Cardiovascular is a word combining “cardio” implying the heart and “vascular” means blood vessels. CVRDs are chronic disorders of the heart and the vascular systems such as arteries, veins, and blood capillaries. CVRDs include both cardiovascular diseases and cardiovascular related diseases such as angina pectoris, myocarditis, myocardial infarction, pericardial disorder, thrombosis, atherosclerosis, hyperlipidemia, hypertension, pulmonary arterial hypertension, stroke, etc. [1]. Altogether, CVRDs are the leading causes of mortality and morbidity in developed countries, owing to their sedentary lifestyles [2]. Furthermore, obesity and diabetes, and related disorders, are linked with CVRDs, hence becoming a comorbid relation. Furthermore, a complication such as coronary artery obstruction is among the number one causes of death in adults that lead to thrombus plagues in the intima of the arterial wall, mainly in the carotid artery [3]. Cardiovascular diseases are prevalent in high-income countries such as the United States of America, but they have also become global issue. In 2016, a report demonstrated that 62.5 and 12.7 million people died due to cardiovascular diseases in India and America, respectively. Out of these deaths, most causes for deaths were observed as ischemic heart disease and stroke, and likely more will be in the future if serious actions are not taken [4].

The latest milestone in the treatment of CVRDs is the surgical implantation of coronary stents, which will be helpful in atherosclerosis and other coronary artery diseases. However, other medical managements of CVRDs rely on conventional medications such as beta-blockers, diuretics, hypolipidemic drugs, etc. The conventional medicines for the management of CVRDs are non-targeted drug delivery systems that can produce some potential side effects and toxicities. Developing targeted nanomedicine for CVRDs can minimize or eliminate these associated problems. Additionally, integrating targeted nanomedicine with diagnostic agents can detect and deliver the drug to the targeted site and provide a better understanding of the disease and its treatment processes [5]. For example, macrophages play a key role in the development and progression of atherosclerosis. Hence, designing targeted theranostic nanomedicine for imaging and targeted therapy of macrophage-associated pathological processes in the CVRDs [6]. Surgical implants suffer from critical problems such as infection at the implantation site, blood clots, and damage to blood vessels, whereas beta-blockers slow down the heartbeat and reduce the force of contraction, leading to the heart’s adaptation to a slower speed if taken regularly. Suddenly stopping medication of the beta-blocker increases the risk of a heart attack. Diuretics have the inherent disadvantages of triggering body ionic imbalances, such as lower sodium and potassium levels. Therefore, newer, safer, and more effective treatment modalities need to be developed to diagnose and treat CVRDs. The emerging theranostic nanomedicine modalities recently developed for diagnosing and treating CVRDs include nanoparticles, liposomes, metallic nanovesicles, etc. [7]. Therapeutic agents in theranostic nanomedicine include, synthetic or semisynthetic drugs, peptides, protein and genomic materials [8]. In contrast, commonly used diagnostic agents in theranostic nanomedicine include fluorescent dye [9] or quantum dots (optical imaging) [10], superparamagnetic iron oxide nanoparticles (magnetic resonance imaging) [11], radioactive nucleoid (nuclear imaging) [12] and heavy elements such as iodine [13] for computed tomography. Quantum dots possess numerous advantages over organic dye that include higher signal intensity, brightness, and photostability. In recent decades, nanomedicines have taken the world by storm for their application in the diagnosis and treatment of cancer. Researchers have recently emphasized theranostic aspects of nanomedicines on other illnesses and diseases such as CVRDs [14].

In addition, targeted nanomedicines are gaining momentum in the medical field because of their advancement in specificity-based therapy through targeting cells and cellular components. Targeted approaches have created advanced nanomedicine platforms for drug targeting and disease diagnosis at a nanoscale level [15]. Conventional treatments have lower efficacy, elevated systemic side effects, and a shorter drug half-life. For instance, an endogenous substance called urokinase acts as a thrombolytic agent. It is often used in various CVRDs, such as strokes, adjunctive therapy after angioplasty of an occluded artery, pulmonary embolism, etc. However, it has a major drawback of having a short half-life, which requires continuous administration to achieve a proper therapeutic window. Furthermore, it has been shown to cause excessive bleeding elsewhere in the body because it prevents platelets from aggregating properly to form blood clots under normal conditions. The use of urokinase encapsulated in a nanoformulation during targeted delivery was shown to result in an increase in half-life associated with a decrease in systemic toxicity, according to the findings [16]. Theranostic nanomedicine has demonstrated its potential role in diagnosing and treating the disease in preclinical studies. However, new advancement in drug delivery and diagnosis have been developed but still remains in their infancy stage for clinical application. Nanoparticulate and biological interaction are the key challenges associated with the clinical translation of theranostic nanomedicine. When a nanoparticle interacts with biomaterials, its possible toxicity or incompatibility might cause problems such as immunoreaction, inflammation, and other disorders. The harmful effects of nanomedicines are highly reliant on numerous aspects such as size, zeta-potential, and solubility. Hence, preclinical studies in numerous animal models will be helpful for addressing this issue. Additionally, academic research laboratories develop theranostic nanomedicine on a modest scale, focusing on emerging scientific and technological advancements. They are frequently aware of the technical obstacles that the industry faces while commercializing techniques. Increased coordination between labs and pharmaceutical industries is required to narrow this gap [17].

2. Diagnostic Application of Targeted Nanomedicine in CVRDs

Early detection of any disease is the key to any treatment, as the higher progression of conditions can be fatal and life-threatening. Hence, with advancements in the medical field, nano-scaled contrasting agents have been employed in the early diagnosis of CVRDs. Contrasting agents such as quantum dots have mainly been used to capture fluorescence tomography images. Additionally, diagnostic agents such as 18F-crosslinked iron oxide (18F CLIO) are used for radioactive scans such as PET, SPECT, etc. In a few diagnoses, gadolinium chelated with diethylenetriamine pentetic acid (Gd-DTPA), iron oxide nanoparticles in magnetic resonance imaging (MRI) [18], gold or iodine-based nanoparticles in computed tomography (CT) imaging [19], gold nanoshells in optical coherent tomography, and colloidal nanobeacons in photoacoustic tomography have been reported [20]. There are also other multimodal techniques have been used, such as copper-CLIO in MRI, positron emission tomography (PET), and near-infrared fluorescence (NIRF) ^[7][21][7,21].

2.1. Quantum Dot-Based Imaging of CVRDs

In one study, a very stable CT-targeted contrasting agent was developed with lisinopril as the targeting ligand, and was further incorporated into citrate-coated gold nanoparticles. The results showed an image of the heart and lung regions indicating the targeting of an angiotensin-converting enzyme (ACE), which was overexpressed in cardiac and pulmonary fibrosis. It was reported that the developed nanoprobes would be very useful tools for monitoring cardiovascular pathophysiology using CT imaging. Furthermore, in vivo studies in mice depicted that lisinopril-thioctic acid conjugated nanoparticles are accumulated specifically in the lungs and heart due to higher density ACE receptors after intravenous administration and produced stable X-ray CT images of the lungs and heart [22]

2.2. Magnetic Nanoparticles-Based Imaging of CVRDs

The polymeric nanoparticles that carry contrasting agents are safer and better alternatives for producing high-resolution images than free contrasting agents. The developed targeted nanocolloids have demonstrated promising in vitro MRI contrast agents due to their higher relaxivity and detection sensitivity than non-targeted nanocolloids [23]. Additionally, with advanced technologies, medical devices are programmed for the rapid diagnosis of CVRDs. Bio-nanochips, made up of nanonets and quantum dots, produce results in minutes [24]. As diagnosis is emphasized in early biomarkers detection, it is necessary to identify biomarkers involved in CVRDs. These biomarkers include troponins, creatine k muscle/brain, B-type natriuretic peptide, myeloperoxidase, apolipoproteins, myoglobin, low-density, and high-density lipoprotein [25]. Furthermore, biomarkers were targeted by paramagnetic/fluorescent micellar nanoparticles in the ischemic or reperfused mouse model. Micellar nanoparticles were found to diagnose the onset of acute myocardial infarction by detecting the overexpressed extracellular matrix metalloproteinase inducer [26]. Currently, with the help of molecular imaging and MRI at the nanoscale, a non-invasive technique of diagnosis has been developed. This MRI allows better photon penetration in a specific nanometer range and the scattering of beams of light can be diminished to show better clarity with heightened sensitivity at detection [27]. Utilizing this technology, imaging of cardiomyocyte apoptosis incorporating magneto-optical nanoparticles can produce high-resolution in vivo images [28]. In a similar study, the diagnosis of cardiomyocyte apoptosis was made with annexin-labeled nanoparticles and it was observed that a low level of apoptosis in the myocardium indicated a healthy heart and the elevated apoptotic levels of cardiomyocytes revealed the heart abnormality. In conclusion, theis study suggested developing a nanoplatform for cardiac diagnosis and developing novel anti-apoptotic heart failure therapies ^[29][30][29,30]. In atherosclerosis, various molecular imagining techniques have been reported, such as intravital microscopy, nanoparticle-enhanced molecular MRI, multicolor spectral CT, and fluorescence imaging; further quantification of blood vessel wall inflammation has also been imaged by PET. Many of these imaging techniques mentioned above are currently undergoing clinical trials [31]. Other cellular targets used as biomarkers in atherosclerosis include macrophages, cell adhesion molecules (CAMs), lipids such as low-density lipoprotein (LDL), high-density lipoprotein (HDL) and fibrin. Furthermore, increases in angiogenesis have been observed at the initial stages of atherosclerotic plaque formation, which serves as a good target for diagnosis. In one study, angiogenesis was evaluated by targeting a molecule called αvβ3 integrin, and it was visualized using an MRI scan [32]. In some studies, imaging techniques of thrombosis have been accomplished using atomic force microscopy through sizes of the thrombotic clots. This tool offers better resolution and clarity at a lesser range of 1 nm. In addition to this, it enabled the analysis of platelet activities and their points of activation in conjunction with the analysis of proteins involved in thrombosis [33]. In the early 2000s, the diagnosis of a thrombotic clot in vivo was also made by an MRI scan in canine models. It was fabricated with anti-fibrin monoclonal antibodies in conjunction with lipid-encapsulated perfluorocarbon nanoparticles comprising gadolinium-chelate as a targeting agent [34]. In another study, ultra-small superparamagnetic iron oxide nanoparticles in conjunction with fucoidan were reported to diagnose arterial thrombi by MRI visualization. Surface plasmon resonance imaging demonstrated that targeted nanoparticles binds to immobilized P-selectin in vitro. All intraluminal hypo-signals detected by MRI after injection targeted the nanoparticle, whereas none could be identified with non-targeted nanoparticles [35].

2.3. Radio-Imaging of CVRDs

Similarly, ligand-targeted 19F perfluorocarbon nanoparticles have been used to visualize and examine unstable in vivo atherosclerotic lesions. In this enstrudy, the nanoformulation includes an exquisite contrast agent for the paramagnetic property. The formulation consisted mainly of lecithin encapsulated liquid perfluorocarbon with a massive amount of chelated gadolinium, which was located within the bounding lipid. The targeting property of formulated particles with distinct monoclonal antibodies showed nanoparticles localization for the MRI signal amplification in imaging areas with minor or no opposing blood pool signal [36].

3. Therapeutic and Theranostic Applications of Targeted Nanomedicine in CVRDs

Nanocarriers are loaded with therapeutic agents which are directly transported to the target site, either by passive or active targeting. For passive targeting, the nanomedicine reaches the target site employing highly perfusable cells. In active targeting, the nanomedicine is conjugated with site-specific molecules or cell-specific targeting ligands ^[15][37][15,37]. A study was carried out with liposome-encapsulated amiodarone showing better therapeutic efficacy with lesser side effects in hypotension. This is an excellent example of how nanoformulation of cardiac drugs can aid in better therapy of CVRDs [38]. Moreover, liposomal vesicles containing surface charge due to their compositions can also be utilized for molecular targets. For example, cationic lipid such as dioleoylphosphatidylethanolamine (DOPE) were used to prepare liposomes that carried a positive charge and showed a greater affinity towards negatively charged targets such as nucleic acids, tumor cells, intestinal mucosa, etc. [39]. Different targeting approaches for nanocarrier-based therapy for cardiovascular and cardiovascular related diseases are presented in Table 1 and Table 2.