Nanomaterials as novel cardiovascular theranostics

So-called nanotechnology platforms have revolutionized the understanding of pathophysiology and therapeutic measures. This also applies to the treatment of cardiovascular diseases.

Cardiovascular diseases (CVDs) are a group of diseases associated with the heart and blood vessels and are considered the leading cause of death worldwide. Coronary heart disease, atherosclerosis, myocardial infarction represent the CVDs. As CVDs are associated with a number of pathophysiological conditions with alarming mortality and morbidity rates, early diagnosis and appropriate therapeutic approaches are crucial to save patients' lives. Conventionally, diagnostic tools are used to detect disease conditions while therapeutic agents are administered to alleviate diseases.

However, the advent of nanotechnology platforms has revolutionized the current understanding of pathophysiology and therapeutic interventions. The concept of combinatorial therapy, where both diagnostics and therapeutics are deployed through a single platform, is referred to as theranostics. As preclinical and clinical studies show, nano-based theranostics are widely used in cancer detection and treatment. Nanotheranostics has gained considerable attention for the efficient treatment of HCCs. The different physicochemical properties of nanoparticles have been exploited for the early diagnosis and therapy of atherosclerosis, myocardial infarction and aneurysms. This paper provides information on the development of nano-based theranostics for the detection and treatment of CVDs such as atherosclerosis, myocardial infarction and angiogenesis [...].

1 Introduction

Since the discovery of antibiotics, a major development in biomedicine and healthcare has revolutionized the current understanding of disease diagnosis and treatment. In recent decades, the advancement of the global health network has also provided a platform to protect and preserve people's health profiles [2]. However, the world has also seen a similar but exponential emergence of a number of infectious diseases and non-communicable diseases (NCDs). Like infectious diseases, NCDs have also gained considerable attention in recent decades due to high mortality and morbidity rates.

The development of cardiovascular diseases (CVDs), respiratory diseases, diabetes and cancer are the most prominent diseases and disorders responsible for most health outcomes and mortality rates in the 21st century. The emergence of NCDs is becoming a public health issue as it has a global impact on human health, the economy and society. The World Health Organization (WHO) estimates that NCDs could be responsible for 70% of global deaths by 2025, with a significant impact on developing countries. Among these, approximately 84% of global deaths by 2025 will be due to the increased incidence of CVDs (48%), cancer (21%), chronic respiratory diseases (12%) and diabetes (3%) [3]. The world is currently experiencing the high risk of comorbidities in chronic diseases, especially in patients with CVDs coinciding with the Covid-19 pandemic, which poses an alarming risk to the healthcare system.

Schematic overview of the concept of nanotheranostics, which envisions the use of engineered nanomaterials for both diagnostic and therapeutic modules through a single platform (translated from [1])

HKEs encompass a collection of different health conditions, including atherosclerosis, cardiomyopathy, cardiac arrhythmias, myocardial infarction, coronary artery disease, aneurysm and hypertension. Since CVDs represent the accumulation of multiple pathological conditions and disorders, the occurrence of CVDs is becoming a serious global trend. The occurrence of CVDs poses serious health complications that have a severe impact on the economy of any country. According to available data, approximately 17.7 million people worldwide died from complications associated with CVDs in 2015. In this context, it is estimated that by 2030, mortality due to CVDs could rise to 22 million. In this context, advances in technological perspectives could provide a range of therapeutic alternatives to minimize the nuisance of chronic diseases and disorders associated with CVDs. However, the co-occurrence of CVDs and chronic infectious diseases poses a major challenge to current therapeutic strategies. Immunotherapy, chemotherapy and other conventional approaches are considered the frontline warriors in the fight against HCAs. The concept of host-directed therapies has also gained much attention in recent years due to their ability to combat NCDs, especially HCEs [4]. Although much work is being done to develop and/or curate the conventional therapies to improve healthcare delivery in emergencies, these strategies fall short due to one limitation or another [5]. In this regard, it is imperative to search for an effective, alternative and specific method for timely diagnosis of CVDs followed by effective treatment procedures. Genome-based approaches have also been shown to lead the way in disease diagnosis and treatment [6].

1.1 Theranostics: an overview

In the treatment of chronic diseases and disorders, it is primarily important to diagnose the course of the disease at an early stage and to initiate the right therapeutic measures on the basis of the diagnostic information. In this context, a combinatorial modality that includes both diagnosis and therapy was brought into the limelight around two decades ago. The integrated concept of "theranostics" was derived from therapy and diagnostics. The term "theranostics" was coined by John Funkhouser in 2002 and refers to a combination of diagnostic tools and appropriate therapeutic interventions under a single platform [7, 8]. Theranostic tools have provided a customized platform for targeted therapy of chronic disease states by utilizing diagnostic and therapeutic modalities in a single platform. The integrated theranostic approach offered a new dimension to overcome the limitations of differential diagnosis and treatment procedures [8, 9]. The development of theranostic strategies focused on target-specific diagnosis and therapy and decidedly distinguished the healthy or unaffected areas from those with pathogenic effects [10]. The notable advantages of the theranostic approach are low toxicity, selectivity, target specificity and tunability [11]. Several internal markers such as variations in pH, adherence to redox reactions, cellular enzyme levels, and response of genetic material are influential in theranostic functional modalities [12].

With the development of theranostics, a selective platform for the transformation of conventional therapeutic drugs to personalized and specific treatment has emerged, representing a more holistic strategy to combat the health consequences of chronic diseases [13]. The concept of theranostics is clearly coming to the fore as next-generation personalized medicine. It enables a series of sequential steps such as early detection and diagnosis of disease, disease prognosis, therapy selection and monitoring of therapeutic efficacy with high precision selectivity [14]. As radionuclides in chemotherapy and nuclear medicine are associated with limitations such as radiation-related health hazards and the risk of allergic reactions, theranostics could mean the development of next-generation nuclear medicines [15]. The specificity with which theranostic modalities integrate diagnostics and therapeutics through a common platform could lead the scientific community into the future as a major arsenal against chronic diseases and other conditions [16]. Theranostic modalities provide a non-invasive platform for disease diagnosis and targeted therapy. This concept has gained considerable recognition in the fight against infectious diseases, inflammatory diseases and in cancer therapy.

1.2 Nanotheranostics: an emerging trend

Nanotechnology in biomedicine and healthcare has led to a paradigm shift in the understanding of disease prognosis as well as efficient treatment strategies for chronic diseases. Nano-based technologies have provided a versatile platform for the rapid and early diagnosis of chronic diseases. In addition, they offered therapeutic applications, including targeted local delivery of therapeutic drug moieties and localization of the therapeutic response of the cellular system using various therapeutic approaches such as gene therapy, chemotherapy, photodynamic therapy, and photothermal therapy with different specificity in terms of therapeutic efficacy [17-19] (Fig. 1). The emerging trend of nanotechnology in biomedicine and healthcare has revolutionized the scientific development of disease diagnosis and therapy with significant future potential. Nanotechnology platforms could be considered as theranostic modules for effective diagnosis and treatment due to their physicochemical properties such as high surface-to-volume ratio, tunability, easy chemical characterization and modification of surface properties [20]. The concept of "nanotheranostics" is an extended version of theranostic methods, using nanomaterials of different nature and physicochemical properties for disease diagnosis and optimized therapies [21]. Nanotheranostics represents the most advanced technological approach with multiple functional properties such as multimodal imaging, drug targeting and improved synergistic therapeutics [22].

The engineered nanomaterials of different classes such as magnetic nanoparticles, carbon-based nanomaterials, silica-based nanomaterials, metal-based nanoparticles and polymeric nanoparticles have shown applications in both diagnostic and therapeutic perspectives at the bimodal level. In particular, the light-emitting and light-responsive nanomaterials, such as metal-based nanoparticles with high plasmon resonance (HPR), semiconductor quantum dots (QDs), organic and polymeric nanomaterials, gained considerable attention as cost-effective and efficient theranostic agents [23]. The unique structural dimension, unique physicochemical properties, ease of functionalization, enhanced biocompatibility, and especially the wide range of single-photon properties of carbon-based nanomaterials are considered as groundbreaking features for biomedical applications. Carbon-based nanomaterials such as carbon nanotubes (CNTs), quantum dots (QDs) and graphene oxide (GO) are used for applications in both diagnostics and therapeutics [24]. In addition to carbon-based nanomaterials, polymeric nanoparticles and their combination with various nanomaterials have added a new dimension to nanomaterial-mediated theranostics for numerous functional properties. The utilization of combinatorial nanomaterials has proven to be crucial for the diagnosis and treatment of diseases [25]. The chemistry associated with combinatorial polymeric nanoparticles fundamentally enables multifunctional imaging of deep tissue with spatial resolution when used as contrast agents in near-infrared (NIR) imaging, two-photon imaging and photoacoustic imaging. It has been shown that these conjugated polymer nanomaterials can be used in the early detection of diseases. In addition, these conjugated nanomaterials have also been observed to enhance therapeutic methods such as photothermal therapy (PTT) and photodynamic therapy (PDT), which are considered to be instrumental in non-invasive cancer therapy as they are already clinically proven and therefore may also be relevant for the treatment of HCCs [26, 27]. The highly specific and unique physicochemical properties of nanomaterials are utilized as excellent contrast agents that prove helpful in the early detection and diagnosis of diseases. Therefore, nanomaterials are categorized as effective bioimaging modalities. Nanomaterials are used as effective contrast agents for various conventional diagnostic methods such as optical imaging, ultrasound, magnetic resonance imaging (MRI), positron emission tomography (PET), photoacoustic tomography and computed tomography (CT). Thus, the role of nanomaterials as bioimaging tools has led the scientific community towards bioimaging-guided therapeutics against NCDs [11].

The straightforward synthesis, unique physicochemical properties, and bimodal applications associated with nanomaterials provided a unique platform for recognizing and redefining therapeutic interventions for various chronic health conditions, including the neurodegenerative diseases Alzheimer's and Parkinson's [16]. The nanotheranostic tools were considered for cancer therapy as the modalities enabled to detect and diagnose cancer progression through bioimaging techniques and provide a novel drug delivery system for systemic and controlled delivery of therapeutic agents to target sites bypassing multiple cellular barriers [28]. The emergence of nanotheranostic techniques has added a new dimension to the concept of personalized nanomedicine for efficient treatment of cancer, inflammatory diseases, HKEs, neurodegenerative diseases, diabetes and other chronic diseases [29, 30]. Since the nanotheranostic tools are different exclusive nanomaterials, the functional properties also vary greatly depending on the requirements. For example, theranostic nanomedicine could utilize various inorganic nanoparticles as effective contrast agents for multimodal imaging. Similarly, the nanotheranostic platforms can also incorporate a range of therapeutic drug moieties and contrast agents so that both the bioimaging and therapeutic aspects can be utilized from a single one of these platforms. In this context, structurally designed multifunctional co-loaded magnetic nanocapsules (MNCPs) have recently been developed that could be used not only for enhanced bioimaging modalities but also for targeted photodynamic therapy [31]. In a recently published research paper, it was shown that phosphatidylcholine/cholesterol-based liposomes modified with sodium cholate hydrate can be considered as a bimodal platform for both diagnostics and therapeutics [32]. The tunability of the nanostructures enables loading with different therapeutic drug moieties, target-specific ligand molecules and specific antibodies for targeted functional properties [33].

The article is a translated excerpt (Chapter 1) from the original article by Pala, R., Pattnaik, S., Busi, S. and Nauli, S. M. [1], published under the open access license CC-BY 4.0(http://creativecommons.org/licenses/by/4.0/).

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