We synthesized three novel STAT3 inhibitors (S3iD1-S3iD3) possessing oxoheptanoic residue enabling linkage to HPMA copolymer carrier via a pH-sensitive hydrazone bond. HPMA copolymer conjugates bearing doxorubicin (Dox) and our STAT3 inhibitors were synthesized to evaluate the anticancer effect of Dox and STAT3 inhibitor co-delivery into tumors. S3iD1-3 and their copolymer-bound counterparts (P-S3iD1-P-S3iD3) showed considerable in vitro cytostatic activities in five mouse and human cancer cell lines with IC50 ~0.6-7.9 μM and 0.7-10.9 μM, respectively. S3iD2 and S3iD3 were confirmed to inhibit the STAT3 signaling pathway. The combination of HPMA copolymer-bound Dox (P-Dox) and P-S3iD3 at the dosage showing negligible toxicity demonstrated significant antitumor activity in B16F10 melanoma-bearing mice and completely cured 2 out of 15 mice. P-Dox alone had a significantly lower therapeutic activity with no completely cured mice. Thus, polymer conjugates bearing STAT3 inhibitors may be used for the chemosensitization of chemorefractory tumors.
- MeSH
- doxorubicin * farmakologie terapeutické užití MeSH
- koncentrace vodíkových iontů MeSH
- kyseliny polymethakrylové MeSH
- lidé MeSH
- methakryláty * MeSH
- myši MeSH
- nádory * farmakoterapie MeSH
- transkripční faktor STAT3 metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Self-assembled bilayer structures such as those produced from amphiphilic block copolymers (polymersomes) are potentially useful in a wide array of applications including the production of artificial cells and organelles, nanoreactors, and delivery systems. These constructs are of important fundamental interest, and they are also frequently considered toward advances in bionanotechnology and nanomedicine. In this framework, membrane permeability is perhaps the most important property of such functional materials. Having in mind these considerations, we herein report the manufacturing of intrinsically permeable polymersomes produced using block copolymers comprising poly[2-(diisopropylamino)-ethyl methacrylate] (PDPA) as the hydrophobic segment. Although being water insoluble at pH 7.4, its pKa(PDPA) ∼ 6.8 leads to the presence of a fraction of protonated amino groups close to the physiological pH, thus conducting the formation of relatively swollen hydrophobic segments. Rhodamine B-loaded vesicles demonstrated that this feature confers inherent permeability to the polymeric membrane, which can still be modulated to some extent by the solution pH. Indeed, even at higher pH values where the PDPA chains are fully deprotonated, the experiments demonstrate that the membranes remain permeable. While membrane permeability can be, for instance, regulated by introducing membrane proteins and DNA nanopores, examples of membrane-forming polymers with intrinsic permeability have been seldom reported so far, and the possibility to regulate the flow of chemicals in these compartments by tuning block copolymer features and ambient conditions is of due relevance. The permeable nature of PDPA membranes possibly applies to a wide array of small molecules, and these findings can in principle be translocated to a variety of disparate bio-related applications.
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Human population is exposed to a broad spectrum of endocrine disruptors. Bisphenol A (BPA) are one of the group that is widely used in items of daily needs. BPA has previously been shown to negatively affecting human reproduction and usage of assisted reproductive technology (ART). However, substitution of BPA by alternative BPs brought serious problems, such as unproven harmlessness of other BPs (BPS, BPF, BPAF) and possible interactions of individual BPs in organism. Moreover, the molecular mechanism of BPs negative effect and real impact on human reproductive health remains unclear. We hypothesize that human population is exposed to BPs, negatively affecting human reproduction. The aim of the project is a) to describe a relationship of BPs' level in human seminal plasma/follicular fluid and ART outcomes and b) to describe mechanism of BPs' action experimentally, using models (i.e. mouse, pig and human follicular cells). The estimation of BPs' risk for human reproductive health and description of molecular mechanism will become a background for the solution of the BPs' problem.
Lidská populace je soustavně exponována spektrem environmentálních polutantů s endokrinně-disrupčním efektem. Do této skupiny patří bisfenoly (BP), z nichž bisfenol (BPA) je široce využíván v předmětech každodenní potřeby. Negativní efekt BPA na reprodukci člověka, včetně postupů asistované reprodukce (ART), byl prokázán a tak je BPA v materiálech postupně nahrazován. Nicméně, alternativní BP (BPS, BPF, BPAF) přináší řadu problémů, protože jejich neškodnost není prokázána. Navíc může docházet k interakcím jednotlivých BP v organizmu. Skutečný dopad BP tak zůstává neobjasněn, stejně jako molekulární mechanizmy účinků BP. Byla stanovena hypotéza, že lidská populace je exponovaná BP, které negativně ovlivňují reprodukční procesy. Cílem projektu je a) popsat souvislost mezi hladinami BP v lidské seminální plazmě/folikulární tekutině a výsledky ART, a b) popsat mechanizmus BP na základě experimentálních modelů (tj. myš, prase, lidské folikulární buňky). Odhad rizika expozice BP a popis molekulárního účinku jejich působení představuje základ pro řešení problému jejich výskytu v prostředí.
- MeSH
- asistovaná reprodukce MeSH
- bisfenol A-glycidyl methakrylát toxicita MeSH
- embryonální vývoj MeSH
- endokrinní disruptory MeSH
- infertilita MeSH
- modely nemocí na zvířatech MeSH
- otrava MeSH
- rozmnožování MeSH
- testy toxicity MeSH
- vrozené vady MeSH
- vystavení vlivu životního prostředí MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- environmentální vědy
- toxikologie
- embryologie a teratologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
OBJECTIVES: Resin-based materials are applied in every branch of dentistry. Due to their tendency to release substances in the oral environment, doubts have been raised about their actual safety. This review aims to provide a comprehensive analysis of the last decade literature regarding the concentrations of elutable substances released from dental resin-based materials in different type of solvents. MATERIALS AND METHODS: All the literature published on dental journals between January 2010 and April 2022 was searched using international databases (PubMed, Scopus, Web of Science). Due to strict inclusion criteria, only 23 papers out of 877 were considered eligible. The concentration of eluted substances related to surface and volume of the sample was analyzed, considering data at 24 h as a reference. The total cumulative release was examined as well. RESULTS: The most eluted substances were HEMA, TEGDMA, and BPA, while the less eluted were Bis-GMA and UDMA. Organic solvents caused significantly higher release of substances than water-based ones. A statistically significant inverse correlation between the release of molecules and their molecular mass was observed. A statistically significant positive correlation between the amount of released molecule and the specimen surface area was detected, as well as a weak positive correlation between the release and the specimen volume. CONCLUSIONS: Type of solvent, molecular mass of eluates, and specimen surface and volume affect substances release from materials. CLINICAL RELEVANCE: It could be advisable to rely on materials based on monomers with a reduced elution tendency for clinical procedures.
- MeSH
- doxorubicin farmakologie MeSH
- kyseliny hydroxamové MeSH
- lidé MeSH
- methakryláty MeSH
- nádory * farmakoterapie MeSH
- nanomedicína * MeSH
- polymery farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Non-specific protein adsorption (fouling) triggers a number of deleterious events in the application of biomaterials. Antifouling polymer brushes successfully suppress fouling, however for some coatings an extremely high variability of fouling for different donors remains unexplained. The authors report that in the case of poly(2-hydroxyethyl methacrylate) (poly(HEMA)) this variability is due to the complement system activation that causes massive acceleration in the fouling kinetics of blood plasma. Using plasma from various donors, the fouling kinetics on poly(HEMA) is analyzed and correlated with proteins identified in the deposits on the surface and with the biochemical compositions of the plasma. The presence of complement components in fouling deposits and concentrations of C3a in different plasmas indicate that the alternative complement pathway plays a significant role in the fouling on poly(HEMA) through the "tick-over" mechanism of spontaneous C3 activation. The generated C3b binds to the poly(HEMA) surface and amplifies complement activation locally. Heat-inactivated plasma prevents accelerated fouling kinetics, confirming the central role of complement activation. The results highlight the need to take into account the variability between individuals when assessing interactions between biomaterials and blood plasma, as well as the importance of the mechanistic insight that can be gained from protein identification.
The effect of 1-week water storage and subsequent 10,000 thermal cycles on light transmission properties (straight-line transmission (G0), diffusion (DF), the amount of transmitted light (AV)), translucency parameter (TP) and refractive index (RI) of four nanofilled flowable composites was examined. The composites included Filtek Supreme Ultra Flowable Restorative (FSU), Estelite Flow Quick (EFQ), Estelite Universal Flow, (EUF), and Clearfil Majesty ES Flow (ESF), all of A3 shade. For composites with lower filler load (FSU, EFQ), water storage increased G0, AV and TP, but subsequent thermocycling decreased them. An opposite tendency was found for DF. Materials with higher filler load (EUF, ESF) were not significantly affected by aging conditions. RI of EFQ and EUF containing bisphenol A polyethoxy methacrylate (Bis-MPEPP) increased significantly after thermocycling. Additionally, morphological changes were observed using scanning electron microscopy which revealed cracks within nanocluster fillers and dislocation of particles in FSU and EFQ after thermocycling.
Research of degradable hydrogel polymeric materials exhibiting high water content and mechanical properties resembling tissues is crucial not only in drug delivery systems but also in tissue engineering, medical devices, and biomedical-healthcare sensors. Therefore, we newly offer development of hydrogels based on poly(2-hydroxyethyl methacrylate-co-2-(acetylthio) ethyl methacrylate-co-2-methacryloyloxyethyl phosphorylcholine) [P(HEMA-ATEMA-MPC)] and optimization of their mechanical and in vitro and in vivo degradability. P(HEMA-ATEMA-MPC) hydrogels differed in chemical composition, degree of crosslinking, and starting molar mass of polymers (15, 19, and 30 kDa). Polymer precursors were synthesized by a reversible addition fragmentation chain transfer (RAFT) polymerization using 2-(acetylthio)ethyl methacrylate containing protected thiol groups, which enabled crosslinking and gel formation. Elastic modulus of hydrogels increased with the degree of crosslinking (Slaughter et al., 2009) [1]. In vitro and in vivo controlled degradation was confirmed using glutathione and subcutaneous implantation of hydrogels in rats, respectively. We proved that the hydrogels with higher degree of crosslinking retarded the degradation. Also, albumin, γ-globulin, and fibrinogen adsorption on P(HEMA-ATEMA-MPC) hydrogel surface was tested, to simulate adsorption in living organism. Rat mesenchymal stromal cell adhesion on hydrogels was improved by the presence of RGDS peptide and laminin on the hydrogels. We found that rat mesenchymal stromal cells proliferated better on laminin-coated hydrogels than on RGDS-modified ones.
Obstructed blood flow and erratic blood supply in the tumor region attenuate the distribution and accumulation of nanomedicines in the tumor. Therefore, improvement of these conditions is crucial for efficient drug delivery. In this study, we designed and synthesized a novel N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer conjugate of BK, which possessed adequate systemic stability and tumor-selective action required to improve the accumulation of nanomedicines in the tumor. Levulinoyl-BK (Lev-BK) was conjugated to an HPMA-based polymer via an acid-cleavable hydrazone bond (P-BK). An acid-responsive release of Lev-BK from P-BK was observed, and P-BK alone after intradermal application showed below 10% of the BK activity, thus proving a reduction in the vascular permeability activity of BK when attached to the polymer carrier. P-BK pre-treatment improved blood flow in the tumor tissue by 1.4-1.7-fold, which was maintained for more than 4 h. In addition, P-BK pre-treatment increased the tumor accumulation of pegylated liposomal doxorubicin (PLD) by approximately 3-fold. Furthermore, P-BK pre-treatment led to superior antitumor activity of PLD and significantly improved the survival of tumor-bearing mice. The release of BK from P-BK in the acidic milieu of the tumor was a prerequisite for P-BK to exert its effect, as the vascular permeability enhancing activity of P-BK was negligible. Collectively, P-BK pre-treatment improved intratumoral blood flow and augmented tumor accumulation of nanomedicine, thereby resulting in a significant suppression of tumor growth. Therefore, these findings demonstrate that P-BK is a potential concomitant drug for improving the tumor delivery of nanomedicines.
- MeSH
- bradykinin terapeutické užití MeSH
- doxorubicin terapeutické užití MeSH
- methakryláty MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory * farmakoterapie MeSH
- nanomedicína MeSH
- nosiče léků terapeutické užití MeSH
- polymery terapeutické užití MeSH
- protinádorové látky * terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Design, controlled synthesis, physico-chemical and biological characteristics of novel well-defined biodegradable star-shaped copolymers intended for advanced drug delivery is described. These new biocompatible star copolymers were synthesised by grafting monodispersed semitelechelic linear (sL) N-(2-hydroxypropyl)methacrylamide copolymers onto a 2,2-bis(hydroxymethyl)propionic acid (bisMPA)-based polyester dendritic core of various structures. The hydrodynamic diameter of the star copolymer biomaterials can be tuned from 13 to 31 nm and could be adjusted to a given purpose by proper selection of the bisMPA dendritic core type and generation and by considering the sL copolymer molecular weight and polymer-to-core molar ratio. The hydrolytic degradation was proved for both the star copolymers containing either dendron or dendrimer core, showing the spontaneous hydrolysis in duration of few weeks. Finally, it was shown that the therapy with the biodegradable star conjugate with attached doxorubicin strongly suppresses the tumour growth in mice and is fully curative in most of the treated animals at dose corresponding approximately to one fourth of maximum tolerated dose (MTD) value. Both new biodegradable systems show superior efficacy and tumour accumulation over the first generation of star copolymers containing non-degradable PAMAM core.
- MeSH
- akrylamidy MeSH
- biokompatibilní materiály * MeSH
- doxorubicin MeSH
- léčivé přípravky * MeSH
- lékové transportní systémy MeSH
- methakryláty MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků MeSH
- polymery MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
