Multi-Color-Emissive Magneto-Luminescent Nanoarchitectures for Targeted Identification of Heterogeneous Exosomes Associated with Lung Cancer Metastasis.

Due to the lack of early detection before metastasis and failure of current therapy to cure the disease, lung cancer contributes to the highest cancer-related mortality worldwide. Tenascin C (TNC) (+) exosomes promote metastasis, amphiregulin (AREG) (+) exosomes are associated with chemotherapy resistance, and programmed cell death ligand-1 (PDL-1) (+) exosomes are associated with immunotherapy resistance, and they are emerging as biomarkers in clinics. However, due to heterogeneity, rapid isolation and multiplex detection of these exosomes are challenging. Herein, we report the design of an antibody-conjugated multi-color (orange, yellow, and green)-emissive carbon dot (CD)-attached cobalt spinel ferrite (CoFe2O4)-based magneto-luminescent nanoarchitecture for targeted capturing and identification of TNC (+), AREG (+), and PDL-1(+) exosomes selectively and simultaneously from whole blood samples. More importantly, to capture and identify the targeted AREG (+) exosome from an infected whole-blood sample, an anti-AREG antibody-attached green (520 nm)-emissive CD-conjugated CoFe2O4 nanoparticle-based magnetic-green luminescence nanoarchitecture was developed. Similarly, an anti-PDL-1 antibody-attached orange (600 nm)-emissive CDs-based magnetic-orange luminescence nanoarchitecture has been produced to capture and identify the PDL-1 (+) exosome. Furthermore, an anti-TNC antibody-attached yellow (560 nm)-emissive CD-based magnetic-orange luminescent nanoarchitecture has been designed to capture and identify the TNC (+) exosome. Notably, our finding reveals that 100% TNC (+) exosomes can be captured and imaged selectively from an infected blood sample using an anti-TNC antibody-conjugated nanoarchitecture. In addition, 100% AREG (+) exosomes can be captured and imaged selectively using an anti-AREG antibody-conjugated nanoarchitecture. Moreover, 100% PDL-1 (+) exosomes can be captured and imaged selectively using an anti-PDL-1 antibody-conjugated nanoarchitecture. Furthermore, we have demonstrated that a multi-color-emissive nanoarchitecture can be used for capturing and imaging all three exosomes simultaneously.

Improved chemotherapy against breast cancer through immunotherapeutic activity of fucoidan decorated electrostatically assembled nanoparticles bearing doxorubicin.

Immunotherapeutic nanoparticles (NPs) could be a viable option for delivering cytotoxic agents in a manner which suppresses their toxic manifestations. Doxorubicin (DOX) loaded NPs were prepared using fucoidan (FCD), an immunomodulatory polysaccharide and evaluated against cancer. FCD was electrostatically assembled with cationic polyethylenimine (PEI) through intermolecular electrostatic interactions to develop an immunomodulatory platform to deliver DOX. FCD NPs offered improved cytotoxicity (2.64 folds), cell cycle arrest in G1-S phase (34.65%) and apoptosis (66.12%) in tumor cells compared to free DOX. The enhanced apoptosis was due to raised mitochondrial depolarization (88.00%). In vivo anticancer activity in 4T1 induced tumor bearing BALB/c mice demonstrated a 2.95 folds enhanced efficacy of NPs. Importantly, NPs treatment generated an immunotherapeutic response indicated by gradual increment of the plasma IL-12 levels and reversed polarization of tumor associated macrophages (TAMs) towards M1 subtype. Furthermore, pharmacokinetic study suggested that NPs administration in tumor infested mice caused serum DOX levels to vary in a biphasic pattern, with twin peaks occurring at 1 h and 6 h which help in maintaining preferential drug localization in tumor. Developed NPs would be an excellent approach for improved immune-chemotherapy (in terms of efficacy, safety and immunocompetency) against cancer.

Nebulized N-Acetylcysteine for Management of Plastic Bronchitis.

BACKGROUND: Plastic bronchitis is characterized by formation of extensive obstructive endobronchial casts and high recurrence rates. CASE CHARACTERISTICS: Two children (1-year-old girl, 7-year-old boy) who had recurrent episodes of respiratory distress with acute worsening. Bronchoscopy revealed membrane-like casts. Both children were managed with nebulized N-acetylcysteine in addition to management for asthma. OUTCOME: Symptom-free without recurrence for more than 9 months of follow-up. MESSAGE: Nebulized N- acetylcysteine may be helpful in prevention of recurrence of plastic bronchitis due to asthma.

Fabrication of 3-O-sn-Phosphatidyl-L-serine Anchored PLGA Nanoparticle Bearing Amphotericin B for Macrophage Targeting.

PURPOSE: To fabricate, characterize and evaluate 3-O-sn-Phosphatidyl-L-serine (PhoS) anchored PLGA nanoparticles for macrophage targeted therapeutic intervention of VL. MATERIALS AND METHODS: PLGA-AmpB NPs were prepared by well-established nanoprecipitation method and decorated with Phos by thin film hydration method. Physico-chemical characterization of the formulation was done by Zetasizer nano ZS and atomic force microscopy. RESULTS: The optimized formulation (particle size, 157.3 ± 4.64 nm; zeta potential, - 42.51 ± 2.11 mV; encapsulation efficiency, ∼98%) showed initial rapid release up to 8 h followed by sustained release until 72 h. PhoS generated 'eat-me' signal driven augmented macrophage uptake, significant increase in in-vitro (with ∼82% parasite inhibition) and in-vivo antileishmanial activity with preferential accumulation in macrophage rich organs liver and spleen were found. Excellent hemo-compatibility justified safety profile of developed formulation in comparison to commercial formulations. CONCLUSION: The developed PhoS-PLGA-AmpB NPs have improved efficacy, and necessary stability which promisingly put itself as a better alternative to available commercial formulations for optimized treatment of VL.

Enhanced apoptosis, survivin down-regulation and assisted immunochemotherapy by curcumin loaded amphiphilic mixed micelles for subjugating endometrial cancer.

Survivin is up-regulated in 83% of endometrial cancer leading to resistance development. As endometrial tumor advances, it also elicits chronic inflammation characterized by increased cytokine secretion and immune cells infiltration. The present study was designed to engineer mixed micellar curcumin loaded formulation for investigating survivin down-regulation, its anti-cancer and cytokine modulatory potential against endometrial cancer Ishikawa cells. Flory-Huggins interaction parameter (χpd) was applied to predict the compatibility between curcumin and surfactant mixture. The developed and characterized formulations were used to comparatively assess hemolysis, cellular uptake, cell-viability, apoptosis, mitochondrial membrane potential loss, rhodamine accumulation and bioavailability. In-vitro cytotoxicity in Vero cells demonstrated no deleterious effects on cell population. We saw better bioavailability, significant rhodamine accumulation, changes in protein expression and modulation in TNF-α, IL-6 and IL-10 levels. In conclusion, developed formulation warrants exploring the therapeutic interventions for overcoming resistance development in endometrial cancer.

Targeting tumor associated macrophages (TAMs) via nanocarriers.

Recruitment of inflammatory cells to tumor has been well documented, with the most frequent inhabitants being macrophages termed as tumor associated macrophages, (TAMs). Their presence was thought to be an evidence of immune system initiating a fight response towards the tumor, i.e. immune surveillance. This is the case too initially, when TAMs majorly exhibit an M1 phenotype, but their continued presence in tumor microenvironment brings about their polarization to M2 phenotype, which not only participate in continued sustenance of existing tumor but also open up deleterious avenues for further progression and metastasis of cancer. Current perspective is built around this very premise and focuses specifically on TAMs and how they are being targeted by researchers working in annals of nanomedicine. To do so, we dwell into tumor microenvironment and focus on nanotechnology based drug delivery aspects which have either been already or can be potentially employed in the future to target tumor associated macrophages for improved immunoadjuvant therapy of cancer.

Lessons Learned from Gemcitabine: Impact of Therapeutic Carrier Systems and Gemcitabine's Drug Conjugates on Cancer Therapy.

Currently, drug delivery systems have a high impact in cancer therapy and are receiving more attention than conventional cancer treatment modalities. Compared with current cancer therapies, gemcitabine (2', 2'-difluoro-2'-deoxycytidine) has been proven to be an effective chemotherapeutic agent against pancreatic, colon, bladder, breast, ovarian, non-small-cell lung, and head and neck cancers in combination with other anticancer agents. To improve the safety and efficacy of cytotoxic drugs, several drug delivery systems have been explored. This review outlines the recent work directed toward gemcitabine delivery systems for cancer therapy, including aerosols, polymeric nanoparticles, liposomes, microparticles, carbon nanotubes, and multifunctional theranostic nanomedicines. It also provides insight into the design and development of gemcitabine conjugation for safe and effective cancer therapy. Despite the clinical promises of gemcitabine, many therapeutic challenges remain. Specifically, its therapeutic use in cancer chemotherapy is impeded by a short biological half-life, caused by its rapid metabolism, and resistance due to increased expression of ribonucleotide reductase. In our opinion, many research investigations have contributed to improve the selectivity and efficacy of gemcitabine. This combined approach of drug delivery systems and gemcitabine conjugates has shown promising efficacy in preclinical models and significant potential for future clinical cancer-therapeutic applications. Also, these strategies overcome most of the aforementioned limits of gemcitabine.

Prevalence, Response to Cysticidal Therapy, and Risk Factors for Persistent Seizure in Indian Children with Neurocysticercosis.

Background. Neurocysticercosis (NCC) is the commonest cause of childhood acquired epilepsy in developing countries. The use of cysticidal therapy in NCC, except "single lesion NCC," is still debated in view of its doubtful usefulness and potential adverse effects. Methods. Children presenting with first episode of seizure or acute focal neurological deficit without fever were screened for NCC and received appropriate therapy (followup done for 1 year to look for the response and side effects). Results. The prevalence of NCC was 4.5%. Most common presenting feature was generalized seizure and commonest imaging finding was single small enhancing lesion in the parietal lobe. Abnormal EEG and CSF abnormalities were found in almost half of the children. The response to therapy was very good with infrequent recurrence of seizure and adverse effects of therapy were encountered rarely. No risk factors for persistent seizure could be identified. Conclusion. Present study shows that the response to cysticidal therapy is very good in NCC as seizure recurrence was observed in only 5%, 4.2%, and 4.2% of cases at 3-month, 6-month, and 1-year followup. Adverse effects of therapy were observed in 20% of cases during therapy but they were mild and self-limiting.

Nanosized complexation assemblies housed inside reverse micelles churn out monocytic delivery cores for bendamustine hydrochloride.

OBJECTIVE: We explore a plausible method of targeting bendamustine hydrochloride (BM) to circulatory monocytes by exploiting their intrinsic endocytic/phagocytic capability. METHODS: We do so by complexation of sodium alginate and chitosan inside dioctyl sulfo succinate sodium (AOT) reverse micelles to form bendamustine hydrochloride loaded nanoparticles (CANPs). Dynamic light scattering, electrophoretic mobility and UV spectroscopy were used to detail intra-micellar complexation dynamics and to prove that drug was co-captured during interaction of carbohydrate polymers. A fluorescent conjugate of drug (RBM) was used to trace its intracellular fate after its loading into nanoparticles. RESULTS: CANPs were sized below 150nm, had 75% drug entrapment and negative zeta potential (-30mV). Confocal microscopy demonstrated that developed chitosan alginate nanoparticles had the unique capability to carry BM specifically to its site of action. Quantitative and mechanism based cell uptake studies revealed that monocytes had voracious capacity to internalize CANPs via simultaneous scavenger receptor based endocytic and phagocytic mechanism. Comparative in vitro pharmacokinetic studies revealed obtainment of significantly greater intracellular drug levels when cells were treated with CANPs. This caused reduction in IC50 (22.5±2.1µg/mL), enhancement in G2M cell cycle arrest, greater intracellular reactive oxygen species generation, and increased apopotic potential of bendamustine hydrochloride in THP-1 cells. CONCLUSION: Selective monocytic targeting of bendamustine hydrochloride using carbohydrate constructs can prove advantageous in case of leukemic disorders displaying overabundance of such cells.

Bioinspired Calcium Phosphate Nanoparticles Featuring as Efficient Carrier and Prompter for Macrophage Intervention in Experimental Leishmaniasis.

PURPOSE: To develop a biocompatible and bioresorbable calcium phosphate (CaP) nanoparticles (NPs) bearing Amphotericin B (AmB) with an aim to provide macrophage specific targeting in visceral leishmaniasis (VL). MATERIALS & METHODS: CaP-AmB-NPs were architectured through emulsion precipitation method. The developed formulation was extensively characterized for various parameters including in-vitro and in-vivo antileishmanial activity. Moreover, plasma pharmacokinetics, tissue biodistribution and toxicity profile were also assessed. RESULTS: Optimized CaP-AmB-NPs exhibited higher entrapment (71.1 ± 6.68%) of AmB. No trend related to higher hemolysis was apparent in the developed formulation as evidenced in commercially available colloidal and liposomal formulations. Cellular uptake of the developed CaP-AmB-NPs was quantified through flow cytometry in J774A.1 cell line, and a 23.90 fold rise in uptake was observed. Fluorescent microscopy also confirmed the time dependent rise in uptake. In-vivo multiple dose toxicity study demonstrated no toxicity upto 5 mg/kg dose of AmB. Plasma kinetics and tissue distribution studies established significantly higher concentration of AmB in group treated with CaP-AmB-NPs in liver and spleen as compared to CAmB, LAmB and AmB suspension group. In-vivo animal experimental results revealed that the CaP-AmB-NPs showed higher splenic parasite inhibition compared to CAmB and LAmB in leishmania parasite infected hamsters. CONCLUSIONS: The investigated CaP-AmB-NPs are effective in provoking macrophage mediated uptake and collectively features lower toxicity and offers a suitable replacement for available AmB-formulations for the obliteration of intra-macrophage VL parasite.

Characterization and identification of the sources of chromium, zinc, lead, cadmium, nickel, manganese and iron in PM10 particulates at the two sites of Kolkata, India.

Monitoring of ambient PM10 (particulate matter which passes through a size selective impactor inlet with a 50% efficiency cut-off at 10 microm aerodynamic diameter) has been done at residential (Kasba) and industrial (Cossipore) sites of an urban region of Kolkata during November 2003 to November 2004. These sites were selected depending on the dominant anthropogenic activities. Metal constituents of atmospheric PM10 deposited on glass fibre filter paper were estimated using Inductively Coupled Plasma Atomic Emission Spectrometer (ICP-AES). Chromium (Cr), zinc (Zn), lead (Pb), cadmium (Cd), nickel (Ni), manganese (Mn) and iron (Fe) are the seven toxic trace metals quantified from the measured PM10 concentrations. The 24 h average concentrations of Cr, Zn, Pb, Cd, Ni, Mn and Fe from ninety PM10 particulate samples of Kolkata were found to be 6.9, 506.1, 79.1, 3.3, 7.4, 2.4 and 103.6 ng/m3, respectively. The 24 h average PM10 concentration exceeded national ambient air quality standard (NAAQS) as specified by central pollution control board, India at both residential (Kasba) and industrial (Cossipore) areas with mean concentration of 140.1 and 196.6 microg/m3, respectively. A simultaneous meteorology study was performed to assess the influence of air masses by wind speed, wind direction, rainfall, relative humidity and temperature. The measured toxic trace metals generally showed inverse relationship with wind speed, relative humidity and temperature. Factor analysis, a receptor modeling technique has been used for identification of the possible sources contributing to the PM10. Varimax rotated factor analysis identified four possible sources of measured trace metals comprising solid waste dumping, vehicular traffic with the influence of road dust, road dust and soil dust at residential site (Kasba), while vehicular traffic with the influence of soil dust, road dust, galvanizing and electroplating industry, and tanning industry at industrial site (Cossipore).

Towards an intelligent hospital environment: OR of the future.

Patients, providers, payers, and government demand more effective and efficient healthcare services, and the healthcare industry needs innovative ways to re-invent core processes. Business process reengineering (BPR) showed adopting new hospital information systems can leverage this transformation and workflow management technologies can automate process management. Our research indicates workflow technologies in healthcare require real time patient monitoring, detection of adverse events, and adaptive responses to breakdown in normal processes. Adaptive workflow systems are rarely implemented making current workflow implementations inappropriate for healthcare. The advent of evidence based medicine, guideline based practice, and better understanding of cognitive workflow combined with novel technologies including Radio Frequency Identification (RFID), mobile/wireless technologies, internet workflow, intelligent agents, and Service Oriented Architectures (SOA) opens up new and exciting ways of automating business processes. Total situational awareness of events, timing, and location of healthcare activities can generate self-organizing change in behaviors of humans and machines. A test bed of a novel approach towards continuous process management was designed for the new Weinburg Surgery Building at the University of Maryland Medical. Early results based on clinical process mapping and analysis of patient flow bottlenecks demonstrated 100% improvement in delivery of supplies and instruments at surgery start time. This work has been directly applied to the design of the DARPA Trauma Pod research program where robotic surgery will be performed on wounded soldiers on the battlefield.

Benzene, toluene and xylene (BTX) pollution in ambient air: a case study.

Volatile Organic Compounds (VOCs) in presence of sunlight and oxides of nitrogen in atmosphere are considered as precursors for ozone production at the ground level. Concentration of Benzene, Toluene and Xylene (BTX) in ambient air was measured near seven traffic junctions in the city of Nagpur. Air samples were collected using Organic Vapour Sampler and analyzed by Gas Chromatograph equipped with Flame Ionization Detector (FID). Benzene concentration was found to be in the range 9.3 to 28.7 microg/m3, Toluene 3.26 to 21.0 microg/m3 and Xylene 4.9 to 15.0 microg/m3. These values are lower than those found in Metropolitan cities like Mumbai.