Current Pharmaceutical Design - Volume 23, Issue 20, 2017

Background: The study of magnetic nanoparticles (MNPs) for drug delivery has recently seen a surge of interest even though the first studies were conducted as early as in the seventies. Despite this, there are still gaps in the knowledge of the field, implicating the complexities in designing the ideal MNP for drug delivery. The large surface area of MNPs and the ability to manipulate with an externally applied magnetic field render the MNP a good candidate for targeted delivery of drugs. Drugs are conjugated to the surface of MNPs or encapsulated within, while the surface of MNPs receives a protective coating and is functionalised with ligands, enzymes, linkers, and active molecules to deliver the drug to a targeted site. Results: These MNPs in the form of nanogels, micelles, polymers, dendrimers, and receptor-targeted have been studied in vitro and in vivo to assess morphology, cytotoxicity, localisation and others, which are the indicators of efficacy. While preclinical studies appear to be promising, there is a limited translation from bench to bedside for reasons such as inconsistent results between similar studies and inadequate profiles of toxicity, drug release and biodistribution amongst many others. However, the substantial number of clinical trials of MNPs in other applications such as hyperthermia for the treatment of cancer and imaging shows that there is indeed potential in the development of MNPs to achieve successful drug delivery. Conclusion: The lack of optimal design for MNP surface functionalization and conjugation to drug and other molecules for delivery to target cells gives plenty of room for the research and development of the ideal MNP, which is indicated for the future of MNPs in biomedical applications.

Drug delivery systems are effective and attractive methods which allow therapeutic substances to be introduced into the body more effectively and safe by having tunable delivery rate and release target site. Gold nanoparticles (AuNPs) have a myriad of favorable physical, chemical, optical, thermal and biological properties that make them highly suitable candidates as non-toxic carriers for drug and gene delivery. The surface modifications of AuNPs profoundly improve their circulation, minimize aggregation rates, enhance attachment to therapeutic molecules and target agents due to their nano range size which further increases their ability to cross cell membranes and reduce overall cytotoxicity. This comprehensive article reviews the applications of the AuNPs in drug delivery systems along with their corresponding surface modifications. The highlighting results obtained from the preclinical trial are promising and next five years have huge possibility move to the clinical setting.

Due to efficacious characteristics of calcium phosphate nanoparticles (CPNs), they have numerously been employed in nanomedicine, particularly as carrier for therapeutic and diagnostic agents, and also in tissue engineering. Although calcium phosphate minerals are noted for their cytocompatibility, there are outstanding findings from various studies that question whether they are still compatible with cells in nanoscale ranges or not and it leads to the controversial issue of CPNs cytocompatibility versus cytotoxicity. In this regard, it is necessary to know how CPNs could result in cytotoxicity for future studies. Interestingly, most of the researchers have attributed the cytotoxicity to triggering of apoptosis in CPNs-exposed cells. Furthermore, it is reported that CPNs could result in cancer cell demise through induction of apoptosis. According to the findings, not only CPNs are promising for cancer cell drug delivery, but also they have the potential to be employed as therapeutic agents. In this review, firstly the physical and chemical properties of CPNs and their application in medicine are reviewed. Moreover, the interaction between CPNs and different kind of cells are covered. Lastly, employment of CPNs as a therapeutic agent is discussed.

Background: Therapeutic efficacy of dreadful diseases like cancer, HIV (Human Immunodeficiency Virus) can be enhanced by delivering molecules which regulate function at gene level rather than at receptor level. Silencing RNA is one such approach recently used to silence target gene expressed diseases; and thereby reduce target protein levels. Many of the non-viral vectors are proved to act as carriers for silencing RNA. Dendrimers being one of them have less size, low poly dispersibility index, water solubility, multivalence, and easy surface modification. Many such surface modifications have been carried out to improve the delivery potential of small interfering RNA (siRNA) modified dendrimers compared to simple plain dendrimers. Methods: Dendrimer was taken as a core whose surface was modified with fluorine, amino acids, phosphate, lipids, folate, specific antibody or RGD (Arg-Gly-Asp). The purpose of these modifications was to increase the therapeutic siRNA efficiency, lower the toxicity and improve the targeting potential of dendrimers. Results: Fluorinated dendrimers have highest electronegativity and highest siRNA loading capacity. Amino acid functionalized dendrimers are made up of endogenous amino acids which improve biocompatibility of dendrimer and endosomal escape. Carbosilane dendrimers increase the gene transfection ability of tissues to be treated. Phosphate dendrimers having hydrophobic backbone and hydrophilic surface increase the permeability towards targeted tissue. Lipid based dendrimer causes endosomal escape and improves the permeability of dendrimers. Targeting of specific tissues is achieved by coupling dendrimer with folate, RGD and specific antibody, thereby reducing off target effect. Conclusion: Thus, surface modified dendrimers render a complete pack which offers increased siRNA loading, increased transfection and permeability, efficient targeting, endosomal escape and protecting siRNA from degradation by RNase and other such enzymes. The objective of this manuscript is to provide different approaches currently available for surface modifications of dendrimers and their overall effect on transfection ability of siRNA to target tissues.

The artificial nanostructures such as nanoparticles and natural nanostructures such as secreted nanosized extracellular vesicles known as exosomes are promising tools for the realization of personalized medicine. Radionanomedicine is a recently coined term for the simultaneous application of either radiation technology or nuclear medicine with nanomedicine. In addition, radioexosomics is our suggested term for the study of exosomes functions, cytotoxicity, cancerogenicity, and biodistribution using radiation technology and nuclear medicine tracing technology. Prostate cancer (PCa) is the most commonly diagnosed cancer in males and a big majority of patients with PC progress to castration-resistant prostate cancer (CRPC) mostly. The mechanisms leading to development of CRPC remain poorly understood and there is still a need to improve the therapeutic options available for PCa. In this review, a wide variety of nanostructure-based prostate cancer research using radiation technology and nuclear medicine is discussed. In addition, we will present what is currently known about the function of exosomes in PCa. The review concludes by summarizing the current status and future perspectives of radionanomedicine and radioexosomics for understanding PCa biology, as well as PCa enhancement of targeting strategies, drug delivery, molecular imaging and therapy.

Animal models have been the main resources for drug discovery and prediction of drugs’ pharmacokinetic responses in the body. However, noticeable drawbacks associated with animal models include high cost, low reproducibility, low physiological similarity to humans, and ethical problems. Engineered tissue models have recently emerged as an alternative or substitute for animal models in drug discovery and testing and disease modeling. In this review, we focus on skeletal muscle and cardiac muscle tissues by first describing their characterization and physiology. Major fabrication technologies (i.e., electrospinning, bioprinting, dielectrophoresis, textile technology, and microfluidics) to make functional muscle tissues are then described. Finally, currently used muscle tissue models in drug screening are reviewed and discussed.

Background: Non-infectious uveitis is a sight-threatening inflammatory disease that often necessitates prolonged use of high-dose corticosteroids, resulting in significant systemic side effects. There is a need for efficacious steroid-sparing immunomodulatory therapy for these patients, and the mTOR inhibitors (sirolimus and everolimus) may be contenders for this role. Methods: A comprehensive review of preclinical and clinical research on mTOR inhibitors for non-infectious uveitis was performed. Articles were identified by a search of MEDLINE (PubMed/OVID) and EMBASE (OVID) the terms (uveitis OR non-infectious uveitis) AND (mTOR inhibitor OR sirolimus OR everolimus). Assessment of study aims, methods, efficacy outcomes and adverse events was performed. Results: Seven pre-clinical and nine clinical studies were identified. One study in each group was on everolimus, the rest sirolimus. Preclinical studies have been performed in rabbit, rat, mouse and in-vitro models. Clinical studies range from comparative open-label trials to case reports, with reported clinical efficacy ranging from 40% to 100% depending on endpoint assessed. The overall rate of drug-related adverse events (such as ocular irritation, visual floaters, nausea and vomiting) was 0.640 events per patient-year with sirolimus, and 0.111 events per patient-year with everolimus. Conclusion: Published evidence suggests that sirolimus and everolimus may be useful in the management of noninfectious uveitis. Both appear to be well tolerated, especially when locally administered. Further high-quality RCTs adopting standardised end-points are required to definitively determine the efficacy of each agent.

The antioxidant properties of caffeic and ferulic acids in biological systems have been extensively demonstrated. As antioxidants, these compounds prevent the production of reactive oxygen species (ROS), which cause cell lesions that are associated with the development of several diseases, including cancer. Recent findings suggest that the chemoprotective action of these phenolic acids occurs through the following mechanisms: regulation of gene expression, chelation and / or reduction of transition metals, formation of covalent adducts and direct toxicity. The biological efficacy of these promising chemoprotective agents is strongly related with their chemical structure. Therefore, in this study, we discuss the structural characteristics of ferulic and caffeic acids that are responsible for their biological activities, as well as the mechanisms of action involved with the anti-cancer activity. Several reports indicated that the antioxidant effect of these phenylpropanoids results from reactions with free radicals with formation of stable products in the cells. The chelating effect of these compounds was also reported as an important protective mechanism against oxidative. Finally, the lipophilicity of these agents facilitates their entry into the cells, and thus, contributes to the anticancer activity.

Background: Cardiovascular morbidity and mortality of dialysis patients are major problems in this group of patients. Methods: The purpose of this study was also to evaluate whether any of the studied markers are better than troponin in early detection of the occurrence of ventricular arrhythmias and prolongation of QT interval. This study included 45 patients undergoing hemodialysis. ECG Holter and echocardiographic examination were performed before and after dialysis. The concentrations of markers: copeptin, GDF-15, HFABP and troponin were measured with the use of ELISA tests. Results: We observed significantly higher QT (p=0.004), QTc (0.018), right atrium volume (p=0.006) and concentrations of copeptin (p<0.0001) and H-FABP (p<0.0001) as well as smaller left atrium volume (p<0.0001) and width of inferior vena cava (p<0.0001) after dialysis than before it. Significantly longer QT and higher copeptin levels were seen in patients with ventricular arrhythmia. A trend between the increase in copeptin concentration and H-FABP level and the presence of ventricular arrhythmias was also noted. Conclusion: Generally, we failed to find any strong predictor of post-dialysis ventricular arrhythmia or the prolongation of QT, however, it seems that copeptin may have prognostic value, but this has to be analyzed in large studies.

Background: In this study, we developed a drug of IFN-α combined with pPB-SSLs, which specifically target at platelet-derived growth factor receptor-β (PDGFR-β). Aim: The aim of this study is to improve the limitations of IFN-α including insufficient drug concentration for the target cells and side-effects causing serious concerns in treatment of hepatic fibrosis. Methods: We constructed the targeted stable liposomes (SSLs) that not only increase the half-life period of IFN-α, but also can deliver IFN-α to hepatic stellate cells (HSCs). Subsequently, the anti-hepatic-fibrosis effect of pPB-SSL-IFN-α was evaluated both in vitro and in vivo. Immunofluorescent assay showed that the pPB-SSL particles were able to be easily taken up by 3T3 cells. The cellular distribution experiment demonstrated that most of the pPB-SSL-IFN-α would accumulate around the fibroblast, and the cell would be invaded by pPB-SSLIFN-α. Results: The pPB-SSL-IFN-α showed an entrapment efficiency of 39.73 ± 5.21% for IFN-α and the particles reached nanoscale level. It showed more significant alleviated performance for hepatic fibrosis than IFN-α. Both in vitro and in vivo, the pPB-SSL-IFN-α could contribute to reduction or inhibition in the expression of TGF-β1 and α-SMA even cleavage of caspase-3. Moreover, it was found that the pPB-SSL-IFN-α induced the apoptosis of 3T3 cells by inhibiting the expression of TGF-β1 as well as α-SMA. Under observation for fibrotic liver of mice treated with pPB-SSL-IFN-α, the semiquantitative score for collagen I, TGF-β1 and α-SMA were all inferior to the control group and those treated with PEG-IFN-α, SSL-IFN-α or IFN-α. In addition, pPB-SSL-IFN-α has been detected to down-regulate the expression of TNF-α and IL-1β in comparison with model group (P<0.01). And the phosphorylations of JAK1 and STAT1 were enhanced by pPB-SSL-IFN-αin comparison with model groups (P < 0.01). Conclusion: All results of our present research indicated that the pPB-SSL-IFN-α might be an alternative antiliver fibrotic drug and the synthetic method may offer a new access to the anti-hepatic fibrosis research and development.