Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system’s natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery vaccine platform. We utilized an injectable and self-healing polymer–nanoparticle (PNP) hydrogel platform to prolong the codelivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique delivery characteristics, whereby physicochemically distinct compounds (such as antigen and adjuvant) could be codelivered over the course of weeks. When administered in mice, hydrogel-based sustained vaccine exposure enhanced the magnitude, duration, and quality of the humoral immune response compared to standard PBS bolus administration of the same model vaccine. We report that the creation of a local inflammatory niche within the hydrogel, coupled with sustained exposure of vaccine cargo, enhanced the magnitude and duration of germinal center responses in the lymph nodes. This strengthened germinal center response promoted greater antibody affinity maturation, resulting in a more than 1000-fold increase in antigen-specific antibody affinity in comparison to bolus immunization. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines.

No abstract

Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput–controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.

Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor resection or in immune-privileged tissues. Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors. The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells. The generation of a transient inflammatory niche following administration affords sustained exposure of CAR-T cells, induces a tumor-reactive CAR-T phenotype, and improves efficacy of treatment.

In diabetic patients, treatment with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. But because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of diabetics needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances post-prandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 hours at 37 ºC under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 hours under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin to 0.7 ± 0.1 from 0.4 ± 0.2 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.

Most studies of road dust composition have sampled a very wide range of particle sizes, but from the perspective of respiratory exposure to resuspended dusts, it is the PM10 fraction which is of most importance. The PM10 fraction of road dust samples was collected at two sites in Birmingham, UK (major highway and road tunnel) and one site in New Delhi, India. Dust loadings were found to be much higher for New Delhi compared to Birmingham, while concentrations of several species were much higher in the case of Birmingham. Detailed chemical source profiles were prepared for both cities and previously generated empirical factors for source attribution to brake wear, tyre wear, and crustal dust were successfully applied to the UK sites. However, 100% of the mass for the Indian site could not be accounted for using these factors. This study highlights the need for generation of local empirical estimation factors for non-exhaust vehicle emissions. A limited number of bulk road dust and brake pad samples were also characterized. Oxidative potential (OP) was also determined for a limited number of PM10 and bulk road dust samples, and Cu was found to be a factor significantly associated with OP in PM10 and bulk road dust.

Background:Epidemiological studies have provided strong evidence that fine particulate matter (PM2.5; aerodynamic diameter ≤ 2.5 μm) can exacerbate asthmatic symptoms in children. Pro-oxidant components of PM2.5 are capable of directly generating reactive oxygen species. Oxidative burden is used to describe the capacity of PM2.5 to generate reactive oxygen species in the lung.Objective:In this study we investigated the association between airway inflammation in asthmatic children and oxidative burden of PM2.5 personal exposure.Methods:Daily PM2.5 personal exposure samples (n = 249) of 62 asthmatic school-aged children in Montreal were collected over 10 consecutive days. The oxidative burden of PM2.5 samples was determined in vitro as the depletion of low-molecular-weight antioxidants (ascorbate and glutathione) from a synthetic model of the fluid lining the respiratory tract. Airway inflammation was measured daily as fractional exhaled nitric oxide (FeNO).Results:A positive association was identified between FeNO and glutathione-related oxidative burden exposure in the previous 24 hr (6.0% increase per interquartile range change in glutathione). Glutathione-related oxidative burden was further found to be positively associated with FeNO over 1-day lag and 2-day lag periods. Results further demonstrate that corticosteroid use may reduce the FeNO response to elevated glutathione-related oxidative burden exposure (no use, 15.8%; irregular use, 3.8%), whereas mold (22.1%), dust (10.6%), or fur (13.1%) allergies may increase FeNO in children with versus children without these allergies (11.5%). No association was found between PM2.5 mass or ascorbate-related oxidative burden and FeNO levels.Conclusions:Exposure to PM2.5 with elevated glutathione-related oxidative burden was associated with increased FeNO.Citation:Maikawa CL, Weichenthal S, Wheeler AJ, Dobbin NA, Smargiassi A, Evans G, Liu L, Goldberg MS, Godri Pollitt KJ. 2016. Particulate oxidative burden as a predictor of exhaled nitric oxide in children with asthma. Environ Health Perspect 124:1616–1622; http://dx.doi.org/10.1289/EHP175

Biofouling on the surface of implanted medical devices and biosensors severely hinders device functionality and drastically shortens device lifetime. Poly(ethylene glycol) and zwitterionic polymers are currently considered “gold‐standard” device coatings to reduce biofouling. To discover novel anti‐biofouling materials, a combinatorial library of polyacrylamide‐based copolymer hydrogels is created, and their ability is screened to prevent fouling from serum and platelet‐rich plasma in a high‐throughput parallel assay. It is found that certain nonintuitive copolymer compositions exhibit superior anti‐biofouling properties over current gold‐standard materials, and machine learning is used to identify key molecular features underpinning their performance. For validation, the surfaces of electrochemical biosensors are coated with hydrogels and their anti‐biofouling performance in vitro and in vivo in rodent models is evaluated. The copolymer hydrogels preserve device function and enable continuous measurements of a small‐molecule drug in vivo better than gold‐standard coatings. The novel methodology described enables the discovery of anti‐biofouling materials that can extend the lifetime of real‐time in vivo sensing devices.