Nanotheranostics for personalized medicine

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Abstract

The application of nanotechnology in the biomedical field, known as nanomedicine, has gained much interest in the recent past, as versatile strategy for selective drug delivery and diagnostic purposes. The already encouraging results obtained with monofunctional nanomedicines have directed the efforts of the scientists towards the creation of “nanotheranostics” (i.e. theranostic nanomedicines) which integrate imaging and therapeutic functions in a single platform. Nanotheranostics hold great promises because they combine the simultaneous non-invasive diagnosis and treatment of diseases with the exciting possibility to monitor in real time drug release and distribution, thus predicting and validating the effectiveness of the therapy. Due to these features nanotheranostics are extremely attractive for optimizing treatment outcomes in cancer and other severe diseases. The following step is the attempt to use nanotheranostics for performing a real personalized medicine which will tailor optimized treatment to each patient, taking into account the individual variability. Clinical application of nanotheranostics would enable earlier detection and treatment of diseases and earlier assessment of the response, thus allowing screening for patients which would potentially respond to therapy and have higher possibilities of a favorable outcome. This concept makes nanotheranostics extremely appealing to elaborate personalized therapeutic protocols for achieving the maximal benefit along with a high safety profile. Among the several systems developed up to now, this review focuses on the nanotheranostics which, due to the promising results, show the highest potential of translation to clinical applications and may transform into concrete practice the concept of personalized nanomedicine.

Introduction

The term "nanomedicine" has been proposed to refer to the application of nanotechnologies to the biomedical field for controlled delivery of drugs as well as for diagnostic purposes [1]. In the past decades, several nanosized carriers, made of different materials such as lipids, polymers, carbon or metal have been designed and widely characterized with the aim to overcome the limitation of the traditional drug delivery modalities [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. For example, drug loaded nanocarriers were found to be able to accumulate at the tumor site by “passive targeting” through the enhanced permeability and retention (EPR) effect, due to the large pores present at tumor endothelial vessels (compared to healthy tissue) and to a reduced tumor lymphatic drainage [13], [14], [15]. Noteworthy, relying only on the EPR effect and therefore on the variable tumor anatomy, passive targeting would, in some cases, not allow a sufficient amount of drug to reach the target site. For this reason, in order to improve the treatment specificity, passive targeting has often been associated to a so called “active targeting” obtained by decorating the surface of the nanocarriers with molecules able to recognize specific ligands expressed by target cells [5], [16], [17], [18], [19], [20]. This approach offers the advantages to improve drug therapeutic efficiency and to dramatically reduce toxicity and unspecific side effects, thus leading to possible future evolution in the management of severe diseases. Mainly, nanomedicines have found wide applications in the treatment of cancers [21], however neurodegenerative [22], [23] and inflammatory/autoimmune diseases [24], [25], diabetes [26], [27], as well as lung [28], and cardiovascular affections [29], [30], can benefit from the use of nanosized carriers for drug delivery. Nevertheless, despite extensive efforts on developing targeted drug delivery systems, up to now, only very few products have achieved success in the clinic and reached the marketplace. Successful examples include liposomal formulation of doxorubicin (Doxil and Myocet) and paclitaxel (Abraxane and Xyotax) [31], [32], [33], [34]. Aside from therapeutic interventions, actively and passively targeted nanomedicines have been employed in recent years also as imaging tools which hold great promises both in preclinical research and in clinical settings [35], [36], [37], [38], [39], [40], [41], [42]. The currently accessible imaging techniques include magnetic resonance imaging (MRI), optical imaging, ultrasonography (US), positron emission tomography (PET), computer tomography (CT) and single photon emission computed tomography (SPECT). The combination of the variety of available nanocarriers with different imaging contrast agents (i.e. paramagnetic metal ions, superparamagnetic iron oxide (SPIO) nanoparticles (NPs), Near Infra Red (NIR) probes, radionuclides) led to the development of versatile platforms which, enabling single or multimodal imaging, are extremely interesting for both detection and diagnosis of diseases [11], [43]. Indeed, in vivo application of these nano-based imaging agents allows achieving an enhancement of the signal to noise ratio in the targeted tissue compared to the surrounding health one. The increase of the imaging resolution enables to discover also small lesions which are undetectable with traditional methods [44]. Moreover, imaging technologies allow following the biodistribution of the nanocarriers, to determine their mechanism of action and to monitor in real time the disease progression [45], [46], [47]. However, these nanocarriers loaded with contrast agents do not usually offer therapeutic effects.

To handle the rapid proliferation of severe diseases such as cancer, neurological and cardiovascular diseases, there is a need for improved diagnostic and therapeutic strategies allowing early detection and treatment. Recent advances in nanoscience and biomedicine and the convergence of these disciplines have now expanded the ability to design and construct “multifunctional” nanoparticles, combining targeted therapeutic and diagnostic functions in a same entity [48], [49], [50], [51], [52], [53]. Thus, theranostic nanomedicines emerge as an alternative to the separate administration of diagnostic probes and pharmacologically active molecules. The various imaging modalities currently available offer the possibility of a longitudinal study which enables to monitor changes at the target site in response to the treatment and to gain insights on disease progression and efficacy of the intervention at an early stage [54]. The efficient combination of a therapeutic agent with an imaging molecule in a single nanomedicine and the extreme versatility of such so called “nanotheranostic” platform would therefore contribute to the development of optimized and individualized treatment protocols, offering the opportunity to perform a “personalized nanomedicine”.

Theranostic nanomedicines have shown interesting results during in vitro studies but there are still some challenges for their application in vivo and in the clinical treatment of patients. A simple research on PubMed® database reveals that more than 400 articles have been published in the last decade within this field. Most of them describe the preparation and physico-chemical characterization of nanotheranostics with sometimes an in vitro evaluation on cell culture but without any proof of concept in vivo. Other are describing in vivo data related to either the therapeutic or the imaging function but not a combination of both. Therefore, they may not be considered as real theranostic systems. The most relevant of these studies, which are too far from the personalized medicine, will not be discussed in this review but are just summarized in Table 1. Noteworthy, the number of papers dealing with the in vivo evaluation of real theranostic nanodevices (i.e. combining therapy and imaging) is progressively increasing (around 15% of currently published articles). It is evident that extensive in vivo investigation is needed before the clinical application of the nanotheranostic concept.

This is the reason why, in this review, we have mainly focused our attention on the nanotheranostics which have demonstrated some preclinical relevance to potentially make shorter the step for their introduction in clinical trials. Here, we have chosen to classify nanotheranostics as function of their imaging properties. In the first part, nanotheranostic for non-invasive imaging and treatment of cancer will be discussed, and then attention will shift to cardiovascular diseases and in particular to atherosclerosis. Detailed description of nanocarriers and imaging modalities was out the scope of this review, but the reader can refer to excellent articles published in the last years [43], [49], [52], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64].

Section snippets

Nanotheranostics for personalized medicine

The expression “personalized nanomedicine” refers to the use of nanosized carriers to elaborate optimized treatment protocols tailored to each specific patient. In the simplest definition, personalized medicine consists to administer “the right drug to the right patient at the right moment” [101], [102]. With the aim of developing a patient specific therapy, pharmacogenomic, pharmacoproteomic and a wide variety of -omic strategies have been developed in the last years [103], [104], [105], [106]

Nanotheranostics in cancer disease

Due to the dramatically high number of death caused every year by cancer [121], much effort has been done to improve the traditional treatment of cancer by developing theranostic nanomedicines. It is probably in the oncology field that the possibility to combine imaging and therapy rises the more useful and interesting opportunities for developing personalized medicine [122]. Indeed, it is obvious that a strategy which would enable the early diagnosis and therapy, the prediction of the

Nanotheranostic in cardiovascular diseases

If the development of theranostic nanomedicines in oncology has received the majority of the attention, multifunctional nanomedicines may also have important impact in the treatment of cardiovascular diseases (CVDs). CVDs, which include various disorders of blood vasculature and the heart, are the main cause of death in the European Union accounting for over 2.0 million deaths each year. Nearly half of all deaths are from CVDs (45% deaths in women and 38% deaths in men). Despite significant

Concluding remarks

The emergence of the nanotheranostic concept and its further development illustrate the need for a pluridisciplinary approach (incl. physics, chemistry, material science, drug delivery and pharmacology) with the common objective of improving the management of cancer and other severe diseases. As detailed in the present review, interesting results have already been obtained and the proof of concept has been provided at the preclinical stage in cancer and cardiovascular disease treatment. The

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