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New approaches integrating stimuli-responsive linkers into prodrugs are currently emerging. These "smart" prodrugs can enhance the effectivity of conventional prodrugs with promising clinical applicability. Oxidative stress is central to several diseases, including cancer. Therefore, the design of prodrugs that respond to ROS stimulus, allowing a selective drug release in this condition, is fairly encouraging. Aiming to investigate the ROS-responsiveness of prodrugs containing the ROS-cleavable moiety, Thioketal (TK), we performed proof-of-concept studies by synthesizing ROS-responsive conjugate, namely mPEG-TK-Cy5, through exploiting Cy5 fluorescent dye. We demonstrated that, differently to non-ROS-responsive control conjugate (mPEG-Cy5), mPEG-TK-Cy5 shows a selective release of Cy5 in response to ROS in both, ROS-simulated conditions and in vitro on glioblastoma cells. Our results confirm the applicability of TK-technology in the design of ROS-responsive prodrugs, which constitutes a promising approach in cancer treatment. The translatability of this technology for other diseases treatment makes this a highly relevant and promising approach., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Polymeric nanoparticles (Np) represent one of the most innovative non-invasive approaches for the drug delivery to the central nervous system (CNS). It is known that the ability of the Np to cross the Blood Brain Barrier (BBB), thus allowing the drugs to exert their pharmacological activity in the central nervous district, is linked to their surface characteristics. Recently it was shown that the biocompatible polyester poly(d,l-lactide-co-glycolide) (PLGA) derivatized with the peptide H(2)N-Gly-l-Phe-d-Thr-Gly-l-Phe-l-Leu-l-Ser(O-beta-d-Glucose)-CONH(2) [g7] was a useful starting material for the preparation of Np (g7-Np); moreover, fluorescent studies showed that these Np were able to cross the BBB. In this research, g-7 Np were loaded with Loperamide in order to assess their ability as drug carriers for CNS, and with Rhodamine-123, in order to qualitatively determine their biodistribution in different brain macro-areas. A pharmacological evidence is given that g7-Np are able to cross the BBB, ensuring, for the first time, a sustained release of the embedded drug, and that these Np are able to reach all the brain areas here examined. The ability to enter the CNS appears to be linked to the sequence of the peptidic moiety present on their surface.

Cellular localization of nanoparticles (Np) represents an important target in the understanding of their distribution after endovenous injection. The need of suitable devices and methodologies capable to detect Np in tissues or in cellular districts can be satisfied by Np which have to be easily recognizable by simple methods. Conjugations of poly(D,L-lactide-co-glycolide) with fluorescein and biotin allow fluorescent and immuno-histochemically active Np to be obtained. The fluorescein Np are detectable using fluorescent microscopy whereas biotin Np can be detected by optical microscopy after streptavidin-biotin-peroxidase complexation. In vivo experiments confirm the ability of these particles to be easily detected in the brain parenchyma or in the liver cell population according to the infusion pathway.

A study concerning the feasibility of microsphere use as sustained delivery systems for N(6)-cyclopentyladenosine (CPA) administration has been performed. The release of this drug and the related stability effects in human whole blood have been tested. Moreover, the impact of the delivery system on CPA interaction toward human adenosine A1 receptor and the related cellular responses has been analyzed. The microspheres were prepared by an emulsion-solvent evaporation method using poly(lactic acid). Free and encapsulated CPA was incubated in fresh blood and the drug stability was analyzed with HPLC. The affinity of CPA to human A1 receptor expressed by CHO cells was obtained by binding experiments. Activity was evaluated by measurements of the inhibition of forskolin-stimulated 3',5'-cyclic adenosine monophosphate (c-AMP) performing competitive binding assays. Encapsulated CPA was released within 72 h and its degradation in blood was negligible. Affinity and activity values of CPA obtained in the absence and in the presence of unloaded microspheres were the same. CPA encapsulation in microspheres allows its sustained release and its stabilization in human whole blood to be obtained. The presence of this release system does not interfere with the CPA activity at its action site.

A new polymeric prodrug was prepared coupling 5-iodo-2'-deoxyuridine (IDU) to poly(d,l-lactic acid) (PLA) via a succinic acid spacer. The PLA-IDU conjugate was characterised by thermal analysis, IR and 1H and 13C NMR spectroscopy. The IDU content (0.024 mequiv.g-1 of PLA) was consistent with the carboxylic acid endgroup present in the polymer sample (0.025 mequiv.g-1 of polymer). The PLA-IDU conjugate was susceptible to degradation in biological environments containing esterase, whereas IDU was not detected by chemical hydrolysis in pH 7.4 phosphate buffer. The conjugate should be used to prepare injectable microspheres and nanospheres containing IDU chemically coupled to the polymer carrier.

The release of fluorescein from polyethylcyanoacrylate (PECA) or polyisobutylcyanoacrylate (PICA) nanoparticles was affected by the surfactants used for the preparation. The different surfactants also modified the molecular weight, size and loading of the nanoparticles. However, these factors were not be responsible for the different release. According to the release profiles and the Baker-Lonsdale model, a portion of fluorescein was concentrated near the nanoparticle surface. Thus, a non-homogeneous distribution of the fluorescent probe inside the nanoparticles was hypothesized. This distribution could reflect the fluorescein position inside the micella during the polymerization stage, or could be reached during the washing stage as the consequence of a different effect of the surfactants on the porosity of the nanoparticle structure.

Ethylene:vinyl acetate pellets were loaded at 20 degrees C by swelling the polymer with 1 and 3% (w/v) chloroformic solutions of tolbutamide. The energy dispersive X-ray analysis showed different concentrations of the tolbutamide sulfur in the pellets sections according to the loading time. At the beginning of the loading process, the sulfur in the pellets showed two concentration peaks which later joined in the center of the section before reaching a homogeneous distribution. The concentration peaks might depend on a drug sieving process as the solution flow reaches a less swollen inner area. Therefore, the concentration distribution of the drug would be affected by the size of the polymer network, which is related to the volume of the solvent in the polymer. Another possible explanation of these concentration profiles is that they could be a result of the solvent evaporation process. The concentration distribution of the drug becomes homogeneous only after the complete swelling of all of the polymer.