Magnetic drug targeting: Preclinical in vivo studies, mathematical modeling, and extrapolation to humans

A sound theoretical rationale for the design of a magnetic nanocarrier capable of magnetic capture in vivo after intravenous administration could help elucidate the parameters necessary for in vivo magnetic tumor targeting. In this work, we utilized our long-circulating polymeric magnetic nanocarriers, encapsulating increasing amounts of superparamagnetic iron oxide nanoparticles (SPIONs) in a biocompatible oil carrier, to study the effects of SPION loading and of applied magnetic field strength on magnetic tumor targeting in CT26 tumor-bearing mice. Under controlled conditions, the in vivo magnetic targeting was quantified and found to be directly proportional to SPION loading and magnetic field strength. Highest SPION loading, however, resulted in a reduced blood circulation time and a plateauing of the magnetic targeting. Mathematical modeling was undertaken to compute the in vivo magnetic, viscoelastic, convective, and diffusive forces acting on the nanocapsules (NCs) in accordance with the Nacev–Shapiro construct, and this was then used to extrapolate to the expected behavior in humans. The model predicted that in the latter case, the NCs and magnetic forces applied here would have been sufficient to achieve successful targeting in humans. Lastly, an in vivo murine tumor growth delay study was performed using docetaxel (DTX)-encapsulated NCs. Magnetic targeting was found to offer enhanced therapeutic efficacy and improve mice survival compared to passive targeting at drug doses of ca. 5–8 mg of DTX/kg. This is, to our knowledge, the first study that truly bridges the gap between preclinical experiments and clinical translation in the field of magnetic drug targeting

Rhinovirus-16 induced release of IP-10 and IL-8 is augmented by Th2 cytokines in a pediatric bronchial epithelial cell model

Th2 cytokines increase release of inflammatory cytokines in the presence of rhinovirus infection. This increase is independent of effects of virus replication. Inhibition of the PI3K pathway inhibits IP-10 expression

Feeding bovine milks with low or high IgA levels is associated with altered re-establishment of murine intestinal microbiota after antibiotic treatment

Antibiotics are a vital and commonly used therapeutic tool, but their use also results in profound changes in the intestinal microbiota that can, in turn, have significant health consequences. Understanding how the microbiota recovers after antibiotic treatment will help to devise strategies for mitigating the adverse effects of antibiotics. Using a mouse model, we have characterized the changes occurring in the intestinal microbiota immediately after five days exposure to ampicillin, and then at three and fourteen days thereafter. During the fourteen day period of antibiotic recovery, groups of mice were fed either water, cows’ milk containing high levels of IgA, or cows’ milk containing low levels of IgA as their sole source of liquid. Effects on microbiota of feeding milks for 14 days were also assessed in groups of mice that had no ampicillin exposure. Changes in microbiota were measured by high throughput sequencing of the V4 to V6 variable regions of the 16S ribosomal RNA gene. As expected, exposure to ampicillin led to profound changes to the types and abundance of bacteria present, along with a loss of diversity. At 14 days following antibiotic exposure, mice fed water had recovered microbiota compositions similar to that prior to antibiotics. However, feeding High-IgA milk to mice that has been exposed to antibiotics was associated with altered microbiota compositions, including increased relative abundance of Lactobacillus and Barnesiella compared to the start of the study. Mice exposed to antibiotics then fed Low-IgA milk also showed increased Barnesiella at day 14. Mice without antibiotic perturbation, showed no change in their microbiota after 14 days of milk feeding. Overall, these findings add to a knowledge platform for optimizing intestinal function after treatment with antibiotics in the human population

Exogenous IFN-? has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from asthmatic subjects exposed to rhinovirus

Background: Rhinoviruses are the major cause of asthma exacerbations. Previous studies suggest that primary bronchial epithelial cells (PBECs) from asthmatic subjects are more susceptible to rhinovirus infection because of deficient IFN-? production. Although augmenting the innate immune response might provide a novel approach for treatment of virus-induced asthma exacerbations, the potential of IFN-? to modulate antiviral and proinflammatory responses in asthmatic epithelium is poorly characterized.Objectives: We sought to compare responses of PBECs from nonasthmatic and asthmatic subjects to exogenous IFN-? and test the inflammatory effects of IFN-? in response to rhinovirus infection.Methods: PBECs were treated with IFN-? and infected with a low inoculum of human rhinovirus serotype 1B to simulate a natural viral infection. Expression of interferon-responsive genes and inflammatory responses were analyzed by using reverse transcription–quantitative real-time PCR, cytometric bead arrays, or both; viral titers were assessed by using the 50% tissue culture infection dose.Results: Expression of IFN-?–stimulated antiviral genes was comparable in PBECs from nonasthmatic or asthmatic donors. Exogenous IFN-? significantly protected PBECs from asthmatic donors against rhinovirus infection by suppressing viral replication. Interferon-inducible protein 10 (IP-10), RANTES, and IL-6 release in response to rhinovirus infection was triggered only in PBECs from asthmatic donors. Although exogenous IFN-? alone stimulated some release of IP-10 (but not IL-6 or RANTES), it significantly reduced rhinovirus-induced IP-10, RANTES, and IL-6 expression when tested in combination with rhinovirus.Conclusions: PBECs from asthmatic donors have a normal antiviral response to exogenous IFN-?. The ability of IFN-? to suppress viral replication suggests that it might limit virus-induced exacerbations by shortening the duration of the inflammatory response

The role of ADAM33 in the pathogenesis of asthma

While asthma is a disorder of the conducting airways characterised by Th2-directed inflammation, a second set of mechanisms is being increasingly recognised as fundamental to disease chronicity and severity, for which the term "remodelling" has been used. The cellular and mediator responses underpinning airway remodelling involve aberrant communication between the airway epithelium and underlying mesenchyme, involving the generation of growth factors that lead to proliferation of fibroblasts and smooth muscle and the deposition of matrix proteins to cause airway wall thickening linked to bronchial hyperresponsiveness and fixed airflow obstruction. The identification of ADAM33 on chromosome 20p13 from positional cloning as a novel candidate gene involved in the pathogenesis of these structural and functional changes has opened the way to further insight into these processes that contribute to corticosteroid refractoriness. The preferential expression of ADAM33 in mesenchymal cells and its multiple molecular actions provide ample opportunity for incriminating this molecule in chronic asthma. Its association with progressive asthma and in predicting reduced lung function in young children suggest that ADAM33 has an important role in the natural history and possibly the origins of asthma, a disease unique to humans

Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function

Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.<br/

Induction of IL-8 but not IP-10 in response to Th2 stimulation.

<p>ppBECs were treated for 24-13 (10 ng/ml) and IL-4 (10 ng/ml) for 24 hours. Protein secretion in cell supernatant was measured by ELISA (R&D). Statistical analysis 1A n = 9 ANOVA P<0.05. 1B n = 15, Wilcoxon, p<0.05. NT-no treatment.</p

Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function

Rationale: Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood.Objectives: Within the context of a prospective birth cohort study, we investigated the association between single nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene and early-life lung function.Methods: Children were genotyped for 17 SNPs in ADAM33. Lung function at age 3 (n = 285) and 5 years (n = 470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age 5, we also measured FEV1. SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus.Main Results: Carriers of the rare allele of F+1 SNP had reduced lung function at age 3 years (p = 0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age 5 years (p &lt; 0.04). Using linkage disequilibrium mapping, we found evidence of a significant causal location between BC+1 and F1 SNPs, at the 5' end of the gene. Four SNPs were associated with lower FEV1 (F+1, M+1, T1, and T2; p &lt;= 0.04). The risk of transient early wheezing more than doubled among children homozygous for the A allele of F+1 (odds ratio, 2.39; 95% confidence intervals, 1.18–4.86; p = 0.02), but there was no association between any SNP and allergic sensitization or physician-diagnosed asthma. Conclusions: Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene

Association of asthma with a functional promoter polymorphism in the IL16 gene

BackgroundIL-16, a multifunctional cytokine with increased expression in the airways of asthmatic subjects, inhibits allergic airway inflammation in animal models. A T?C single nucleotide polymorphism (SNP) at the ?295 position in the promoter region of the IL16 gene has been described.ObjectiveWe sought to examine the functional significance of this promoter SNP and its relationship to asthma.MethodsWe examined the effect of the ?295 SNP on promoter activity in cell-line (HBE4-E6/E7) transfection experiments. We investigated the association of the IL16 ?295 genotype with asthma among 341 affected sib-pair white families and 184 unrelated nonasthmatic control subjects. We analyzed the association between the IL16 genotype and asthma using family-based association test and case-control analyses.ResultsIn in vitro transfection experiments the T allele in the ?295 position was associated with substantially reduced promoter activity compared with the C allele. In the family study the more common T allele at the ?295 position was significantly associated with all asthma phenotypes (P = .002 to P = .015). In the case-control analysis asthmatic subjects were more likely than unrelated nonasthmatic control subjects to have the ?295 TT genotype, but this did not reach statistical significance (odds ratio, 1.36; 95% CI, 0.92-2.02).ConclusionsThe T allele at the ?295 position in the IL16 promoter region is associated with reduced promoter activity relative to the C allele and with asthma in this white population. Further investigation is needed to delineate the mechanisms underlying these findings and the relationship of the IL16 ?295 genotype to asthma in other populations