mL [72]. The in vivo studies showed that their intravenous administration leads to their accumulation in liver what may increase the amount of free iron and may increase probability of inflammation and oxidative stress [73]. The clinical study [74] indicated, however, that USPIO nanoparticles are cleared out of the atherosclerotic plaques within 6 months and no adverse effects following multiple USPIO infusions were observed, confirming that these particles are clinically safe and well tolerated [75]. Iron ions liberated from the inorganic cores during biodegradation may be also stored in nontoxic ferritin protein [76]. The problem can be also diminished by coating nanoparticles with biocompatible polymeric layer, such as dextran, chitosan or poly(ethylene glycol) [18]. One should be aware, however, that surface modification may result in nanoparticle aggregation, what usually increases their toxicity. The size of nanoparticles should be optimized depending on the purpose; for atherosclerotic theranostics, the nanoparticle diameter should not exceed 100 nm, because the larger nanoparticles have difficulties in penetrating the endothelium. Nanoparticles smaller than 5 nm can be dangerous as they can pass the blood-brain barrier (BBB) [77]. Conclusions Considering the growing threat CVD pose for worldwide population, the researchers and clinicians search for novel therapeutic approaches. Although in the last decades, a considerable progress in the CVD therapy was achieved, the clinical outcome is still not satisfactory, mainly because of late diagnosis. The diagnosis of early atherosclerotic changes, the initial step of most CVD, is thus essential. It requires novel methods and tools that can be provided by the development in nanotechnology. These allow for the personalized medicine and theranostics. Theranostics of CVD can be realized, thanks to the development of multifunctional nanoparticles which can be used to detect the inflammatoryrelated endothelium changes as well as to direct drug to the lesions in a targeted manner and to monitor the healing process (retardation of atherosclerotic plaques or induction of thrombolysis). The in vitro and in vivo experiments carried out using the animal models and some preliminary pilot studies in humans are very promising, however, much more has to be done to ensure the safety, both immediately after application and on a long-term timescale. Extended and careful toxicological and pharmacological studies are necessary before considering the application of nanoparticles in patients. Conflict of interest There is no conflict of interest. Funding This study was supported by the European Union from the resources of the European Regional Development Fund under the
Innovative Economy Programme (Grant coordinated by JCET-UJ, No. POIG.01.01.02-00-69/09).
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PHAREP-350; No. of Pages 5 Pharmacological Reports xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep
Review article
Nanoparticles in endothelial theranostics Szczepan Zapotoczny, Krzysztof Szczubiałka, Maria Nowakowska * Faculty of Chemistry, Jagiellonian University, Krako´w, Poland
A R T I C L E I N F O
Article history: Received 9 February 2015 Received in revised form 18 May 2015 Accepted 20 May 2015 Available online xxx
A B S T R A C T
The paper presents the recent advances in the development and studies of multifunctional nanoparticles which can be used to prevent/cure the cardiovascular diseases by detecting, treating and monitoring the early stages of atherosclerotic and thrombotic changes in endothelium. ß 2015 Published by Elsevier Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.
Keywords: Nanoparticles Theranostics Cardiovascular diseases Atherosclerosis Thrombosis
Contents Introduction . . . . . . . . . . . . . . Nanotheranostic strategies in Atherosclerosis . . . . . . . . . . . . Thrombosis. . . . . . . . . . . . . . . Toxicity/safety . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . Funding . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . .
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Introduction Development of nanotechnology affected many areas of human activity, including medicine. Application of nanotechnology in medicine resulted in the advent of nanomedicine which revolutionized both diagnostics and therapy. Nanomedicine utilizes materials and devices of nanometric dimensions, often prepared via operations carried out on the molecular level. The properties of such systems are quite different than these characteristics of the macroscopic ones and can be adjusted to the specific needs [1]. Nanoparticles are the most popular nanostructures utilized in
* Corresponding author. E-mail address: [email protected] (M. Nowakowska).
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nanomedicine. They have tunable electronic, optical, magnetic and biological properties. Nanoparticles can be manufactured as the objects of various chemical composition, surface characteristics, size and shape. They can be prepared from various materials such as metals, metal oxides, silica, natural and synthetic polymers, carbon, lipids and biomolecules. They can exist as hollow, porous or solid structures of different morphologies such as spheres, cylinders, tubes or platelets [2]. Nanoparticles can be loaded with various substances, e.g. drug molecules. These objects have large surface area per unit of volume what is particularly important for their interactions with other objects/(bio)surfaces. The nanoparticle surface can be tailor-made or designed to address specific needs. The modification can involve attaching the specific ligands/ antibodies/peptides allowing active drug delivery to the targeted tissue as well as the prolonged circulation in the blood, thus
http://dx.doi.org/10.1016/j.pharep.2015.05.018 1734-1140/ß 2015 Published by Elsevier Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.
Please cite this article in press as: Zapotoczny S, et al. Nanoparticles in endothelial theranostics. Pharmacol Rep (2015), http:// dx.doi.org/10.1016/j.pharep.2015.05.018
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increasing the probability of the passive drug delivery, e.g. by the Enhanced Permeability and Retention (EPR) effect in the abnormal vasculature of the cancer tissue. Recently, there has been a considerable effort to use the same nanoparticles for multimodal diagnosis and therapy, which include targeted drug delivery and its sustained and/or controlled release (Fig. 1). Such integration of both of these medical procedures was named ‘‘theranostics’’. The most often used nano-sized materials for theranostic purposes include: polymeric, lipid-based or metal oxide nanoparticles, dendrimers and cage proteins [3–6]. These nanoparticles are attractive for the theranostic applications, mainly because of their ability to be located in pathological lesions rather than in normal tissues, particularly in the case of cancer or in dysfunctional endothelium [7,8]. It is believed that theranostic approach can improve the outcome and increase the safety of medical procedures. It should allow identification and treatment of the diseases at their earliest stage when the chances for patient’s recovery are relatively high and to monitor/correct the treatment. In that regard, theranostics can be very helpful in the development of personalized medicine which replaces the standard diagnostic and therapeutic strategies by individualized approach taking into account the inter-individual variability in therapeutic response. Recently, there has been a growing interest in the potential application of the personalized treatment for widely spread and difficult to cure degenerative diseases such as cancer, neurodegenerative disorders and cardiovascular diseases. To develop that person-oriented and disease-oriented theranostic treatment for all these diseases, one has to design and synthesize the multifunctional nanoparticles and study their interactions with endothelium, the thin continuous layer of cells lining the luminal surface of blood vessels which is the interface between circulating blood and the vessel wall. Thus, endothelium is the first contact point for nanoparticles, especially when introduced via injection, but also serves as a barrier protecting extravascular sites. It is a main target in the treatment of inflammation, neurological, cardiovascular (ischemia, thrombosis and stroke), pulmonary and oncological diseases. In the current paper, we discuss the recent advances in nanotheranostics of early stages of cardiovascular diseases.
Fig. 1. Schematic structure of nanoparticles/nanocapsules for biomedical applications.
Nanotheranostic strategies in cardiovascular diseases Cardiovascular diseases (CVD) are the leading cause of morbidity/mortality worldwide. Each year CVD account for over 4 million deaths in Europe and over 1.9 million deaths in the EU. It is predicted that in 2030, the number of CVD-related deaths will increase to 23.6 million world-wide [9]. There is a number of identified causes, both biological and environmental, for the development of these diseases. Although the medical procedures were considerably improved in the last decades, their general therapeutic results are not satisfactory. That is mostly due to the fact that the therapy is implemented when the disease is already advanced, or quite often even after it has been manifested in cardiovascular events (such as myocardial infarction (MI) or stroke). It should be also noted that some patients do not respond positively to the currently used treatment. Thus, there is a need for the sensitive and possibly noninvasive procedures allowing detection of these diseases at the early stage and for novel drugs/therapeutic methods [10]. Atherosclerosis As the majority of CVD start from the atherosclerosis, which has been recognized as an inflammatory-type disease, the tools for its detection and inhibition are necessary [11,12]. Currently, atherosclerosis is diagnosed at the advanced stages by direct measurements of degree of stenosis, or indirectly, by the determination of the effect of arterial stenosis on organ perfusion. However, even at the early stages of atherosclerosis, there are considerable changes in endothelium structure and chemistry– the gaps between endothelial cells are formed leading to increased endothelial permeability and the level of the expressed adhesion molecules is growing. Those changes induce accumulation of low-density lipoproteins and activated macrophages followed by adhesion of extracellular proteinases, apoptotic cells and free radicals, resulting in building of atherosclerosis plaques. The progression of the plaque formation induces the hypoxiadriven angiogenesis leading to the formation of new blood vessels. In the final stage of atherosclerosis, the components of plaques are exposed to blood and induce thrombosis manifested by the clinical symptoms, such as MI or stroke. Surprisingly, there have been only very few studies on atherosclerosis detection based on monitoring the level of inflammatory biomarkers. There is, however, much more activity on improvement of the sensitivity and efficiency of various molecular imaging techniques, such as magnetic resonance imaging (MRI), optical fluorescence imaging (OFI) or positron emission tomography (PET). Recent progress in MRI was possible due to the application of properly designed and synthesized contrast agents. There are so-called positive and negative MRI contrast agents. The former ones reduce proton longitudinal relaxation time, T1, providing the positive contrast (bright signal), while the latter ones are T2 agents that shorten proton transverse relaxation time causing negative contrast (dark signal) [13]. Positive contrast agents are typically paramagnetic compounds, usually gadolinium complexes or manganese ions, while superparamagnetic materials, mainly these based on iron oxide nanoparticles, act as the negative contrasts [14,15]. It is believed that dual-mode T1–T2 contrast agents, combining the advantages of positive and negative contrasts, may improve diagnosis [16,17]. Nanostructural materials were shown to have clear advantages over conventional MRI agents. Nanometer dimensions of these materials have considerable impact on magnetic properties and ability to operate on cellular level [18–21]. Originally, single functional superparamagnetic iron oxide nanoparticles (SPION) with size of 100 180 nm and ultrasmall superparamagnetic iron
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oxide nanoparticles (USPIO) with size of 40 60 nm were synthesized and shown to be the effective MRI contrast agents. That was followed by the development of multifunctional nanoparticles both holding various diagnostic functionalities, targeting ligands and carrying drug agents. That allows simultaneous application of several imaging techniques, application of a drug and facilitates following the progress of therapy and its respective correction. It has been shown that USPIO conjugated to the ligands targeting endothelial cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) or selectins can be used for noninvasive identification of expression of these compounds indicating early stages of atherosclerosis [22–25]. They have been also used for in vivo MRI detection of vulnerable atherosclerosis plaques in humans and animals (rabbits) [26–29]. That was effective because plaques contain various inflammatory cells, in particular macrophages, which can take up (via phagocytosis) USPIO. These nanoparticles can also interact with deposits of other types such as lipids and these formed as a result of endothelial inflammation. As the macrophages can lead to inflammatory atherosclerotic plaques destabilization and disruption, resulting in MI and stroke [30], their monitoring is essential for identifying and treating the vulnerable plaques, the immediate cause of these life-threatening complications [31,32]. The multifunctional, characterized by low systemic toxicity, imaging liposomal formulations containing glucocorticoids (L-PLP) have been developed and used to deliver the drugs to the atherosclerotic plaques and to follow up the delivery and track anti-inflammatory effects of these drugs in atherosclerotic lesions [33–35]. The in vivo experiments performed using the rabbit model with pronounced atherosclerotic lesions have shown significant and fast decrease in inflammation by a single injection of liposomeencapsulated glucocorticoids. The changes were visible already in 2 days after administration of that system and could be followed up for at least 7 days. The USPIO g Fe2O3 nanoparticles (with a mean hydrodynamic diameter of 21 nm) were used to detect and monitor the change in plaque inflammation induced by statin (atorvastatin) and dietary change in a rabbit model of atherosclerosis. A significant decrease of activated macrophage content within the atherosclerotic plaques of the group treated with atorvastatin compared with the untreated one was observed [36]. That corresponded well with the earlier observation on the role of atorvastatin on high-cholesterol-diet-induced atherosclerosis in humans and monitored using histological procedures [37]. The therapeutic approach proposed for high-risk patients is to stabilize atherosclerotic lesions by inducing regression. Stabilization of plaques was manifested with lowered density of intraplaque macrophages and increased interstitial collagen content [38]. The high-density lipoprotein (HDL) nanoparticles (10 2 nm) labeled with amphiphilic gadolinium chelates and functionalized with collagen-specific peptides were developed and used to monitor in vivo plaque compositional changes from high macrophage/low collagen to low macrophage/high collagen on plaque regression, in a Reversa mouse model of atherosclerosis regression. The results of these studies can facilitate the search for therapeutics and the methods of their application [39]. By using the iron oxide nanoparticles covered with protein and functionalized with LyP-1 peptide or receptor-targeted nanoparticles, one can image the endothelium lesions [39–42]. The polyclonal antibodies OxLDL conjugated to iron oxide nanoparticles have been demonstrated to be useful for in vivo MRI detection of perivascular carotid-collar-induced atherosclerotic lesions in ApoE-deficient mice [43]. The vulnerable plaques can be also detected by imaging the apoptotic cells. That was done using iron oxide nanoparticles decorated with annexin A5 [44]. Development of atherosclerotic plaque and progression of the disease is accompanied by neovascularization of the vessel wall accompanied with intraplaque hemorrhage, which increases the rate of plaque growth and
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induces destabilization [45–48]. Therefore, the inhibition of angiogenesis is considered as a potential therapeutic approach to plaque stabilization. Synthetic analogs of fumagillin have been demonstrated to inhibit angiogenesis [49]. Fumagillin was delivered to the aortic wall of rabbit using avb3-integrin-targeted paramagnetic nanoparticles and shown to inhibit neovascularization. The therapeutic process can be noninvasively assessed by MRI [50,51]. Thrombosis Advanced atherosclerosis can result in the formation around atherosclerotic plaques, in the lumen of the blood vessel, the thrombus (blood clot) which hinders the blood flow leading to hypoxia, or even anoxia and infarction. These can be manifested in a number of ways, the most common life-threatening events being stroke and MI (heart attack). The early diagnosis and treatment of thrombosis can reduce the probability of occurrence of these conditions [52]. Although the thrombosis is a quite complex phenomenon, it has been recognized that the specific binding of activated platelets and fibrinogen are essential steps in its pathway. That finding was crucial for the development of detecting tools, e.g. nanoparticles conjugated to fibrin targeting peptides have been demonstrated to be useful for that purpose [53,54]. The currently available thrombolytic therapy is not satisfactory. Intravenous therapy is the treatment of choice in thrombosis. The intravenous tissue plasminogen activator (IV tPA) was approved as the thrombolytic agent by FDA for use in acute ischemic stroke patients. It is recommended for up to 3 h from the symptom onset [55,56]. The European Cooperative Acute Stroke Study III (ECASS III) has shown that alteplase administered for up to 3 4.5 h after the onset of stroke symptoms resulted in significant benefits for the patients [57]. Although there are various clinically used antithrombotics (thrombolytics, anticoagulants and antiplatelet drugs), they suffer from a short half-life in plasma, a low targeting ability, and the tendency to induce hemorrhage. Thus, there is a search for targeted local thrombolytic therapy and for the systems allowing for targeted detection of thrombi, local drug supply and the dynamic monitoring of its thrombolytic efficiency. The in vitro studies have shown that tPA encapsulated in liposomes [58,59] or in poly(lactide-co-glycolide) (PLGA) nanoparticles coated with chitosan was more efficient in dissolving the blood clots than tPA in solution [60,61]. For magnetically targeted detection of thrombi and dynamic in vivo monitoring of the thrombolytic drug efficiency using MRI, the SPION conjugated with tPA have been synthesized [62,63]. To take advantage from the biochemical targeting, the surfaces of tPA containing nanoparticles were modified with cyclic arginine glycine aspartic acid (RGD) tripeptide. RGD is a receptor antagonist of platelet membrane glycoprotein GP IIb/IIIa that restrains the platelets from accumulation at the thrombus [64]. It has been shown that RGD conjugated to the surface of liposomes or PLGA nanoparticles loaded with tPA enhanced in vitro thrombolysis [59,65–67]. The thrombus-targeting nanoparticles with a dual function of early detection and treatment of a thrombus were also prepared. The systems were constructed from Fe3O4-based PLGA nanoparticles carrying recombinant tissue plasminogen activator (rtPA), coated with a film made of chitosan grafted with RGD. They showed good affinity to thrombi and exhibited strong thrombolytic and contrast-enhancing effects as seen using in vitro and in vivo experiments [68]. Toxicity/safety Before considering the clinical applications of nanoparticles, the studies on their toxicity are necessary. In that regard, the effect of
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nanoparticles on the targeted tissue but also on other tissues/ organs exposed to the interactions with them during their circulation and clearance should be evaluated. Also, the cytotoxicity and immunogenicity of the possible products of nanoparticle biodegradation have to be determined [69]. Although these issues are not fully understood, it has been recognized that the parameters such as chemical composition, size, geometry, charge and type of surface affect the toxicity. Gadolinium-containing nanoparticles were shown to induce nephrogenic systemic fibrosis, which is particularly dangerous in patients with kidney problems [70]. SPION were demonstrated as being much safer [71]. They were shown to be non-cytotoxic for endothelial cells in vitro at concentrations below 0.1 mg/mL [72]. The in vivo studies showed that their intravenous administration leads to their accumulation in liver what may increase the amount of free iron and may increase probability of inflammation and oxidative stress [73]. The clinical study [74] indicated, however, that USPIO nanoparticles are cleared out of the atherosclerotic plaques within 6 months and no adverse effects following multiple USPIO infusions were observed, confirming that these particles are clinically safe and well tolerated [75]. Iron ions liberated from the inorganic cores during biodegradation may be also stored in nontoxic ferritin protein [76]. The problem can be also diminished by coating nanoparticles with biocompatible polymeric layer, such as dextran, chitosan or poly(ethylene glycol) [18]. One should be aware, however, that surface modification may result in nanoparticle aggregation, what usually increases their toxicity. The size of nanoparticles should be optimized depending on the purpose; for atherosclerotic theranostics, the nanoparticle diameter should not exceed 100 nm, because the larger nanoparticles have difficulties in penetrating the endothelium. Nanoparticles smaller than 5 nm can be dangerous as they can pass the blood-brain barrier (BBB) [77]. Conclusions Considering the growing threat CVD pose for worldwide population, the researchers and clinicians search for novel therapeutic approaches. Although in the last decades, a considerable progress in the CVD therapy was achieved, the clinical outcome is still not satisfactory, mainly because of late diagnosis. The diagnosis of early atherosclerotic changes, the initial step of most CVD, is thus essential. It requires novel methods and tools that can be provided by the development in nanotechnology. These allow for the personalized medicine and theranostics. Theranostics of CVD can be realized, thanks to the development of multifunctional nanoparticles which can be used to detect the inflammatoryrelated endothelium changes as well as to direct drug to the lesions in a targeted manner and to monitor the healing process (retardation of atherosclerotic plaques or induction of thrombolysis). The in vitro and in vivo experiments carried out using the animal models and some preliminary pilot studies in humans are very promising, however, much more has to be done to ensure the safety, both immediately after application and on a long-term timescale. Extended and careful toxicological and pharmacological studies are necessary before considering the application of nanoparticles in patients. Conflict of interest There is no conflict of interest. Funding This study was supported by the European Union from the resources of the European Regional Development Fund under the
Innovative Economy Programme (Grant coordinated by JCET-UJ, No. POIG.01.01.02-00-69/09).
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