Molecularly imprinted polymeric nanoparticles for the therapeutic drug monitoring of anticancer drugs

La chemoterapia consiste nell\u2019impiego di uno o di una combinazione di farmaci antitumorali per il trattamento del cancro. Tuttavia tali farmaci sono caratterizzati da una famacocinetica molto variabile e da una elevata tossicit\ue0 che porta alla comparsa di molti effetti indesiderati nei pazienti, diminuendo l\u2019efficienza della terapia. In questo contesto l\u2019impiego del \u201cTherapeutic Drug Monitoring\u201d (TDM) risulta particolarmente importante in quanto permette per lo sviluppo di terapie personalizzate per i pazienti aumentando l\u2019efficienza della terapia e la qualit\ue0 della vita dei pazienti. Questo progetto \ue8 finalizzato alla sintesi e allo sviluppo di sensori, basati su nanoparticelle polimeriche ad impronta molecolare, per i farmaci antitumorali: sunitinib, paclitaxel, SN38 e irinotecano, suo profarmaco. Tali nanoparticelle solubili sono state ottenute mediante polimerizzazione radicalica ad elevata diluizione utilizzando diversi monomeri funzionali: N-acriloil-tirosina metil estere, N-acriloil triptofano metil estere, 4-vinilpiridina e 7-acrilossicumarina. La reazione \ue8 stata effettuata lasciando interagire i monomeri funzionali e il farmaco mediante interazioni deboli (legami idrogeno, \u3c0-staking, interazioni di Van der Waals) in DMSO e dopo l\u2019aggiunta dell\u2019acrilamide come co-monomero, dell\u2019N,N\u2019-etilenebisacrilamide come crosslinker e dell\u2019iniziatore radicalico azobisisobitironitrile (AIBN) la polimerizzazione \ue8 stata ottenuta scaldando a 70\ub0C per 4 giorni. La molecola templato \ue8 stata rimossa mediante dialisi prima in una miscela di metanolo e acido acetico, e poi in acqua. Le particelle ottenute dopo liofilizzazione, sono state caratterizzate mediante 1H-NMR, Nanosigh e Dynamic Laser Ligh Scattering. La capacit\ue0 di legame e la selettivit\ue0 dei polimeri \ue8 stata studiata mediante test di recupero utilizzando un metodo HPLC per la quantificazione del farmaco catturato. Mentre le propriet\ue0 fluorescenti di alcuni dei polimeri sintetizzati sono state utilizzate per studiare le affinit\ue0 di legame dei polimeri a basse concentrazioni di farmaco. Il polimero contenente cumarina e specifico per il sunitinib \ue8 stato utilizzato come sensore fluorescente per lo sviluppo di un test di validazione in DMSO:plasma. Il sensore ha mostrato un\u2019accuratezza del 15%, una precisione del 10% e una buona robustezza. Inoltre due diversi sensori fluorescenti sono stati sviluppati per la quantificazione dell\u2019irinotecano in metanolo:plasma. Il primo sensore si basa sul quenching della fluorescenza intrinseca dell\u2019irinotecano, mentre il secondo \ue8 un polimero molto fluorescente contenente un monomero funzionale con un gruppo naftalimidico la cui fluorescenza \ue8 spenta in seguito all\u2019interazione con l\u2019irinotecano. Inoltre un test fluorimetrico e colorimetrico \ue8 stato sviluppato per quantificare il paclitaxel mediante la tecnica del \u201cdye displacement\u201d. Il test infatti, si basa sulla competizione tra il farmaco libero ed il farmaco legato covalentemente al DABCYL per il legame ad un polimero ad imprinting molecolare contenente EDANS come monomero funzionale fluorescente. Infatti il DABCYL \ue8 sia un colorante rosso, sia un FRET quencher dell\u2019EDANS, perci\uf2 il suo legame nel polimero porta ad una variazione del colore e della fluorescenza del polimero. Infine un test colorimetrico per la quantificazione dell\u2019irinotecano \ue8 stato sviluppato utilizzando un polimero ad imprinting molecolare contenente l\u2019acido 2-acrilamido-2-metil propansolfonico come monomero funzionale. Il test si basa sul legame del colorante: anilina gialla nei siti di legame del polimero rimasti liberi dopo interazione con i campioni di farmaco. L\u2019interazione tra il colorante e l\u2019acido solfonico nel polimero genera un cambio di colore da giallo a rosso.Chemotherapy consists in cancer treatment by the administration of a single or a combination of anticancer drugs. However chemotherapy agents are often characterized by an high variability of pharmacokinetic among patients and an high toxicity that leads to the appearance of many side effects decreasing the therapy efficiency. Therefore the therapeutic drug monitoring (TDM) become useful to develop personalized therapies for patients in order to increase the efficiency of the therapy and patient compliance. This project is aimed on the synthesis and development of specific sensors based on molecularly imprinted polymeric nanoparticles, to be applied in TDM of the anticancer drugs: sunitinib, paclitaxel, SN38 and its prodrug irinotecan. Soluble nanoparticles were obtained by high dilution radical polymerization with different functional monomers: N-acryloyl-tyrosine methyl ester, N-acryloyl-tryptophan methyl ester, 4-vinyl pyridine or 7-acryloyloxy-coumarin. The reactions were carried out allowing the functional monomer to interact with the drug by weak interactions (H-bonds, \uf070-staking and Van der Waals) in DMSO and after the addition of the co-monomer acrylamide, the crosslinker N,N\u2019-ethylene bisacrylamide, and the radical initiator azobisisobutyronitrile (AIBN) the polymerization was achieved heating at 70\ub0C for 4 days. The template was removed by dialysis first in methanol:acetic acid mixture and after in water. After the freeze-drying the polymers were characterized by 1H-NMR, Nanosight, and Dynamic Laser Light Scattering. The polymers binding capabilities and selectivity were investigated by rebinding tests using an HPLC method for the quantification of drug captured. while the fluorescence properties of some of these polymers were exploited to study the polymers binding affinities at low drug concentrations. The polymer containing coumarin and imprinted with sunitinib was used as fluorescence sensor to set up a validation test in DMSO:plasma mixture. The system showed an accuracy of 15%, a precision of 10% and a good robustness. Two different fluorescence sensors were also developed for irinotecan able to quantify the drug in methanol:plasma mixtures. The first sensor is based on the quenching of the intrinsic fluorescence of irinotecan, while the second is an highly fluorescence polymer containing a functional monomer with a naphthalimide mojety whose fluorescence is quenched upon interaction with the drug. Moreover the dye displacement technique was used to set up a fluorescent and colorimetric test for paclitaxel quantification. The test is based on the competition between the free paclitaxel and the drug covalently linked to DABCYL dye, for the binding in to an imprinted polymer containing EDANS fluorescent functional monomer. Since DABCYL is both a red dye and a FRET quencher of EDANS, its binding into the polymer gives a change in the polymer fluorescence and colour. Finally a colorimetric test for irinotecan quantification was developed using an imprinted polymer containing 2-acrylamido-2-methylpropane sulfonic acid as functional monomer. The test is based on the binding of aniline yellow dye in to the remaining free binding sites of the polymer after treatment with drug samples. The interaction between the dye and the sulfonic acid in to the polymer gives a change of colour from yellow to red

Give Away Your Digital Services: Leveraging Big Data to Capture Value

Consumers are getting used to receiving free services in many different fields, and the popularity of the mobile app industry is feeding this phenomenon. Historically, advertising—a typical two-sided market mechanism—is the primary method that companies relying on a free-to-consumers business model have used to appropriate value in digital environ- ments. But new strategies are needed to make free services sustainable and profitable in the long term. At the same time, companies are gathering a huge amount of data from consumers, especially through mobile apps, by leveraging the sensors embedded in smartphones; this data represents a powerful new source of value. Through a case study analysis, we show how leveraging a two-sided structure can enable companies to capture value from user-sourced data, enabling a sustainable free-to-consumers business model. In this model, users are more than eyeballs to be targeted with advertising; they become data providers, and companies may capture value by using that data to customize advertising messages, lever- age e-ethnography to improve their own core offer, serve as fodder for research, or create knowledge for third partie

The design process of corporate universities: A stakeholder approach

Purpose – Corporate universities (CUs) have been experiencing tremendous growth during the past years and can represent a real driving force for structured organizations. The paper aims to define the process of CU design shaped around company strategy. For each step, the authors propose specific roles, activities and methods. Design/methodology/approach – The paper exploits some managerial theories and past research on CUs to draw a two-step framework for their design and development process, then tests (and validating) it through action research and applies its guidelines to two different case studies. Findings – The authors conclude the CU design process can be divided into two steps (development and management), with specific roles assigned to the different activities, and this allocation represents a prerequisite for the CU project success. Moreover, flexibility and potential recycles should be considered when configuring the process. Originality/value – The paper is original in two ways: it proposes a framework for CU design and development (which is unique in its type) and an application of this framework to two real cases, discussing its benefits, criticalities and limitations (thus ensuring generalizability)

Spotting local environments in self-assembled monolayer-protected gold nanoparticles

Organic-inorganic (O-I) nanomaterials are versatile platforms for an incredible high number of applications, ranging from heterogeneous catalysis, molecular sensing, cell targeting, imaging, cancer diagnosis and therapy, just to name a few. Much of their potential stems from the unique control of organic environments around inorganic sites within a single O-I nanomaterial, which allows for new properties inaccessible using purely organic or inorganic materials. Structural and mechanistic characterization plays a key role in understanding and rationally designing such hybrid nanoconstructs. Here, we introduce a general methodology to identify and classify local (supra)molecular environments in an archetypal class of O-I nanomaterials, i.e. self-assembled monolayer-protected gold nanoparticles (SAM-AuNPs). By using an atomistic machine-learning guided workflow based on the Smooth Overlap of Atomic Positions (SOAP) descriptor, we analyze a collection of chemically different SAM-AuNPs, and detect and compare local environments in a way that is agnostic and automated, i.e. with no need of a-priori information and minimal user intervention. In addition, the computational results coupled with experimental electron spin resonance measurements prove that is possible to have more than one local environment inside SAMs, being thickness of the organic shell and solvation primary factors in determining number and nature of multiple co-existing environments. These indications are extended to complex mixed hydrophilic-hydrophobic SAMs. This work demonstrates that it is possible to spot out and compare local molecular environments in SAM-AuNPs exploiting atomistic machine-learning approaches, establishes ground rules to control them, and holds the potential for rational design of O-I nanomaterials instructed from data

AGILE TGFS AND GLOBAL LIGHTNING ACTIVITY

[1] The AGILE satellite detects Terrestrial Gamma-ray Flashes (TGFs) in the 0.35–100 MeV energy range using its Mini-Calorimeter (MCAL) instrument with an average detection rate of 10 TGFs/month. Thanks to its Low Earth Orbit with only 2.5 degree of inclination, AGILE guarantees an unprecedented exposure above the equator, where both lightning activity and TGF detection peak. Here we report the comparison between the AGILE TGFs detected between March 2009 and February 2010 and full climatology lightning worldwide distribution based on satellite optical observations from LIS (Lightning Imaging Sensor) and OTD (Optical Transient Detector) instruments. This approach is complementary to the one-to-one TGF/lightning correlations by ground-based sferics measurements. Based on mono and bi-dimensional Kolmogorov-Smirnov tests, we show that the AGILE TGFs and time-averaged global lightning in the equatorial area are not drawn from the same distribution. However, we find significant regional differences in the degree of correlation as well as in the TGF/lightning ratio. In the case of south east Asia we find a 87% probability for the TGF and lightning being samples of the same distribution. This result supports the idea that the physical conditions at play in TGF generation can have strong geographical and climatological modulation. Based on the assumption that the observed range of TGF/flash ratio holds at all latitudes we can estimate a global rate of ≃ 220 ÷ 570 TGFs per day. The observed TGF/flash geographical modulation as well as the TGF global rate estimate are in agreement with previous observations

TGF DETECTION BY AGILE

We report the detection by the Astrorivelatore Gamma a Immagini Leggero (AGILE) satellite of terrestrial gamma ray flashes (TGFs) obtained with the minicalorimeter (MCAL) detector operating in the ..

The 2009 december gamma-ray flare of 3C 454.3: The multifrequency campaign

During the month of 2009 December, the blazar 3C 454.3 became the brightest gamma-ray source in the sky, reaching a peak flux F 2000 × 10 -8 photons cm-2 s-1 for E > 100 MeV. Starting in 2009 November intensive multifrequency campaigns monitored the 3C 454 gamma-ray outburst. Here, we report on the results of a two-month campaign involving AGILE, INTEGRAL, Swift/XRT, Swift/BAT, and Rossi XTE for the high-energy observations and Swift/UVOT, KANATA, Goddard Robotic Telescope, and REM for the near-IR/optical/UV data. GASP/WEBT provided radio and additional optical data. We detected a long-term active emission phase lasting 1 month at all wavelengths: in the gamma-ray band, peak emission was reached on 2009 December 2-3. Remarkably, this gamma-ray super-flare was not accompanied by correspondingly intense emission in the optical/UV band that reached a level substantially lower than the previous observations in 2007-2008. The lack of strong simultaneous optical brightening during the super-flare and the determination of the broadband spectral evolution severely constrain the theoretical modeling. We find that the pre- and post-flare broadband behavior can be explained by a one-zone model involving synchrotron self-Compton plus external Compton emission from an accretion disk and a broad-line region. However, the spectra of the 2009 December 2-3 super-flare and of the secondary peak emission on 2009 December 9 cannot be satisfactorily modeled by a simple one-zone model. An additional particle component is most likely active during these states. © 2010. The American Astronomical Society. All rights reserved

AGILE detection of extreme γ -ray activity from the blazar PKS 1510-089 during March 2009: Multifrequency analysis

We report on the extreme gamma-ray activity from the FSRQ PKS 1510-089 observed by AGILE in March 2009. In the same period a radio-to-optical monitoring of the source was provided by the GASP-WEBT and REM. Moreover, several Swift ToO observations were triggered, adding important information on the source behaviour from optical/UV to hard X-rays. We paid particular attention to the calibration of the Swift/UVOT data to make it suitable to the blazars spectra. Simultaneous observations from radio to gamma rays allowed us to study in detail the correlation among the emission variability at different frequencies and to investigate the mechanisms at work. In the period 9-30 March 2009, AGILE detected an average gamma-ray flux of (311+/-21)x10^-8 ph cm^-2 s^-1 for E>100 MeV, and a peak level of (702+/-131)x10^-8 ph cm^-2 s^-1 on daily integration. The gamma-ray activity occurred during a period of increasing activity from near-IR to UV, with a flaring episode detected on 26-27 March 2009, suggesting that a single mechanism is responsible for the flux enhancement observed from near-IR to UV. By contrast, Swift/XRT observations seem to show no clear correlation of the X-ray fluxes with the optical and gamma-ray ones. However, the X-ray observations show a harder photon index (1.3-1.6) with respect to most FSRQs and a hint of harder-when-brighter behaviour, indicating the possible presence of a second emission component at soft X-ray energies. Moreover, the broad band spectrum from radio-to-UV confirmed the evidence of thermal features in the optical/UV spectrum of PKS 1510-089 also during high gamma-ray state. On the other hand, during 25-26 March 2009 a flat spectrum in the optical/UV energy band was observed, suggesting an important contribution of the synchrotron emission in this part of the spectrum during the brightest gamma-ray flare, therefore a significant shift of the synchrotron peak