RAFT polymerization
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Superparamagnetic iron oxide nanoparticles (SPION) with a "non-fouling" surface represent a versatile group of biocompatible nanomaterials valuable for medical diagnostics, including oncology. In our study we present a synthesis of novel maghemite (γ-Fe2O3) nanoparticles with positive and negative overall surface charge and their coating by copolymer P(HPMA-co-HAO) prepared by RAFT (reversible addition-fragmentation chain-transfer) copolymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) with N-[2-(hydroxyamino)-2-oxo-ethyl]-2-methyl-prop-2-enamide (HAO). Coating was realized via hydroxamic acid groups of the HAO comonomer units with a strong affinity to maghemite. Dynamic light scattering (DLS) demonstrated high colloidal stability of the coated particles in a wide pH range, high ionic strength, and the presence of phosphate buffer (PBS) and serum albumin (BSE). Transmission electron microscopy (TEM) images show a narrow size distribution and spheroid shape. Alternative coatings were prepared by copolymerization of HPMA with methyl 2-(2-methylprop-2-enoylamino)acetate (MMA) and further post-polymerization modification with hydroxamic acid groups, carboxylic acid and primary-amino functionalities. Nevertheless, their colloidal stability was worse in comparison with P(HPMA-co-HAO). Additionally, P(HPMA-co-HAO)-coated nanoparticles were subjected to a bio-distribution study in mice. They were cleared from the blood stream by the liver relatively slowly, and their half-life in the liver depended on their charge; nevertheless, both cationic and anionic particles revealed a much shorter metabolic clearance rate than that of commercially available ferucarbotran.
- Publikační typ
- časopisecké články MeSH
This paper introduces a new class of amphiphilic block copolymers created by combining two polymers: polylactic acid (PLA), a biocompatible and biodegradable hydrophobic polyester used for cargo encapsulation, and a hydrophilic polymer composed of oligo ethylene glycol chains (triethylene glycol methyl ether methacrylate, TEGMA), which provides stability and repellent properties with added thermo-responsiveness. The PLA-b-PTEGMA block copolymers were synthesized using ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization (ROP-RAFT), resulting in varying ratios between the hydrophobic and hydrophilic blocks. Standard techniques, such as size exclusion chromatography (SEC) and 1H NMR spectroscopy, were used to characterize the block copolymers, while 1H NMR spectroscopy, 2D nuclear Overhauser effect spectroscopy (NOESY), and dynamic light scattering (DLS) were used to analyze the effect of the hydrophobic PLA block on the LCST of the PTEGMA block in aqueous solutions. The results show that the LCST values for the block copolymers decreased with increasing PLA content in the copolymer. The selected block copolymer presented LCST transitions at physiologically relevant temperatures, making it suitable for manufacturing nanoparticles (NPs) and drug encapsulation-release of the chemotherapeutic paclitaxel (PTX) via temperature-triggered drug release mechanism. The drug release profile was found to be temperature-dependent, with PTX release being sustained at all tested conditions, but substantially accelerated at 37 and 40 °C compared to 25 °C. The NPs were stable under simulated physiological conditions. These findings demonstrate that the addition of hydrophobic monomers, such as PLA, can tune the LCST temperatures of thermo-responsive polymers, and that PLA-b-PTEGMA copolymers have great potential for use in drug and gene delivery systems via temperature-triggered drug release mechanisms in biomedicine applications.
- Publikační typ
- časopisecké články MeSH
19F magnetic resonance imaging (MRI) using fluoropolymer tracers has recently emerged as a promising, non-invasive diagnostic tool in modern medicine. However, despite its potential, 19F MRI remains overlooked and underused due to the limited availability or unfavorable properties of fluorinated tracers. Herein, we report a straightforward synthetic route to highly fluorinated 19F MRI nanotracers via aqueous dispersion polymerization-induced self-assembly of a water-soluble fluorinated monomer. A polyethylene glycol-based macromolecular chain-transfer agent was extended by RAFT-mediated N-(2,2,2-trifluoroethyl)acrylamide (TFEAM) polymerization in water, providing fluorine-rich self-assembled nanoparticles in a single step. The resulting nanoparticles had different morphologies and sizes ranging from 60 to 220 nm. After optimizing their structure to maximize the magnetic relaxation of the fluorinated core, we obtained a strong 19F NMR/MRI signal in an aqueous environment. Their non-toxicity was confirmed on primary human dermal fibroblasts. Moreover, we visualized the nanoparticles by 19F MRI, both in vitro (in aqueous phantoms) and in vivo (after subcutaneous injection in mice), thus confirming their biomedical potential.
Upconverting luminescent lanthanide-doped nanoparticles (UCNP) belong to promising new materials that absorb infrared light able to penetrate in the deep tissue level, while emitting photons in the visible or ultraviolet region, which makes them favorable for bioimaging and cell labeling. Here, we have prepared upconverting NaYF4:Yb,Er@NaYF4:Nd core-shell nanoparticles, which were coated with copolymers of N,N-dimethylacrylamide (DMA) and 2-(acryloylamino)-2-methylpropane-1-sulfonic acid (AMPS) or tert-butyl [2-(acryloylamino)ethyl]carbamate (AEC-Boc) with negative or positive charges, respectively. The copolymers were synthesized by a reversible addition-fragmentation chain transfer (RAFT) polymerization, reaching Mn ~ 11 kDa and containing ~ 5 mol% of reactive groups. All copolymers contained bisphosphonate end-groups to be firmly anchored on the surface of NaYF4:Yb,Er@NaYF4:Nd core-shell nanoparticles. To compare properties of polymer coatings, poly(ethylene glycol)-coated and neat UCNP were used as a control. UCNP with various charges were then studied as labels of carcinoma cells, including human hepatocellular carcinoma HepG2, human cervical cancer HeLa, and rat insulinoma INS-1E cells. All the particles proved to be biocompatible (nontoxic); depending on their ξ-potential, the ability to penetrate the cells differed. This ability together with the upconversion luminescence are basic prerequisites for application of particles in photodynamic therapy (PDT) of various tumors, where emission of nanoparticles in visible light range at ~ 650 nm excites photosensitizer.
- MeSH
- akrylamidy chemie MeSH
- buňky Hep G2 MeSH
- fluorescenční barviva chemie MeSH
- fluoridy chemie MeSH
- HeLa buňky MeSH
- lidé MeSH
- nádory diagnostické zobrazování MeSH
- nanočástice chemie MeSH
- optické zobrazování metody MeSH
- ytrium chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Here, we describe innovative synthesis of well-defined biocompatible N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer carriers and their drug conjugates with pirarubicin intended for controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with dispersity close to 1 and molar mass close to renal threshold with minimal synthesis steps. The developed synthesis enables preparation of tailored polymer nanomedicines with highly enhanced biological behavior in vivo, especially the biodistribution, urine elimination, tumor accumulation and anticancer activity. STATEMENT OF SIGNIFICANCE: The manuscript reports on novel synthesis and detailed physicochemical characterization and in vivo evaluation of well-defined biocompatible hydrophilic copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) and their drug conjugates with pirarubicin enabling controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with minimal synthesis steps using controlled polymerization. Compared to previously published HPMA-based polymer drug conjugates whose polymer carriers were prepared by classical route via free radical polymerization, the newly prepared polymer drug conjugates exhibited enhanced biological behavior in vivo, especially the prolonged blood circulation, urine elimination, tumor accumulation and excellent anticancer activity. We believe that the newly prepared well-defined polymer conjugates could significantly enhance tumor therapy in humans.
- MeSH
- akrylamidy chemická syntéza farmakokinetika terapeutické užití MeSH
- doxorubicin analogy a deriváty chemická syntéza farmakokinetika terapeutické užití MeSH
- experimentální sarkom farmakoterapie MeSH
- kapronáty chemická syntéza farmakokinetika terapeutické užití MeSH
- lékové transportní systémy MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nanomedicína metody MeSH
- polymerizace MeSH
- protinádorové látky chemická syntéza farmakokinetika terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Two conjugates of anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond to the polymer carrier based on water-soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesized and their properties were compared, namely their behavior in vivo. The polymer carriers differed in dispersity due to different methods of synthesis; the carrier with relatively high dispersity (HD) was prepared by free radical polymerization (Mw=29,900 g/mol, D=1.75) and the carrier with low dispersity (LD) by controlled radical polymerization (Mw=30,000 g/mol, D=1.13). Both polymer-Dox conjugates showed prolonged blood circulation and tumor accumulation of the drug in comparison with the free drug; e.g. the tumor-to-blood ratio for the polymer-bound Dox was 3-5 times higher. The LD polymer-Dox conjugate exhibited moderately higher tumor accumulation than the HD one at a dose of 1x15 mg Dox (eq.)/kg. Also, their anti-tumor activity did not differ when injected at this dose. However, the increase of the dose to 1x25 mg Dox (eq.)/kg resulted in the enhanced therapeutic activity of the conjugates, especially of the LD one with 100% of long-term survivals. The dispersity of polymer drug carriers influenced the tumor accumulation rate, which affected the overall anti-cancer activity of polymer-drug conjugates.
- MeSH
- analýza přežití MeSH
- doxorubicin chemie farmakokinetika farmakologie MeSH
- experimentální nádory farmakoterapie metabolismus patologie MeSH
- léky s prodlouženým účinkem MeSH
- methakryláty chemie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nosiče léků MeSH
- polymery chemická syntéza MeSH
- protinádorová antibiotika chemie farmakokinetika farmakologie MeSH
- tkáňová distribuce MeSH
- volné radikály chemie MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
V poslední době dochází k velmi příznivému vývoji na poli cílené léčby karcinomu prsu. Léčba šitá na míru individuální nemocné podle typu jejího nádoru dostává stále jasnější obrysy. Některé léky, především trastuzumab, zaměřený na HER2 receptor, mají už svoje stálé místo v rutinní léčbě karcinomu prsu. Problém, který je třeba vyřešit, je nástup rezistence a selhání léčby trastuzumabem. Další léky zasahují do angiogeneze nebo využívají speciální mechanismy jako například PARP inhibitory. Problém indikace léčby, jejího dávkování, trvání a kombinace řeší řada klinických studií, z nichž mnohé teprve probíhají.
Recently, there is a very positive development in the field of targeted treatment of breast cancer. Treatment pointing at individual patients according to the type of their tumor is becoming clearer. Some drugs, especially trastuzumab, targeting the HER2 receptor, already have a constant position in the routine treatment of breast cancer. The problem to be solved is an emerging resistance and failure of trastuzumab treatment. Other drugs interfere with angiogenesis or use special mechanisms, such as for example PARP inhibitors. A series of clinical studies, some of which are still on-going, are solving the problem of treatment indication, its dosage, duration and combinations.
- Klíčová slova
- HER2, angiogeneze,
- MeSH
- chinazoliny aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- chinoliny škodlivé účinky terapeutické užití MeSH
- duktální karcinom prsu farmakoterapie genetika MeSH
- lidé MeSH
- monoklonální protilátky aplikace a dávkování farmakologie MeSH
- nádory prsu MeSH
- neoadjuvantní terapie metody MeSH
- PARP inhibitory MeSH
- poly(ADP-ribosa)polymerasy farmakologie terapeutické užití MeSH
- receptor erbB-2 účinky léků MeSH
- TOR serin-threoninkinasy antagonisté a inhibitory MeSH
- vaskulární endoteliální růstový faktor A antagonisté a inhibitory škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinické zkoušky kontrolované MeSH
Among the class of zwitterionic polymers poly(carboxybetaine)s (poly(CB)s) are unique, emerging as the only ultra-low fouling materials known allowing the preparation of biosensors, fouling resistant nanoparticles, and non-adhesive surfaces for bacteria. Poly(carboxybetaine methacrylate) and poly(carboxybetaine acrylamide) have been prepared via atom transfer radical polymerization (ATRP), however a polymerization with living characteristics has not been achieved yet. Herein, the first successful living/controlled reversible addition fragmentation transfer (RAFT) polymerization of (3-methacryloylamino-propyl)-(2-carboxy-ethyl)-dimethyl-ammonium (carboxybetaine methacrylamide) (CBMAA-3) in acetate buffer (pH 5.2) at 70 and 37 °C is reported. The polymerization afforded very high molecular weight polymers (determined by absolute size exclusion chromatography, close to 250,000 g·mol(-1) in less than 6 h) with low PDI (<1.3) at 70 °C. The polymerization was additionally carried out at 37 °C allowing to achieve yet lower PDIs (1.06 ≤ PDI ≤ 1.15) even at 90% conversion, demonstrating the suitability of the polymerization conditions for bioconjugate grafting. The living character of the polymerization is additionally evidenced by chain extending poly(CBMAA-3) at 70 and 37 °C. Block copolymerization from biologically relevant poly[N-(2-hydroxypropyl)methacrylamide] macroCTAs was additionally performed.
Controlled radical reversible addition-fragmentation chain transfer (RAFT) polymerisation was used to prepare water-soluble polymer-drug carriers based on copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) with a hydrazide group-containing monomer, showing well-defined structure with narrow molecular weight distribution (approx. 1.1-1.2). The anticancer therapeutic doxorubicin was bound to the polymeric carrier by a hydrazone bond, enabling pH-controlled release under mildly acid conditions that mimics the environment in endosomes/lysosomes of tumour cells. RAFT polymerisation facilitated the synthesis of semitelechelic copolymers, which were used in the synthesis of monoclonal anti-CD20 antibody-polymer-drug conjugate designed for cell-specific tumour targeting. They were also used for producing a biodegradable high-molecular-weight graft polymer-drug conjugate that degrade in the presence of glutathione, which is designed for passive targeting to solid tumours. The conjugates exhibited well-defined structures with narrow molecular weight distributions of approx. 1.3 and pH-controlled drug release.
- MeSH
- akrylamidy chemie MeSH
- doxorubicin chemie farmakologie MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- lékové transportní systémy metody MeSH
- molekulární struktura MeSH
- monoklonální protilátky MeSH
- nosiče léků chemie MeSH
- polymerizace MeSH
- protinádorová antibiotika chemie farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
