Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

A new hydrophilic polymer for biomaterial coatings with low protein adsorption

BIOPOL® polyurethane polymers, an extension of the HYPOL® Polymer series of foamable hydrophilic polymers, have been developed which exhibit improved performance for selected biomedical applications. Members of the BIOPOL polyurethane polymer series, with molecular weights in the range of 7000 to 30000, are larger molecules than HYPOL polymers (MW < 3000) and produce hydrogels, rather than foams, when mixed with water. The prototype material in this series, BIOPOL XP-5, is a liquid prepolymer which chain extends in water and forms a hydrogel which can contain >85% water. The time required for polymerization with water was dependent on the prepolymer : water ratio. This prepolymer was coated onto silica and medical grade tubing and then cured in place with water to form a stable coating which was resistant to non-specific protein binding. In addition, soluble, isocyanate-free forms of the prepolymer were tested for toxicity and shown to produce no adverse effects when injected intravenously into mice or when applied to a chicken chorioallantoic membrane. BIOPOL polymers can be useful in applications where protein adsorption is an undesirable event.     

Replacement therapy with piperazine oestrone sulphate('Harmogen') and its effect on memory

Summary

A formal memory test was administered to 18 female patients with signs or symptoms of oestrogen deficiency taking part in a double-blind study of piperazine oestrone sulphate. A significant improvement in memory was seen in the treated group compared with the placebo group. The findings are discussed.     

Photorefractive Composite Based on a Monolithic Polymer

A new class of photorefractive (PR) composite based on a fully functionalized polymer with high phase‐stability is reported. The polymer containing non‐linear optical (NLO) chromophores and charge‐transporting carbazole moieties is synthesized by a polymer‐analogous reaction. The polymer is doped with plasticizer, NLO dye, and sensitizer to fabricate the PR composite. The NLO dye is the same as the NLO chromophore moiety in the polymer side chain. The PR performance of the composite is evaluated by degenerated four‐wave mixing and two‐beam coupling measurements. A diffraction efficiency of 30% at a relatively low applied electric field of 45 V μm^?1 is achieved. Despite a high concentration of NLO dye, the composites show good stability for a long period without phase separation.     

New Applications of Photolabile Nitrobenzyl Groups in Polymers

This article describes progress in the author's laboratory in two new areas of photoresponsive polymers: (1) photochemical control of electrostatics, and (2) conjugated materials with photocleavable pendants. In both cases, incorporation of o‐nitrobenzyl esters (NBEs) imparts this photoreactivity. NBE‐derivatized, ring‐opening metathesis polymerization (ROMP)‐derived polycations form positive photoresist layer‐by‐layer (LbL) films that dissolve in base upon irradiation. NBE‐derivatized conjugated oligomers show photoactivated fluorescence, whereas NBE‐substituted polythiophenes are negative photoresists due to photolysis of solubilizing alkyl chains.     

Tyrosine-derived novel antimicrobial hydantoin polymers: synthesis and evaluation of anti-bacterial activities

A new approach for the design and synthesis of cyclic N-halamine polymers having anti-bacterial activity based on a vinyl derivative of tyrosine-derived hydantoin is reported. The synthesis of N-halamine polymers generally involves the chemical modification of 5,5′-disubstituted hydantoin to introduce polymerizable vinyl moieties thereby restricting the halogen capture only on the amide nitrogen. Here we show the possibility of synthesizing vinyl monomers of N-halamine from α-amino acids wherein both the amide and imide nitrogens are available for halogen capture. Thus, a hydantoin monomer was synthesized from L-tyrosine and copolymerized with methyl methacrylate and 2-(hydroxyethyl)methacrylate, to obtain random co-polymers. The monomer and its co-polymers were characterized using NMR, IR, HRMS, GPC, DSC, EDAX and TGA analysis. Films of the co-polymers cast from 10% acetone solutions were exposed to sodium hypochlorite solution to activate the hydantoin moieties. The oxidative chlorine content of the films ranged from 0.6 to 0.9%. The activated films were exposed to both Gram positive (S. aureus) and Gram negative (E. coli) bacteria using standard protocols. Polymers having chlorine content as little as 0.6% exhibited 6 log reduction in the bacterial growth within 30 min of exposure. The method allows the halogenation of both amide and imide nitrogens and could be applied to the preparation of a number of vinyl hydantoins from many amino acids.     

New hydrophilic polyesters and related polymers as bioerodible polymeric matrices

A survey is reported on our activity performed in the last few years on the preparation of new synthetic and semisynthetic polymeric materials endowed with bioerodible-biodegradable characteristics and designed for applications in the practice of controlled release of active principles of pharmaceutical and agrochemical significance. The presentation of the results will be arranged into the following sections: (1) hydroxyl containing polyesters, that comprise polymerization products based on racemic and optically active glyceric acid, or attained by polyaddition reactions among cyclic anhydrides, including also carbon dioxide, with monoglycidyl ethers of reversibly protected polyols. In this class are also presented the related polyhydroxylated systems obtained by selective grafting functional epoxides on cyclodextrins. (2) Bioerodible carboxyl containing plolymeric systems as derived from the alternating copolymerization of maleic anhydride with alkyl vinyl ethers followed by partial esterification of maleic anhydride groups. (3) Linear and cross-linked functional polymers of synthetic and semisynthetic origin with hydrogel forming capability. Typical examples of their applications in the release of drugs and phytodrugs are also presented.     

Neural tissue engineering: Adrenal chromaffin cell attachment and viability on chitosan scaffolds

Abstract

This study introduces chitosan-based matrices as cell substrates for bovine chromaffin cell attachment in transplantation procedures. Chitosan ([1 → ] linked 2-amino-2-deoxy-β-O-glucopyranose), having structural similarity to glycosaminoglycans, was modified using several proteins (collagen, albumin and gelatin) to increase surface area and improve biocompatibility. In vitro, collagen-blended chitosan (CC) matrices were found to attach more readily to chromaffin cells than to gelatin- or albumin-blended matrices. Morphological evidence showed that the chromaffin cells attached to CC substrates integrated well with the hydrogel matrix and survived for at least two weeks, under in vivo culture conditions. The chromaffin cells within chitosan scaffolds also survived for at least two weeks in vitro and after subarachnoid grafting to rats. [Neural Res 1998; 20: 648–654]     

Study of a cross-linked hydrogel of Karaya gum and Starch as a controlled drug delivery system

Abstract

A cross-linked hydrogel was synthesized using a hybrid backbone of karaya gum starch and grafted with polyacrylic acid. It showed a maximum swelling ratio (SR) of 30.5?g/g at pH 10 and was explored as an oral drug delivery carrier using paracetamol and aspirin as model drugs. In vitro release experiments revealed that maximum drug release at pH 7.4 in comparison to pH 1.2 (simulated intestinal vs gastric fluid) and neutral medium. The release profiles of these drugs showed no initial burst. It also showed good hemocompatibilty and non-cytotoxicity for its employment as a site specific drug delivery agent.     

Nanocomposites of iridium oxide and conducting polymers as electroactive phases in biological media

Much effort is currently devoted to implementing new materials in electrodes that will be used in the central nervous system, either for functional electrostimulation or for tests on nerve regeneration. Their main aim is to improve the charge capacity of the electrodes, while preventing damaging secondary reactions, such as peroxide formation, occurring while applying the electric field. Thus, hybrids may represent a new generation of materials. Two novel hybrid materials are synthesized using three known biocompatible materials tested in the neural system: polypyrrole (PPy), poly(3,4-ethylenedioxythiophene) (PEDOT) and iridium oxide (IrO₂). In particular, PPy–IrO₂ and PEDOT–IrO₂ hybrid nanocomposite materials are prepared by chemical polymerization in hydrothermal conditions, using IrO₂ as oxidizing agent. The reaction yields a significant ordered new hybrid where the conducting polymer is formed around the IrO₂ nanoparticles, encapsulating them. Scanning electron microscopy and backscattering techniques show the extent of the encapsulation. Both X-ray photoelectron and Fourier transform infrared spectroscopies identify the components of the phases, as well as the absence of impurities. Electrochemical properties of the final phases in powder and pellet form are evaluated by cyclic voltammetry. Biocompatibility is tested with MTT toxicity tests using primary cultures of cortical neurons grown in vitro for 6 and 9 days.