Background: Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, trigger biodegradation of polymer-based nanoparticles (NPs) bearing pinacol-type boronic ester groups. These NPs may selectively release their cargo, in this case paclitaxel (PTX), at the high levels of ROS present in the intracellular environment of inflamed tissues and most tumors. Purpose: The main objective was to determine anti-tumor efficacy of PTX-loaded ROS-sensitive NPs and to examine whether macrophage infiltration had any impact on treatment efficacy. Methods: NPs were synthesized and their characteristics in the presence of H2O2 were demonstrated. Both confocal microscopy as well as flow cytometry approaches were used to determine degradation of ROS-sensitive NPs. HeLa cells were cultured in vitro and used to establish tumor xenografts in nude mice. In vivo experiments were performed to understand toxicity, biodistribution and anti-tumor efficacy of the NPs. Moreover, we performed immunohistochemistry on tumor sections to study infiltration of M1 and M2 subsets of macrophages. Results: We demonstrated that PTX delivered in NPs containing a ROS-sensitive polymer exhibits a better anti-tumor efficacy than PTX in NPs containing ROS-non-sensitive polymer, free PTX or Abraxane® (nab-PTX). The biodistribution revealed that ROS-sensitive NPs exhibit retention in liver, spleen and lungs, suggesting a potential to target cancer metastasizing to these organs. Finally, we demonstrated a correlation between infiltrated macrophage subsets and treatment efficacy, possibly contributing to the efficient anti-tumor effects. Conclusion: Treatment with ROS-sensitive NPs containing PTX gave an improved therapeutic effect in HeLa xenografts than their counterpart, free PTX or nab-PTX. Our data revealed a correlation between macrophage infiltration and efficiency of the different antitumor treatments, as the most effective NPs resulted in the highest infiltration of the anti-tumorigenic M1 macrophages.

• MeSH
• albuminy farmakologie   terapeutické užití   MeSH
• HeLa buňky MeSH
• hydrodynamika MeSH
• lidé MeSH
• makrofágy účinky léků   metabolismus   MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• nanočástice terapeutické užití   MeSH
• paclitaxel farmakologie   terapeutické užití   MeSH
• paklitaxel vázaný na albumin terapeutické užití   MeSH
• polymery chemie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• tkáňová distribuce účinky léků   MeSH
• velikost částic MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Stereolithography-assisted fabrication of hydrogels of carboxybetaine methacrylamide (CBMAA) and a α,ω-methacrylate poly(d,l-lactide-block-ethylene glycol-block- d,l-lactide) (MA-PDLLA-PEG-PDLLA-MA) telechelic triblock macromer is presented. This technique allows printing complex structures with gyroid interconnected porosity possessing extremely high specific area. Hydrogels are characterized by infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and laser scanning confocal microscopy (LSCM). The copolymerization with zwitterionic comonomer leads hydrogels with high equilibrium water content (EWC), up to 700% while maintaining mechanical robustness. The introduction of carboxybetaine yields excellent resistance to nonspecific protein adsorption while providing a facile way for specific biofunctionalization with a model protein, fluorescein isothiocyanate labeled bovine serum albumin (BSA). The homogeneous protein immobilization across the hydrogel pores prove the accessibility to the innermost pore volumes. The remarkably low protein adsorption combined with the interconnected nature of the porosity allowing fast diffusion of nutrient and waste product and the mimicry of bone trabecular, makes the hydrogels presented here highly attractive for tissue engineering.

• MeSH
• hydrogely chemie   MeSH
• methakryláty chemie   MeSH
• poréznost MeSH
• skot MeSH
• tkáňové inženýrství * MeSH
• tkáňové podpůrné struktury chemie   MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Polyester-based nanostructures are widely studied as drug-delivery systems due to their biocompatibility and biodegradability. They are already used in the clinic. In this work, we describe a new and simple biodegradable and biocompatible system as the Food and Drug Administration approved polyesters (poly-ε-caprolactone, polylactic acid, and poly(lactic- co-glycolic acid)) for the delivery of the anticancer drug paclitaxel (PTX) as a model drug. A hydrophobic polyester, poly(propylene succinate) (PPS), was prepared from a nontoxic alcohol (propylene glycol) and monomer from the Krebs's cycle (succinic acid) in two steps via esterification and melt polycondensation. Furthermore, their amphiphilic block copolyester, poly(ethylene oxide monomethyl ether)- block-poly(propylene succinate) (mPEO- b-PPS), was prepared by three steps via esterification followed by melt polycondensation and the addition of mPEO to the PPS macromolecules. Analysis of the in vitro cellular behavior of the prepared nanoparticle carriers (NPs) (enzymatic degradation, uptake, localization, and fluorescence resonance energy-transfer pair degradation studies) was performed by fluorescence studies. PTX was loaded to the NPs of variable sizes (30, 70, and 150 nm), and their in vitro release was evaluated in different cell models and compared with commercial PTX formulations. The mPEO- b-PPS copolymer analysis displays glass transition temperature < body temperature < melting temperature, lower toxicity (including the toxicity of their degradation products), drug solubilization efficacy, stability against spontaneous hydrolysis during transport in bloodstream, and simultaneous enzymatic degradability after uptake into the cells. The detailed cytotoxicity in vitro and in vivo tumor efficacy studies have shown the superior efficacy of the NPs compared with PTX and PTX commercial formulations.

• MeSH
• antitumorózní látky aplikace a dávkování   farmakokinetika   MeSH
• micely MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanočástice škodlivé účinky   chemie   metabolismus   MeSH
• paclitaxel aplikace a dávkování   farmakokinetika   MeSH
• polyestery chemická syntéza   chemie   MeSH
• polyethylenglykoly chemie   MeSH
• polypropyleny chemie   MeSH
• sukcináty chemie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A conceptually new bimodal immunoradiotherapy treatment was demonstrated using thermoresponsive polymer β-glucan-graft-poly(2-isopropyl-2-oxazoline-co-2-butyl-2-oxazoline) bearing complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid with yttrium-90(III) at the graft ends. The behavior of this thermoresponsive polymer in aqueous solutions was studied, and it showed the appropriate cloud point temperature for brachytherapy applications. The polymer was tested in vitro, and it exhibited nontoxicity and active uptake into cancer cells and macrophages with colocalization in the lysosomes and macrophagosomes. Moreover, the observed oxidative burst response of the leukocytes established the immunostimulatory properties of the polymer, which were also studied in vivo after injection into the thigh muscles of healthy mice. The subsequent histological evaluation revealed the extensive immune activation reactions at the site of injection. Furthermore, the production of tumor necrosis factor α induced by the prepared polymer was observed in vitro, denoting the optimistic prognosis of the treatment. The biodistribution study in vivo indicated the formation of the polymer depot, which was gradually degraded and excluded from the body. The radiolabeled polymer was used during in vivo antitumor efficiency experiments on mice with EL4 lymphoma. The immunoradiotherapy group (treated with the radiolabeled polymer) demonstrated the complete inhibition of tumor growth during the beginning of the treatment. Moreover, 7 of the 15 mice were completely cured in this group, while the others exhibited significantly prolonged survival time compared to the control group. The in vivo experiments indicated the considerable synergistic effect of using immunoradiotherapy compared to separately using immunotherapy or radiotherapy.

• MeSH
• antibakteriální látky chemická syntéza   farmakologie   MeSH
• antitumorózní látky chemická syntéza   farmakologie   terapeutické užití   MeSH
• aza sloučeniny chemie   MeSH
• beta-glukany chemie   MeSH
• brachyterapie metody   MeSH
• heterocyklické sloučeniny monocyklické chemie   MeSH
• imunitní systém účinky léků   MeSH
• komplexní sloučeniny chemie   MeSH
• leukocyty účinky léků   metabolismus   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• oxazoly chemie   MeSH
• oxidace-redukce MeSH
• polymery chemie   MeSH
• radioimunoterapie metody   MeSH
• radioizotopy ytria chemie   MeSH
• Staphylococcus aureus účinky léků   MeSH
• teplota MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We designed and synthesized a new delivery system for the anticancer drug doxorubicin based on a biocompatible hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) carrier with linear architecture and narrow molar mass distribution. The drug is connected to the polymer backbone via an acid-sensitive hydrazone linker, which allows its triggered release in the tumor. The in vitro studies demonstrate successful cellular uptake of conjugates followed by release of the cytostatic cargo. In vivo experiments in EL4 lymphoma bearing mice revealed prolonged blood circulation, increased tumor accumulation and enhanced antitumor efficacy of the PEtOx conjugate having higher molecular weight (40 kDa) compared to the lower molecular weight (20 kDa) polymer. Finally, the in vitro and in vivo anti-cancer properties of the prepared PEtOx conjugates were critically compared with those of the analogous system based on the well-established PHPMA carrier. Despite the relatively slower intracellular uptake of PEtOx conjugates, resulting also in their lower cytotoxicity, there are no substantial differences in in vivo biodistribution and anti-cancer efficacy of both classes of polymer-Dox conjugates. Considering the synthetic advantages of poly(2-alkyl-2-oxazoline)s, the presented study demonstrates their potential as a versatile alternative to well-known PEO- or PHPMA-based materials for construction of drug delivery systems.

• MeSH
• akrylamidy chemie   MeSH
• doxorubicin chemie   terapeutické užití   MeSH
• HeLa buňky MeSH
• konfokální mikroskopie MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanomedicína metody   MeSH
• nosiče léků chemie   MeSH
• polyaminy chemie   MeSH
• polymery chemie   MeSH
• průtoková cytometrie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH