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.
A wide range of microfluidic paper-based analytical devices (μPADs) have been developed in the last decade. Despite this, the quality of colorimetric analysis has not substantially improved as the ...data is vulnerable to heterogeneous color distribution (
e.g.
, coffee ring effects), non-uniform shapes of colored detection area, and noise from the underlying paper structure. These limitations are here addressed by a colorimetric method to quantify freely discharged dye on paper substrate, without the need for a defined channel or hydrophobic barrier. For accurate quantification, colorimetric absorbance values are calculated for each pixel based on the recorded RGB values and noise from the paper structure eliminated, to extract accurate absorbance information at the pixel level. Total analyte quantity is then calculated through the conversion of absorbance values into quantity values for each pixel followed by integration across the entire image. The resulting quantity is shown to be independent of the shape of the applied colored dye spot, with a cross, circle or rod shape all giving the same quantity information. The approach is applied to a capillary-based potassium-selective sensor, where the sample solution is loaded with the dye thioflavin T (ThT) obtained by quantitative exchange with K
+
in a sensing capillary, which is discharged onto a bare paper substrate without any channels. The resulting dye quantity is successfully obtained by flatbed scanner and smartphone. The successful automated computation of colorimetric data on μPADs will help realize simpler paper-based assay and reaction systems that should be more applicable to addressing real world analytical problems.
A pixel-level colorimetric absorbance analysis can measure the total quantity of dye on paper, irrespective of shape and size.
Optical sensors continue to demonstrate tremendous potential across a wide range of applications due to their high versatility and low cost. This feature article will focus on a number of recent ...advances made in improving the performance of extraction-based optical ion sensors within our group. This includes the progress of anchored solvatochromic transduction to provide pH and sample volume independent optical responses in nanoemulsion-based sensors. A recent breakthough is in polyion sensing in biological fluids that uses a novel indirect transduction mechanism that significantly improves the selectivity of dinonylnaphthalenesulfonate-based protamine sensors and its potential applications beyond polyion sensing. The role of particle stabilizers in relation to the response of emulsified sensors is shown to be important. Current challenges in the field and possible opportunities are also discussed.
Selectivity remains a constant challenge in the development of optical extraction-based sensors. Fortunately, there are several mechanistic and compositional changes with the potential to improve selectivity without developing new ionophores.
Optical nanosensors for the detection of polyions, including protamine and heparin, have to date relied upon ion-exchange reactions involving an analyte and an optical transducer. Unfortunately, due ...to the limited selectivity of the available ionophores for polyions, this mechanism has suffered from severe interference in complex sample matrices. To date no optical polyion nanosensors have demonstrated acceptable performance in serum, plasma or blood. Herein we describe a new type of nanosensor based on our discovery of a "hyper-polarizing lipophilic phase" in which dinonylnaphthalenesulfonate (DNNS
−
) polarizes a solvatochromic dye much more than even an aqueous environment. We have found that the apparent polarity of the organic phase is only modulated when DNNS
−
binds to large polyions such as protamine, unlike singly charged ions that lack the cooperative binding required to cause a significant shift in the distribution of the polarizing DNNS
−
ions. Our new sensing mechanism allows solvatochromic signal transduction without the transducer undergoing ion exchange. The result is significantly improved sensitivity and selectivity, enabling for the first time the quantification of protamine and heparin in human plasma using optical nanosensors that correlates with the current gold standard analysis method, the anti-Xa factor assay.
Novel optical nanosensors for the selective detection of the polycationic protamine based on solvatochromic signal change allow one to detect heparin in plasma.
In ion sensing applications, selective ion-receptor complexation is the molecular basis for endowing the sensing material with selectivity. In this work, thin polymeric membrane-based ion transfer ...voltammetry is used to investigate ion-receptor complexation, using a range of electrically neutral ionophores and surfactants as examples. Previous studies lacked a convincing approach to eliminate the influence from transducing layer, resulting in deviations of the observed binding constants compared to potentiometric methods. A recently developed method allows for subtracting the potential changes of the transducing layer, thereby overcoming this challenge. Using this approach, a range of ionophores are assessed. Valinomycin for the detection of potassium gave a logarithmic complex formation constant in the membrane of 9.69 ± 0.25 with a 1:1 stoichiometry. Lithium ionophore VI for lithium gave a logarithmic stability constant of 5.97 ± 0.06 with 1:2 complexes; while sodium ionophore X for sodium (7.57 ± 0.03, 1:1) and calcium ionophore IV for calcium (21.57 ± 0.25, 1:3) were also characterized, in addition to their complexes with potential interfering ions. The complex formation of three surfactants with potassium are also explored in membranes containing valinomycin, with Brij-35 (4.88 ± 0.08, 1:1), Triton X-100 (5.63 ± 0.10, 1:1), F-127 (4.63 ± 0.49, 1:1). Limitations of the approach are discussed, which includes the need for electrochemical reversibility and a sufficiently high lipophilicity to adequately retain the components in the membrane
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•Thin film ion transfer voltammetry is analyzed by an equilibrium approach.•Formation constants and stoichiometries of ion-ionophore are evaluated.•The approach gives sensor selectivity coefficients as a function of ion-exchanger concentration.•Binding properties of four ionophores and three nonionic surfactants are described.
The last decade has witnessed a rapid development of nano- and microparticle-based optical ion sensors, including ion-selective optodes (ISOs). While the application of nano-ISOs has shown promising ...performance for sensing inorganic ions, polyion sensing using nanoscale ISOs has encountered significant interference in complex samples such as blood plasma. Recently, we have reported on a new polyion sensing principle that operates through a novel mechanism to overcome this challenge. The new sensing mechanism showed improved characteristics not observed with conventional ion-exchange type sensors, but the precise mechanism of operation remained thus far unclear. This paper aims to clarify how protamine, the arginine-rich target polycation, behaves during optical signal transduction to give dramatically improved selectivity. Based on thermodynamic data, sensor performance and ζ-potential analysis, two discrete phases of protamine extraction are identified. Initially, protamine extracts into the bulk nanosensor phase, a process that is concurrent with the optical signal change. This is then followed by protamine accumulation onto the nanosensor surface, which starts only upon saturation of the optical signal change. The data indicate that the improved selectivity is due to the inability of small ions to form a sufficiently strong interaction with an active sensing ingredient, DNNS–. Any exchange of one inorganic cation for another therefore remains optically silent, suppressing matrix effects. Moreover, the recognition of protamine is shown to be an exhaustive extraction process, making the response independent of the nature and concentration of the initial small cation in the nanosensor phase.
Nanoparticle–cell interactions between silica nanomaterials and mammalian cells have been investigated extensively in the context of drug delivery, diagnostics, and imaging. While there are also ...opportunities for applications in infectious disease, the interactions of silica nanoparticles with pathogenic microbes are relatively underexplored. To bridge this knowledge gap, here, we investigate the effects of organosilica nanoparticles of different sizes, concentrations, and surface coatings on surface association and viability of the major human fungal pathogen Candida albicans. We show that uncoated and PEGylated organosilica nanoparticles associate with C. albicans in a size and concentration-dependent manner, but on their own, do not elicit antifungal activity. The particles are also shown to associate with human white blood cells, in a similar trend as observed with C. albicans, and remain noncytotoxic toward neutrophils. Smaller particles are shown to have low association with C. albicans in comparison to other sized particles and their association with blood cells was also observed to be minimal. We further demonstrate that by chemically immobilizing the clinically important echinocandin class antifungal drug, caspofungin, to PEGylated nanoparticles, the cell–material interaction changes from benign to antifungal, inhibiting C. albicans growth when provided in high local concentration on a surface. Our study provides the foundation for defining how organosilica particles could be tailored for clinical applications against C. albicans. Possible future developments include designing biomaterials that could detect, prevent, or treat bloodstream C. albicans infections, which at present have very high patient mortality.
Point-of-care quantification of the anticoagulant heparin still remains a significant clinical challenge as the reference method (colorimetric anti-factor Xa assay) cannot be performed in whole ...blood. Our group recently put forth the novel optical nanosensing principle using an ionic solvatochromic dye as a signal transducer. These nanosensors demonstrated significantly improved selectivity and sensitivity compared to ion-exchange-type polyion nanosensors and enabled protamine/heparin quantification in blood plasma samples. However, because the readout is absorbance-based, they are still not suitable for whole blood measurements. To overcome the background absorbance of blood, the nanosensors were here embedded in an agarose hydrogel capable of filtering out red blood cells while allowing plasma components to diffuse into the gel. Calibration curves for both protamine and heparin were successfully obtained in buffer, undiluted plasma, and undiluted whole blood using different colorimetric image analysis methods and a simple experimental setup.
Recent work has shown that ion-selective components may be transferred from nanoemulsions (NEs) to endow polymeric membranes with ion-selective sensing properties. This approach has also been used ...for nanopipette electrodes to achieve single-entity electrochemistry, thereby sensing the ion-selective response of single adhered nanospheres. To this date, however, the mechanism and rate of component transfer remain unclear. We study here the transfer of lipophilic ionic compounds from nanoemulsions into thin plasticized poly(vinyl chloride) (PVC-DOS) films by chronoamperometry and quartz crystal microbalance. Thin-film cyclic coulovoltammetry measurements serve to quantify the uptake of lipophilic species into blank PVC
DOS membranes. Electrochemical quartz crystal microbalance data indicate that the transfer of the emulsion components is insignificant, ruling out simple coalescence with the membrane film. Ionophores and ion-exchangers are shown to transfer into the membrane at rates that correlate with their lipophilicity if mass transport is not rate-limiting, which is the case with more lipophilic compounds (calcium and sodium ionophores). On the other hand, with less lipophilic compounds (valinomycin and cation-exchanger salts), transfer rates are limited by mass transport. This is confirmed with rotating disk electrode experiments in which a linear relationship between the diffusion layer thickness and current is observed. The data suggests that once the nanoemulsion container approaches the membrane surface, transfer of components occur by a three-phase partition mechanism where the aqueous phase serves as a kinetic barrier. The results help better understand and quantify the interaction between nanoemulsions and ion-selective membranes and predict membrane doping rates for a range of components.
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–1 in either PBS or 20% serum.
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