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.

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Herein we demonstrate the use of a wearable device that can selectively capture two distinct circulating protein biomarkers (recombinant P. falciparum rPf HRP2 and total IgG) from the intradermal fluid of live mice in situ, for subsequent detection in vitro. The device comprises a microprojection array that, when applied to the skin, penetrates the outer skin layers to interface directly with intradermal fluid. Because of the complexity of the biological fluid being sampled, we investigated the effects of solution conditions on the attachment of capture antibodies, to optimize the assay detection limit both in vitro and on live mice. For detection of the target antigen diluted in 20% serum, immobilization conditions favoring high antibody surface density (low pH, low ionic strength) resulted in 100fold greater sensitivity in comparison to standard conditions, yielding a detection limit equivalent to the plate enzyme-linked immunosorbent assay (ELISA). We also show that blocking the device surface to reduce nonspecific adsorption of target analyte and host proteins does not significantly change sensitivity. After injecting mice with rPf HRP2 via the tail vein, we compared analyte levels in both plasma and skin biopsies (cross-sectional area same as the microprojection array), observing that skin samples contained the equivalent of ∼8 μL of analyte-containing plasma. We then applied the arrays to mice, showing that surfaces coated with a high density of antibodies captured a significant amount of the rPf HRP2 target while the standard surface showed no capture in comparison to the negative control. Next, we applied a triplex device to both control and rPf HRP2-treated mice, simultaneously capturing rPf HRP2 and total IgG (as a positive control for skin penetration) in comparison to a negative control device. We conclude that such devices can be used to capture clinically relevant, circulating protein biomarkers of infectious disease via the skin, with potential applications as a minimally invasive and lab-free biomarker detection platform.

Novel optical nanosensors for the selective detection of the polycationic protamine based on solvatochromic signal change allow one to detect heparin in plasma.

Continuous monitoring using nanoparticle-based sensors has been successfully employed in complex biological systems, yet the sensors still suffer from poor long-term stability partially because of the scaffold materials chosen to date. Organosilica core-shell nanoparticles containing a mixture of covalently incorporated pH-sensitive (shell) and pH-insensitive (core) fluorophores is presented as a continuous pH sensor for application in biological media. In contrast to previous studies focusing on similar materials, we sought to investigate the sensor characteristics (dynamic range, sensitivity, response time, stability) as a function of material properties. The ratio of the fluorescence intensities at specific wavelengths was found to be highly sensitive to pH over a physiologically relevant range (4.5-8) with a response time of <100 ms, significantly faster than that of previously reported response times using silica-based particles. Particles produced stable, pH-specific signals when stored at room temperature for more than 80 days. Finally, we demonstrated that the nanosensors successfully monitored the pH of a bacterial culture over 15 h and that pH changes in the skin of mouse cadavers could also be observed via in vivo fluorescence imaging following subcutaneous injection. The understanding gained from linking sensor characteristics and material properties will inform the next generation of optical nanosensors for continuous-monitoring applications.

Selective capture of disease-related proteins in complex biological fluids and tissues is an important aim in developing sensitive protein biosensors for in vivo applications. Microprojection arrays are biomedical devices whose mechanical and chemical properties can be tuned to allow efficient penetration of skin, coupled with highly selective biomarker capture from the complex biological environment of skin tissue. Herein, the authors describe an improved surface modification strategy to produce amine-modified polycarbonate arrays, followed by the attachment of an antifouling poly(sulfobetaine-methacrylate) (pSBMA) polymer or a linear polyethylene glycol (PEG) polymer of comparative molecular weight and hydrodynamic radius. Using a "grafting to" approach, pSBMA and linear PEG coatings yielded comparative antifouling behavior in single protein solutions, diluted plasma, or when applied to mouse flank skin penetrating into the vascularized dermal tissue. Interestingly, the density of immobilized immunoglobulin G (IgG) or bovine serum albumin protein on pSBMA surfaces was significantly higher than that on the PEG surfaces, while the nonspecific adsorption was comparable for each protein. When incubated in buffer or plasma solutions containing dengue non-structural protein 1 (NS1), anti-NS1-IgG-coated pSBMA surfaces captured significantly more NS1 in comparison to PEG-coated devices. Similarly, when wearable microprojection arrays were applied to the skin of dengue-infected mice using the same coatings, the pSBMA-coated devices showed significantly higher capture efficiency (>2-fold increase in signal) than the PEG-coated substrates, which showed comparative signal when applied to naïve mice. In conclusion, zwitterionic pSBMA polymers (of equivalent hydrodynamic radii to PEG) allowed detection of dengue NS1 disease biomarker in a preclinical model of dengue infection, showing significantly higher signal-to-noise ratio in comparison to the PEG controls. The results of this study will be useful in the future development of a range of protein biosensors designed for use in vivo.

A pixel-level colorimetric absorbance analysis can measure the total quantity of dye on paper, irrespective of shape and size.

Development of antifouling films which selectively capture or target proteins of interest is essential for controlling interactions at the "bio/nano" interface. However, in order to synthesize biofunctional films from synthetic polymers that incorporate chemical "motifs" for surface immobilization, antifouling, and oriented biomolecule attachment, multiple reaction steps need to be carried out at the solid/liquid interface. EKx is a zwitterionic peptide that has previously been shown to have excellent antifouling properties. In this study, we recombinantly expressed EKx peptides and genetically encoded both surface attachment and antibody-binding motifs, before characterizing the resultant biopolymers by traditional methods. These peptides were then immobilized to organosilica nanoparticles for binding IgG, and subsequently capturing dengue NS1 as a model antigen from serum-containing solution. We found that a mixed layer of a short peptide (4.9 kDa) "backfilled" with a longer peptide terminated with an IgG-binding Z-domain (18 kDa) demonstrated selective capture of dengue NS1 protein down to ∼10 ng mL in either PBS or 20% serum.