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ABSTRACT In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clinical trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biologic. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clinical trials, with ~40% of trials listed in clinicaltrials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorganic and metallic particles in clinical trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clinical trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials (“theranostics”) and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what additional testing (e.g. safety and toxicity) is required before products become available.

Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.Radiopharmaceutical therapy is emerging as a safe and effective approach for the treatment of cancer, offering several advantages over existing therapeutic strategies. Here, Sgouros and colleagues provide an overview of the fundamental properties of radiopharmaceutical therapy, discuss agents in use and in clinical development and highlight the associated translational challenges.

Key Points Nanoparticulate pharmaceutical drug delivery systems (NDDSs) are used in research and clinical settings to overcome several issues associated with traditional drugs, such as poor aqueous solubility, low bioavailability and nonspecific distribution in the body, and to enhance drug efficiency. Multifunctional NDDSs are able to simultaneously bear a sufficient load of a drug, have increased circulation times and target the drug to the intended site of action. Moreover, they can respond to various stimuli that are characteristic of the pathological site and can even be supplemented with a contrast moiety to enable monitoring of their biodistribution, target accumulation or the efficacy of the therapy. One of the most common properties of NDDSs is the combination of prolonged circulation times with targetabilty. Active targeting of NDDSs can be achieved by surface modification of the NDDS with targeting ligands. Diseases that could benefit from NDDS-based therapy include cancer, cardiovascular diseases and infectious diseases. NDDSs that respond to different types of stimuli are an important and continuously growing area of research. This responsiveness can be used to control the properties and behaviour of NDDSs. The stimuli can be internal and intrinsic for the target site (such as changes in pH, temperature, redox condition or the activity of certain enzymes) or ones that are external and artificially applied (such as a magnetic field, ultrasound and various types of irradiation). After reaching the target, NDDSs may still need to cross the barrier of the cell membrane to deliver their drug load into the cell cytoplasm or specific organelles inside the cell; strategies to facilitate this process have been developed or are under investigation. Multifunctional NDDSs have been constructed for multimodal imaging, which could overcome several problems associated with individual imaging modalities, such as insufficient sensitivity or resolution. Multifunctional and stimulus-sensitive nanoparticles can overcome issues associated with traditional drug delivery by, for example, improving targeting and bioavailability. Here, Torchilin highlights recent developments in these types of nanocarriers and how they can also include imaging contrast moieties to track their real-time biodistribution and accumulation at the target site. The use of nanoparticulate pharmaceutical drug delivery systems (NDDSs) to enhance the in vivo effectiveness of drugs is now well established. The development of multifunctional and stimulus-sensitive NDDSs is an active area of current research. Such NDDSs can have long circulation times, target the site of the disease and enhance the intracellular delivery of a drug. This type of NDDS can also respond to local stimuli that are characteristic of the pathological site by, for example, releasing an entrapped drug or shedding a protective coating, thus facilitating the interaction between drug-loaded nanocarriers and target cells or tissues. In addition, imaging contrast moieties can be attached to these carriers to track their real-time biodistribution and accumulation in target cells or tissues. Here, I highlight recent developments with multifunctional and stimuli-sensitive NDDSs and their therapeutic potential for diseases including cancer, cardiovascular diseases and infectious diseases.

β-Carotene intake and tissue/blood concentrations have been associated with reduced incidence of several chronic diseases. Further bioactive carotenoid-metabolites can modulate the expression of specific genes mainly via the nuclear hormone receptors: retinoic acid receptor- and retinoid X receptor-mediated signalling. To better understand the metabolic conversion of β-carotene, inter-individual differences regarding β-carotene bioavailability and bioactivity are key steps that determine its further metabolism and bioactivation and mediated signalling. Major carotenoid metabolites, the retinoids, can be stored as esters or further oxidised and excreted via phase 2 metabolism pathways. In this review, we aim to highlight the major critical control points that determine the fate of β-carotene in the human body, with a special emphasis on β-carotene oxygenase 1. The hypothesis that higher dietary β-carotene intake and serum level results in higher β-carotene-mediated signalling is partly questioned. Alternative autoregulatory mechanisms in β-carotene / retinoid-mediated signalling are highlighted to better predict and optimise nutritional strategies involving β-carotene-related health beneficial mediated effects.

The economic and health burden caused by adverse drug reactions has increased dramatically in the last few years. This is likely to be mediated by increasing polypharmacy, which increases the likelihood for drug–drug interactions. Tools utilized by healthcare practitioners to flag potential adverse drug reactions secondary to drug–drug interactions ignore individual genetic variation, which has the potential to markedly alter the severity of these interactions. To date there have been limited published studies on impact of genetic variation on drug–drug interactions. In this review, we establish a detailed classification for pharmacokinetic drug–drug–gene interactions, and give examples from the literature that support this approach. The increasing availability of real-world drug outcome data linked to genetic bioresources is likely to enable the discovery of previously unrecognized, clinically important drug–drug–gene interactions.

Background Human adipose-derived mesenchymal stem cells (haMSCs) have shown efficacy in treating osteoarthritis (OA) both preclinically and clinically via intra-articular (IA) injection. However, understanding the mode of action of the cell therapy has been limited by cell tracking capability and correlation between the pharmacokinetics of the injected cells and the intended pharmacodynamics effect. This study aims to explore methodology and to understand in vivo biodistribution of clinical-grade haMSCs labeled with fluorescent dye and injected into an immunocompetent OA rat model. Methods haMSCs labeled with fluorescent dye were investigated for their proliferation and differentiation capabilities. Labeled cells were used to establish detection threshold of a noninvasive biofluorescent imaging system before the cells (2.5 × 10 6 ) were injected into a conventional rat OA model induced by medial meniscectomy for 8 weeks. We attempted to reveal the existence of labeled cells in vivo by imaging and a molecular biomarker approach, and to correlate with the in vivo efficacy and physical presence over a follow-up period up to 10 weeks. Results In vitro proliferation and differentiation of haMSCs were not affected by the labeling of DiD dye. Detection thresholds of the labeled cells in vitro and in vivo were determined to be 10 4 and 10 5 cells, respectively. When 2.5 × 10 6 haMSCs were injected into the joints of a rat OA model, fluorescent signals (or >10 5 cells) lasted for about 10 weeks in the surgical knee joint at the same time as efficacy was observed. Signals in nonsurgical rats only lasted for 4 weeks. The human MSCs were shown to engraft to the rat joint tissues and were proliferative. Human FOXP2 gene was only detected in the knee joint tissue, suggesting limited biodistribution locally to the joints. Conclusions The current study represents the first attempt to correlate cell therapy efficacy on OA with the physical presence of the injected haMSCs in the OA model, and demonstrates that human adipose-derived mesenchymal stem cells persisted for 10 weeks locally in the rat joint, coinciding with the efficacy observed. It is postulated that persistence and/or proliferation of the haMSCs in the joint is required in order to exert their functions on promoting joint regeneration and/or cartilage protection, further supporting the safety and feasibility of IA injection of MSCs for the treatment of OA patients.

Fucus vesiculosus L., known as bladderwrack, belongs to the brown seaweeds, which are widely distributed throughout northern Russia, Atlantic shores of Europe, the Baltic Sea, Greenland, the Azores, the Canary Islands, and shores of the Pacific Ocean. Fucoidan is a major fucose-rich sulfated polysaccharide found in Fucus (F.) vesiculosus. The pharmacokinetic profiling of active compounds is essential for drug development and approval. The aim of the study was to evaluate the pharmacokinetics and tissue distribution of fucoidan in rats after a single-dose oral administration. Fucoidan was isolated from F. vesiculosus. The method of measuring anti-activated factor X (anti-Xa) activity by amidolytic assay was used to analyze the plasma and tissue concentrations of fucoidan. The tissue distribution of fucoidan after intragastric administration to the rats was characterized, and it exhibited considerable heterogeneity. Fucoidan preferentially accumulates in the kidneys (AUC0–t = 10.74 µg·h/g; Cmax = 1.23 µg/g after 5 h), spleen (AUC0–t = 6.89 µg·h/g; Cmax = 0.78 µg/g after 3 h), and liver (AUC0–t = 3.26 µg·h/g; Cmax = 0.53 µg/g after 2 h) and shows a relatively long absorption time and extended circulation in the blood, with a mean residence time (MRT) = 6.79 h. The outcome of this study provides additional scientific data for traditional use of fucoidan-containing plants and offers tangible support for the continued development of new effective pharmaceuticals using fucoidan.

Compartmentation is a key strategy enacted by plants for the storage of specialized metabolites. The saffron spice owes its red color to crocins, a complex mixture of apocarotenoid glycosides that accumulate in intracellular vacuoles and reach up to 10% of the spice dry weight. We developed a general approach, based on coexpression analysis, heterologous expression in yeast (Saccharomyces cerevisiae), and in vitro transportomic assays using yeast microsomes and total plant metabolite extracts, for the identification of putative vacuolar metabolite transporters, and we used it to identify Crocus sativus transporters mediating vacuolar crocin accumulation in stigmas. Three transporters, belonging to both the multidrug and toxic compound extrusion and ATP binding cassette C (ABCC) families, were coexpressed with crocins and/or with the gene encoding the first dedicated enzyme in the crocin biosynthetic pathway, CsCCD2. Two of these, belonging to the ABCC family, were able to mediate transport of several crocins when expressed in yeast microsomes. CsABCC4a was selectively expressed in C. sativus stigmas, was predominantly tonoplast localized, transported crocins in vitro in a stereospecific and cooperative way, and was able to enhance crocin accumulation when expressed in Nicotiana benthamiana leaves.

Tunneling nanotubes (TNTs), discovered in 2004, are thin, long protrusions between cells utilized for intercellular transfer and communication. These newly discovered structures have been demonstrated to play a crucial role in homeostasis, but also in the spreading of diseases, infections, and metastases. Gaining much interest in the medical research field, TNTs have been shown to transport nanomedicines (NMeds) between cells. NMeds have been studied thanks to their advantageous features in terms of reduced toxicity of drugs, enhanced solubility, protection of the payload, prolonged release, and more interestingly, cell-targeted delivery. Nevertheless, their transfer between cells via TNTs makes their true fate unknown. If better understood, TNTs could help control NMed delivery. In fact, TNTs can represent the possibility both to improve the biodistribution of NMeds throughout a diseased tissue by increasing their formation, or to minimize their formation to block the transfer of dangerous material. To date, few studies have investigated the interaction between NMeds and TNTs. In this work, we will explain what TNTs are and how they form and then review what has been published regarding their potential use in nanomedicine research. We will highlight possible future approaches to better exploit TNT intercellular communication in the field of nanomedicine.

ABSTRACT Purpose Solid lipid nanoparticles (SLNs) have been proposed as a colloidal carrier system that could enhance the oral bioavailability of curcumin. However, a burst release of the loaded drug, which occurs in acidic environments, has been a main obstacle to the oral delivery of curcumin by using SLNs as a carrier system. We hypothesized that a quarternized chitosan derivative could be used for acid-resistant coating to stabilize the SLNs and circumvent the burst release. Methods N -trimethyl chitosan (TMC) was synthesized and determined by 1 H-NMR and FT-IR. To investigate the details of chitosan and TMC surface modification on SLCNs composed of palmitic acid, cholesterol, TPGS and curcumin, a number of factors such as optimized SLNs composition, solid state characterization, stability, cell viability, in vitro release in GI conditions, curcumin oral bioavailability and brain distribution studies, were evaluated. Results The TMC-SLCNs exhibited prolonged stability in room and refrigerated conditions, controlled drug release in simulated intestinal fluid, significantly higher oral bioavailability, and brain distribution of curcumin than free curcumin, chitosan and non-coated SLCNs. Conclusions These finding suggests that the TMC-SLCNs is a promising nanocarrier system for oral delivery and brain distribution of curcumin.