Thermo-responsive Fluorescent Nanoparticles for Multimodal Imaging and Treatment of Cancers

Theranostic systems capable of delivering imaging and therapeutic agents at a specific target are the focus of intense research efforts in drug delivery. To overcome non-degradability and toxicity concerns of conventional theranostic systems, we formulated a novel thermo-responsive fluorescent polymer (TFP) and conjugated it on the surface of iron oxide magnetic nanoparticles (MNPs) for imaging and therapeutic applications in solid tumors. Methods: TFP-MNPs were synthesized by copolymerizing poly(N-isopropylacrylamide), allylamine and a biodegradable photoluminescent polymer, and conjugating it on MNPs via a free radical polymerization reaction. Physicochemical properties of the nanoparticles were characterized using Fourier transform infrared spectroscopy, dynamic light scattering, and vibrational sample magnetometry. Nanoparticle cytocompatibility, cellular uptake and cytotoxicity were evaluated using in vitro cell assays. Finally, in vivo imaging and therapeutic efficacy studies were performed in subcutaneous tumor xenograft mouse models. Results: TFP-MNPs of ~135 nm diameter and -31 mV ζ potential maintained colloidal stability and superparamagnetic properties. The TFP shell was thermo-responsive, fluorescent, degradable, and released doxorubicin in response to temperature changes. In vitro cell studies showed that TFP-MNPs were compatible to human dermal fibroblasts and prostate epithelial cells. These nanoparticles were also taken up by prostate and skin cancer cells in a dose-dependent manner and exhibited enhanced killing of tumor cells at 41°C. Preliminary in vivo studies showed theranostic capabilities of the nanoparticles with bright fluorescence, MRI signal, and therapeutic efficacy under magnetic targeting after systemic administration in tumor bearing mice. Conclusion: These results indicate the potential of TFP-MNPs as multifunctional theranostic nanoparticles for various biological applications, including solid cancer management

Air pollution in Delhi: A review of past and current policy approaches

Delhi National Capital Region (Delhi NCR) is facing serious challenges linked to worrying levels of air pollution (mainly NO2, PM10 and PM2.5). The CADTIME prject (Clean Air in Delhi through Implementation, Mitigation and Engagement) aims to understand what is required to deliver significant reductions in levels of air pollution. This paper presents the results of the first stage of the project: it firstly contextualises the challenges of air quality management in Delhi within the broader evolution of environmental policies and governance in India, with particular consideration to the tensions between environmental protection and the country's development objectives. Secondly, it sets out how CADTIME will combine multiple source qualitative and quantitative data to develop an air quality action plan and an implementation strategy. In particular, through two workshops with local and national experts and stakeholders, and two rounds of focus groups with citizens of Delhi we will contrast stakeholders' priorities and preferences for existing and potential solutions to air pollution with citizens' lived experiences, thus assessing the political/technical feasibility and public acceptability of current and proposed measures. Furthermore, we will complement the primary qualitative data with a critical review examining the successes and failures of UK and European policies to draw lessons that can be relevant for Delhi and to avoid ineffective policies and achieve cost-effective solutions for the city in the shortest possible time

Personal exposure to fine particulate matter concentrations in central business district of a tropical coastal city

<p>In the present study, personal exposure to fine particulate matter (particulate matter with an aerodynamic diameter <2.5 μm [PM_2.5]) concentrations in an urban hotspot (central business district [CBD]) was investigated. The PM monitoring campaigns were carried out at an urban hotspot from June to October 2015. The personal exposure monitoring was performed during three different time periods, i.e., morning (8 a.m.−9 a.m.), afternoon (12.30 p.m.–1.30 p.m.), and evening (4 p.m.–5 p.m.), to cover both the peak and lean hour activities of the CBD. The median PM_2.5 concentrations were 38.1, 34.9, and 40.4 µg/m³ during the morning, afternoon, and evening hours on the weekends. During weekdays, the median PM_2.5 concentrations were 59.5, 29.6, and 36.6 µg/m³ in the morning, afternoon, and evening hours, respectively. It was observed that the combined effect of traffic emissions, complex land use, and micrometeorological conditions created localized air pollution hotspots. Furthermore, the total PM_2.5 lung dose levels for an exposure duration of 1 hr were 8.7 ± 5.7 and 12.3 ± 5.2 µg at CBD during weekends and weekdays, respectively, as compared with 2.5 ± 0.8 µg at the urban background (UB). This study emphasizes the need for mobile measurement for short-term personal exposure assessment complementing the fixed air quality monitoring.</p> <p><i>Implications</i>: Personal exposure monitoring at an urban hotspot indicated space and time variation in PM concentrations that is not captured by the fixed air quality monitoring networks. The short-term exposure to higher concentrations can have a significant impact on health that need to be considered for the health risk–based air quality management. The study emphasizes the need of hotspot-based monitoring complementing the already existing fixed air quality monitoring in urban areas. The personal exposure patterns at hotspots can provide additional insight into sustainable urban planning.</p

Synthesis and characterization of a novel pH-responsive drug-releasing nanocomposite hydrogel for skin cancer therapy and wound healing

Local skin cancer recurrence occurs in ∼12% of the patients post-surgery due to persistent growth of residual cancer cells. Wound infection is another significant complication following surgery. We report a novel in situ-forming nanocomposite hydrogel (NCH) containing PLGA-carboxymethyl chitosan nanoparticles (186 nm) for localized pH-responsive skin cancer therapy and wound healing. This injectable hydrogel, comprising of a citric acid-derived polymer backbone, gelled within 5 minutes, and demonstrated excellent swelling (283% of dry weight) and compressive strengths (∼5.34 MPa). Nanoparticle incorporation did not significantly affect hydrogel properties. The NCH effluents were cytocompatible with human dermal fibroblasts at 500 μg ml-1 concentration and demonstrated pH-dependent drug release and promising therapeutic efficacy against A431 and G361 skin cancer cells in vitro. Significant zones of inhibition were observed in S. aureus and E. coli cultures on NCH treatment, confirming its antibacterial properties. Our studies show that the pH-responsive NCH can be potentially used for adjuvant skin cancer treatment and wound healing. This journal i

Structure Guided Lead Generation for <i>M. tuberculosis</i> Thymidylate Kinase (Mtb TMK): Discovery of 3‑Cyanopyridone and 1,6-Naphthyridin-2-one as Potent Inhibitors

<i>M. tuberculosis</i> thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and an NMR based fragment screen through which we discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively. We describe three cyanopyridone subseries that arose during our hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment hit from 500 μM to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivatives containing sulfoxides and sulfones showed cellular activity against <i>M. tuberculosis</i>. To the best of our knowledge, these compounds are the first reports of non-thymidine-like inhibitors of Mtb TMK