Current Medicinal Chemistry - Volume 25, Issue 34, 2018

Nanomedicine is a recent promising setting for the advancement of current medical therapies, in particular for cancer. Nanoparticle-mediated therapies are aimed to tackle extremely complex phenomena, involving different biochemical, mechanical and biophysical factors. Computational models can contribute to medical research by helping the understanding of biological mechanisms and by providing quantitative analyses. In this work, we report on computational models that address four main issues related to the use of nanoparticles in anti-cancer therapies, namely the delivery of nanoparticles, their uptake by cells, the release of drugs from nano-platforms and nanoparticle-based therapeutics. In silico approaches constitute a valuable tool to aid clinical studies, to guide the rational design of new nanoparticle formulations and to identify the optimal strategies for existing treatments.

Cancer treatment still remains a challenge due to the several limitations of currently used chemotherapeutics, such as their poor pharmacokinetics, unfavorable chemical properties, as well as inability to discriminate between healthy and diseased tissue. Nanotechnology offered potent tools to overcome these limitations. Drug encapsulation within a delivery system permitted i) to protect the payload from enzymatic degradation/ inactivation in the blood stream, ii) to improve the physicochemical properties of poorly water-soluble drugs, like paclitaxel, and iii) to selectively deliver chemotherapeutics to the cancer lesions, thus reducing the off-target toxicity, and promoting the intracellular internalization. To accomplish this purpose, several strategies have been developed, based on biological and physical changes happening locally and systemically as a consequence of tumorigenesis. Here, we will discuss the role of inflammation in the different steps of tumor development and the strategies based on the use of nanoparticles that exploit the inflammatory pathways in order to selectively target the tumor-associated microenvironment for therapeutic and diagnostic purposes.

Background: The application of nanotechnology in the medical field is called nanomedicine. Nowadays, this new branch of science is a point of interest for many investigators due to the important advances in which we assisted in recent decades, in particular for cancer treatment. Cancer nanomedicine has been applied in different fields such as drug delivery, nanoformulation and nanoanalytical contrast reagents. Nanotechnology may overcome many limitations of conventional approaches by reducing the side effects, increasing tumor drug accumulation and improving the efficacy of drugs. In the last two decades, nanotechnology has rapidly developed, allowing for the incorporation of multiple therapeutics, sensing and targeting agents into nanoparticles (NPs) for developing new nanodevices capable to detect, prevent and treat complex diseases such as cancer. Method: In this review, we describe the main drug nanoformulations based on different types of organic NPs, the advantages that the new formulations present in comparison with their free drug counterparts and how nanodrugs have improved clinical care. We subdivided them into four main groups: polymeric NPs, liposomes, micelles and exosomes, a small subgroup that has only recently been used in clinical trials. Results: The application of nanotechnology to pharmaceutical science has allowed us to build up nanosystems based on at least two stage vectors (drug/nanomaterial), which often shown better pharmacokinetics (PK), bioavailability and biodistribution. As a result of these advantages, the nanomaterials accumulate passively in the tumor (due to the enhanced permeability and retention, effect, EPR), thereby decreasing the side effects of free drug. Recently, many new drug formulations have been translated from bench to bedside. Conclusion: It is important to underline that the translation of nanomedicines from the basic research phase to clinical use in patients is not only expensive and time-consuming, but that it also requires appropriate funding. After many years spent in the design of innovative nanomaterials, it is now the time for the research to take into consideration the biological obstacles that nanodrugs have to overcome. Barriers such as the mononuclear phagocyte system, intratumoral pressure or multidrug resistance are regularly encountered when a cancer patient is treated, especially in the metastatic setting.

Background: Inorganic nanoparticles (NPs) including those derived from metals (e.g., gold, silver), semiconductors (e.g., quantum dots), carbon dots, carbon nanotubes, or oxides (e.g., iron oxide), have been deeply investigated recently for diagnostic and therapeutic purposes in oncology. Compared to organic nanomaterials, inorganic NPs have several advantages and unique characteristics for better imaging and drug delivery. Still, only a limited number of inorganic NPs are translated into clinical practice. Method: In this review, we discuss the progression of inorganic NPs for cancer therapy and imaging, focusing our attention on opportunities, limitations and challenges for the main constituting nanomaterials, including metallic and magnetic NPs. In particular, the pre-clinical and clinical trials from the bench toward the clinic are here investigated. Results: Over the last few decades, the development of wide range of NPs with the ability to tune size, composition and functionality, has provided an excellent resource for nanomedicine. Inorganic NPs provide a great opportunity as drug carriers, due to the easy modification of targeting molecules, the control of drug release by different stimuli, and the effective delivery to target sites, thus resulting in having an improved therapeutic efficacy and in reducing side effects. Inorganic NPs are investigated in preclinical and clinical studies for the detection, diagnosis and treatment of many diseases. The stability of inorganic NPs offers a potential advantage over the traditional delivery methods. Inorganic NPs could enhance and improve current imaging and diagnostic techniques, such as MRI or PET. Even though, they have not yet been approved for drug delivery applications, their ability to respond to external stimuli is now widely investigated in clinic. Conclusion: The successful translation of inorganic NPs to the clinic requires the development of a simple, safe, cost-effective, ecofriendly mode of synthesis, and a better understanding of the safety mechanisms, biodistribution and the pharmacokinetics of NPs. However, more attention should be given to concerns on long-term toxicity, carcinogenesis, immunogenicity, inflammation and tissue damage. Although, some inorganic NPs, which were apparently promising in the preclinical phase, were found not to be successful when translated to the clinic, several encouraging NPs are currently being developed for treatment and cancer care and for a wide variety of other diseases.

Nowadays, fast and sensitive methods for biomarkers detection exist, but the performance of most of them still rely centralized laboratory testing. The development of small, fast and simple to use medical devices that can help in making diagnosis accurate and with low-invasiveness is now a major challenge for nanotechnology. Nanomaterialsbased systems have significant advantages over current conventional approaches in terms of simplicity, sensitivity, specificity, and rapidity. In this review, we describe the most interesting nanotechnological devices/approaches proposed for circulating biomarkers detection in oncology. In particular, new applicable nanobiosensors for nucleic acids and proteins identification are discussed and classified into four most interesting nanotechnologies: bio-barcodes, quantum dots, metal nanoparticles and carbon-based nanosensors. Their versatility has been demonstrated in different applications aiming to detect and quantify cancer biomarkers in real biological samples, in order to show how these methods can lead, in the future, to the development of devices for routine clinical application.

Background: PET and SPECT imaging methods can be of excellent assistance for the development of new nanoparticle drug delivery systems, and at the same time, these investigations also offer the opportunity to produce exceptional new diagnostic and therapeutic radiopharmaceuticals, as well. With a multifunctional, nano-scaled drug delivery system, the diagnostic (imaging) methods and the therapy (delivering drugs or beta-emitter radionuclides) can be carried out using the same biological and pharmacological mechanisms. By combining therapy and diagnostics in one method or in one specifically targeted nanoparticle system, we can product theranostic pharmaceuticals, and its applications are important elements of personalized medicine. Objectives: This review takes a short historical look back to the radiocolloids, the great ancestors of (radiolabeled) nanoparticles and then describes the general features of current types of PET and SPECT imaging associated nanoparticle-based products and key radiolabeling methods; entering into details of potential prospective challenges related to radiotheranostic approaches and imaging guided therapy.

Background and Rationale: Therapeutic drug monitoring (TDM) is the clinical practice of measuring pharmaceutical drug concentrations in patients' biofluids at designated intervals to allow a close and timely control of their dosage. This practice allows for rapid medical intervention in case of toxicity-related issues and/or adjustment of dosage to better fit the therapeutic demand. Currently, TDM is performed in centralized laboratories employing instruments, such as immunoassay analyzers and mass spectrometers that can be run only by trained personnel. However, the time required for the preparation, samples analysis, and data processing, together with the related financial cost, severely affects the application of TDM in medical practices. Therefore, a new generation of analytical tools is necessary to respond to the timely need of drug administration or reduction aiming at effectively treating oncologic patients. Aim of the Review: State-of-the-Art Technologies for TDM: Technological advances in the field of nanosciences and biosensors offer the unique opportunity to address such issues. The interest for the so-called nanobiosensors is considerably increasing, particularly in drug discovery and clinical chemistry, even though there are only few examples reporting their use for TDM. The techniques employing nanobiosensors are mainly based on electrochemical, optical, and mass detection systems. Conclusions: In this review, we described the most promising methodologies that, in our opinion, will bring TDM towards the next stage of clinical practice in the future.

Hydrogen sulfide (H2S), previously known only as a toxic agent, in the last decades has been recognized as an important endogenous gasotransmitter, playing a key role in the homeostasis of the cardiovascular system. In the last years, the growing evidence about a protective role exhibited by H2S against myocardial ischemia/reperfusion (I/R), led to an increasing interest for the possible mechanism of action accounting for the H2S cardioprotective effect, and to the discovery of the involvement of several targets. Currently, many mechanisms of action have been proposed and verified through in vitro and in vivo models of I/R injury, such as the anti-inflammatory or the anti-oxidant ones, or mechanisms of Ssufhydration able to modify proteins such as ion channels. Particular attention was focused on the mitochondrial preservation and on anti-apoptotic mechanisms, and finally even a pro-angiogenesis effect has been described. At the same time, the design, the development and the pharmacological characterization of moieties able to release H2S, employed alone as H2S-donor, or conjugated with another drug in hybrid molecules, led to the production of novel chemical entities in the panorama of cardioprotective drugs.

In acute myocardial infarction (AMI), the first line of treatment is to rapidly restore blood flow to the ischemic myocardium to limit infarct size. It is now well established that though clearly beneficial, the positive outcomes of this intervention are limited by injury in response to the reperfusion itself in addition to the prior ischemia. This process is described as reperfusion injury and is considered to contribute to the arrhythmias, microvascular dysfunction and impaired cardiac contractility that is observed even after the restoration of coronary blood flow. Thus an important, currently unmet, therapeutic challenge is to address the outcomes of this reperfusion injury. In this article, we review the evidence that flavonols and flavones may prove useful in preserving cardiac function after ischemia and reperfusion and consider the possible mechanisms, in particular, the inhibition of kinases, by which they may exert protection.

Background: Excessive norepinephrine (NE) release in the ischemic heart elicits severe and often lethal arrhythmias. Resident cardiac mast cells synthesize and store active renin, which is released upon degranulation, causing the activation of a local cardiac renin-angiotensin system (RAS) responsible for NE release and consequent arrhythmias. Toxic aldehydes, known to be formed by lipid peroxidation in ischemia/reperfusion (I/R), have been shown to degranulate mast cells and activate a local RAS. Objective: To provide an up-to-date description of the roles of ischemic preconditioning (IPC) and Gicoupled receptors in anti-RAS cardioprotection. Methods: Ex-vivo I/R models in cavian and murine hearts, and human and murine mast cell lines in vitro. Results: IPC not only drastically reduces the injury subsequent to a prolonged ischemic event, but also decreases mast cell renin release, thus affording anti-RAS cardioprotection. Similarly, activation of Gicoupled receptors, such as histamine-H4, adenosine-A3 and sphingosine-1-phosphate-S1P1 receptors, all expressed at the mast cell surface, mimic the cardioprotective anti-RAS effects of IPC. The mechanism of this action depends on the sequential activation of a specific isoform of protein kinase C, PKC, and mitochondrial aldehyde dehydrogenase-type 2 (ALDH2). Increased ALDH2 enzymatic activity exerts a pivotal role in the sequential inhibition of aldehyde-induced mast-cell renin release, prevention of RAS activation, reduction of NE release and alleviation of reperfusion arrhythmias. Conclusion: These recently discovered protective pathways indicate that activation of mast-cell Gicoupled receptors and subsequent ALDH2 phosphorylation/activation represent a novel therapeutic target for the alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.

SIRT1 is a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, which removes acetyl groups from many target proteins, such as histone proteins, transcription factors and cofactors. SIRT1-catalyzed deacetylation of these factors modulates the activity of downstream proteins, thus influencing many biological processes. SIRT1 is involved in the regulation of metabolism, inflammation, and tumor growth. The activity of this enzyme is related to the beneficial health effects of calorie restriction, such as lifespan extension and, in particular, the activation of SIRT1 has a positive impact on the cardiovascular system. Therefore, SIRT1 is considered as an attractive drug target and modulation of SIRT1 may represent a new therapeutic strategy against cardiovascular diseases, as small molecules able to activate SIRT1 can be considered as cardioprotective agents. In this review, we summarize both natural and synthetic compounds developed as SIRT1 activators, with a focus on their promising therapeutic applications in cardiovascular pathologies.

Moderate exercise training is a key aspect of primary and secondary prevention strategies. Shear-induced upregulation of eNOS activity and function in the vascular endothelium is considered as one of the main molecular mechanisms of exercise-induced protection against myocardial ischemia/ reperfusion (I/R) injury. It has been reported that levels of plasma nitrite, which are largely dependent on eNOS activity, were increased in healthy subjects after acute exercise, while this increase was abolished in coronary artery disease (CAD) patients. Our group and others demonstrated that RBCs contain a functional eNOS, which contributes to systemic nitrite homeostasis and to cardioprotection; moreover, expression and activity of red cell eNOS are decreased in CAD patients and significantly correlated with flow-mediated dilation, a diagnostic marker of endothelial function. Therefore, in addition to vascular eNOS, also red cell eNOS (or in more general terms NO metabolic activity of RBCs) may play a role in exercise-dependent changes of NO-bioavailability. In this review, we will focus on what is known and what is unknown about the role of RBCs in exercise-dependent cardioprotection with emphasis on RBC signaling and red cell eNOS. In detail, we will discuss the effects and molecular mechanisms of shear stress and exercise training on RBC signaling and function, review how these changes may influence blood rheology and systemic hemodynamics and highlight the potential role of red cell eNOS-mediated cardiovascular protection induced by physical activity against myocardial injury in animal and human studies and in clinical settings.