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.
- Klíčová slova
- Doxorubicin, HPMA copolymer carrier, STAT3 inhibitor, pH-sensitive drug release,
- 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
- Názvy látek
- doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate MeSH Prohlížeč
- doxorubicin * MeSH
- hydroxypropyl methacrylate MeSH Prohlížeč
- kyseliny polymethakrylové MeSH
- methakryláty * MeSH
- STAT3 protein, human MeSH Prohlížeč
- transkripční faktor STAT3 MeSH
Biodegradable polymer-based therapeutics have recently become essential drug delivery biomaterials for various bioactive compounds. Biodegradable and biocompatible polymer-based biomaterials fulfill the requirements of these therapeutics because they enable to obtain polymer biomaterials with optimized blood circulation, pharmacokinetics, biodegradability, and renal excretion. Herein, we describe an adaptable polymerization platform employed for the synthesis of long-circulating, stimulus-sensitive and biodegradable biomaterials, therapeutics, or theranostics. Four chain transfer agents (CTA) were designed and successfully synthesized for the reversible addition-fragmentation chain transfer polymerization, allowing the straightforward synthesis of hydrolytically biodegradable structures of block copolymers-based biomaterials. The controlled polymerization using the CTAs enables controlling the half-life of the hydrolytic degradation of polymer precursors in a wide range from 5 h to 21 days. Moreover, the antitumor drug pirarubicin (THP) was successfully conjugated to the polymer biomaterials via a pH-sensitive hydrazone bond for in vitro and in vivo experiments. Polymer conjugates demonstrated superior antitumor efficacy compared to basic linear polymer-based conjugates. Notably, the biodegradable systems, even though those with degradation in the order of hours were selected, increased the half-life of THP in the bloodstream almost two-fold. Indeed, the presented platform design enables the main chain-end specific attachment of targeting ligands or diagnostic molecules. The adaptable polymerization platform design allows tuning of the biodegradability rate, stimuli-sensitive drug bonding, and optimized pharmacokinetics to increase the therapy outcome and system targeting, thus allowing the preparation of targeted or theranostic polymer conjugates. STATEMENT OF SIGNIFICANCE: Biodegradable and biocompatible polymer-based biomaterials are recognized as potential future bioactive nanomedicines. To advance the development of such biomaterials, we developed polymerization platforms utilizing tailored chain transfer agents allowing the straightforward synthesis of hydrolytically degradable polymer biomaterials with tuned biodegradability from hours to several days. The platform allows for the synthesis of long-circulating, stimulus-sensitive and biodegradable biomaterial serving as drug carriers or theranostics. The therapeutic potential was validated by preparation of polymer biomaterials containing pirarubicin, anticancer drug, bound via pH sensitive bond and by showing prolonged blood circulation and increased antitumor activity while keeping the drug side effects low. This work paves the way for future development of biodegradable polymer biomaterials with advanced properties in drug delivery.
- Klíčová slova
- CTA, Drug delivery, HPMA, Polymer carriers, RAFT polymerization,
- MeSH
- antitumorózní látky * terapeutické užití MeSH
- biokompatibilní materiály farmakologie chemie MeSH
- doxorubicin * chemie MeSH
- nosiče léků chemie MeSH
- polymerizace MeSH
- polymery chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky * MeSH
- biokompatibilní materiály MeSH
- doxorubicin * MeSH
- nosiče léků MeSH
- pirarubicin MeSH Prohlížeč
- polymery MeSH
Chronic inflammatory diseases such as rheumatoid arthritis represent a substantial socio-economic impact and have a high prevalence in the modern world. Nano-sized polymer therapeutics have shown suitable characteristics for becoming the next generation of anti-inflammatory nanomedicines. Here, we present biocompatible and stimuli-sensitive N-(2-hydroxypropyl)methacrylamide based polymer conjugates with the anti-inflammatory drug dexamethasone (DEX), which has been tailored for prolonged blood circulation, enhanced inflammatory site accumulation, site-specific drug release and subsequent elimination of the carrier via urine excretion. The hydrodynamic size of novel polymer-DEX nanomedicine was adjusted to prolong its blood circulation whilst maintaining the renal excretability of the polymer carrier after drug release in inflamed tissue. The therapeutic efficacy of the studied polymer nanomedicines was evaluated in a model of dissipated chronic arthritis, i.e. collagen II-induced arthritis, in mice. The pH-sensitive drug attachment enabled enhanced blood circulation with minimal systemic drug release, as well as rapid drug activation in affected joints. Importantly, unlike free DEX, the polymer nanomedicines were able to diminish joint inflammation and arthritis-induced bone damage - even at a reduced dosing regimen - as evaluated by micro computed tomography (micro-CT).
- Klíčová slova
- Collagen II-induced arthritis, Dexamethasone, Drug delivery, HPMA, Inflammation, Passive targeting, Polymer conjugate,
- MeSH
- antiflogistika terapeutické užití MeSH
- artritida experimentální * diagnostické zobrazování farmakoterapie MeSH
- myši MeSH
- nanomedicína MeSH
- polymery terapeutické užití MeSH
- rentgenová mikrotomografie MeSH
- revmatoidní artritida * diagnostické zobrazování farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antiflogistika MeSH
- polymery MeSH
In this review we summarize several synthetic approaches to the advanced synthesis of star-like polymer-based drug carriers. Moreover, their application as nanomedicines for therapy or the diagnosis of neoplastic diseases and their biodistribution are reviewed in detail. From a broad spectrum of star-like systems, we focus only on fully water-soluble systems, mainly based on poly(ethylene glycol) or N-(2-hydroxypropyl)methacrylamide polymer and copolymer arms and polyamidoamine dendrimers serving as the core of the star-like systems.
- MeSH
- lidé MeSH
- methakryláty aplikace a dávkování chemie metabolismus MeSH
- nosiče léků aplikace a dávkování chemie metabolismus MeSH
- polyethylenglykoly aplikace a dávkování metabolismus MeSH
- polymery aplikace a dávkování chemie metabolismus MeSH
- tkáňová distribuce účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- hydroxypropyl methacrylate MeSH Prohlížeč
- methakryláty MeSH
- nosiče léků MeSH
- polyethylenglykoly MeSH
- polymery MeSH
Inflammation is a vital defense mechanism of living organisms. However, persistent and chronic inflammation may lead to severe pathological processes and evolve into various chronic inflammatory diseases (CID), e.g. rheumatoid arthritis, multiple sclerosis, multiple sclerosis, systemic lupus erythematosus or inflammatory bowel diseases, or certain types of cancer. Their current treatment usually does not lead to complete remission. The application of nanotherapeutics may significantly improve CID treatment, since their accumulation in inflamed tissues has been described and is referred to as extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS). Among nanotherapeutics, water-soluble polymer-drug conjugates may be highly advantageous in CID treatment due to the possibility of their passive and active targeting to the inflammation site and controlled release of active agents once there. The polymer-drug conjugate consists of a hydrophilic biocompatible polymer backbone along which the drug molecules are covalently attached via a biodegradable linker that enables controlled drug release. Their active targeting or bio-imaging can be achieved by introducing the cell-specific targeting moiety or imaging agents into the polymer conjugate. Here, we review the relationship between polymer conjugates and inflammation, including the benefits of the application of polymer conjugates in inflammation treatment, the anti-inflammatory activity of polymer drug conjugates and potential polymer-promoted inflammation and immunogenicity.
- MeSH
- antiflogistika aplikace a dávkování chemie metabolismus MeSH
- idiopatické střevní záněty farmakoterapie metabolismus MeSH
- lidé MeSH
- nádory farmakoterapie metabolismus MeSH
- polymery aplikace a dávkování chemie metabolismus MeSH
- revmatoidní artritida farmakoterapie metabolismus MeSH
- výsledek terapie MeSH
- zánět farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antiflogistika MeSH
- polymery MeSH
Novel star polymers based on the water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer and cyclodextrin were synthesized and the physico-chemical behavior of these precursors was studied. Semitelechelic HPMA copolymers were grafted onto the cyclodextrin core, thus forming star-like structure. Both prepared systems were designed as possible polymer carriers for the controlled release of cytostatic drugs, which after the drug release and degradation will be eliminated from the organism. Two synthesis approaches were used to obtain similar polymer carriers with different degradation rates. All the polymers were prepared by reversible addition-fragmentation chain-transfer polymerization, which guarantees low dispersity of the prepared systems.
- MeSH
- chemie farmaceutická metody MeSH
- cyklodextriny chemická syntéza metabolismus MeSH
- methakryláty chemická syntéza metabolismus MeSH
- polymery chemická syntéza metabolismus MeSH
- rozpustnost MeSH
- voda chemie metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cyklodextriny MeSH
- hydroxypropyl methacrylate MeSH Prohlížeč
- methakryláty MeSH
- polymery MeSH
- voda MeSH
The present review focuses on the description of the design, synthesis and physico-chemical and biological evaluation of polymer nanogels. Nanogels are robust swollen cross-linked polymer nanoparticles that can be used as highly efficient and biodegradable carriers for the transport of drugs in controlled drug delivery. In this article, various types of nanogels are described and methods for their preparation discussed. The possibility of using synthesized nanosystems for targeting are reviewed to show the potential of tailored structures to reach either solid tumor tissue or direct tumor cells. Finally, the methods for encapsulation or attachment of biologically active molecules, e.g. drugs, proteins, are described and compared.
- MeSH
- gely MeSH
- lidé MeSH
- nádory farmakoterapie metabolismus MeSH
- nanočástice chemie metabolismus MeSH
- polymery aplikace a dávkování chemická syntéza metabolismus MeSH
- systémy cílené aplikace léků metody trendy MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- gely MeSH
- polymery MeSH
Cell-penetrating compounds are substances that enhance the cellular uptake of various molecular cargoes that do not easily cross the cellular membrane. The majority of cell-penetrating compounds described in the literature are cell-penetrating peptides (CPPs). This review summarizes the various structural types of cell-penetrating compounds, with the main focus on CPPs. The authors present a brief overview of the history of CPPs, discuss the various types of conjugation of CPPs to biologically active cargoes intended for cell internalization, examine the cell-entry mechanisms of CPPs, and report on the applications of CPPs in research and in preclinical and clinical studies.
- MeSH
- buněčná membrána účinky léků metabolismus MeSH
- endocytóza účinky léků fyziologie MeSH
- lidé MeSH
- penetrační peptidy aplikace a dávkování genetika metabolismus MeSH
- sekvence aminokyselin MeSH
- systémy cílené aplikace léků metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- penetrační peptidy MeSH
BACKGROUND: Galectin-3 (Gal-3) is a promising target in cancer therapy with a high therapeutic potential due to its abundant localization within the tumor tissue and its involvement in tumor development and proliferation. Potential clinical application of Gal-3-targeted inhibitors is often complicated by their insufficient selectivity or low biocompatibility. Nanomaterials based on N-(2-hydroxypropyl)methacrylamide (HPMA) nanocarrier are attractive for in vivo application due to their good water solubility and lack of toxicity and immunogenicity. Their conjugation with tailored carbohydrate ligands can yield specific glyconanomaterials applicable for targeting biomedicinally relevant lectins like Gal-3. RESULTS: In the present study we describe the synthesis and the structure-affinity relationship study of novel Gal-3-targeted glyconanomaterials, based on hydrophilic HPMA nanocarriers. HPMA nanocarriers decorated with varying amounts of Gal-3 specific epitope GalNAcβ1,4GlcNAc (LacdiNAc) were analyzed in a competitive ELISA-type assay and their binding kinetics was described by surface plasmon resonance. We showed the impact of various linker types and epitope distribution on the binding affinity to Gal-3. The synthesis of specific functionalized LacdiNAc epitopes was accomplished under the catalysis by mutant β-N-acetylhexosaminidases. The glycans were conjugated to statistic HPMA copolymer precursors through diverse linkers in a defined pattern and density using Cu(I)-catalyzed azide-alkyne cycloaddition. The resulting water-soluble and structurally flexible synthetic glyconanomaterials exhibited affinity to Gal-3 in low μM range. CONCLUSIONS: The results of this study reveal the relation between the linker structure, glycan distribution and the affinity of the glycopolymer nanomaterial to Gal-3. They pave the way to specific biomedicinal glyconanomaterials that target Gal-3 as a therapeutic goal in cancerogenesis and other disorders.
- Klíčová slova
- Carbohydrate, ELISA, Galectin-3, Glyconanomaterial, HPMA copolymer, Surface plasmon resonance,
- MeSH
- akrylamidy chemie metabolismus MeSH
- galektin 3 metabolismus MeSH
- galektiny MeSH
- glykokonjugáty chemie metabolismus MeSH
- krevní proteiny MeSH
- lidé MeSH
- nanostruktury chemie MeSH
- nosiče léků chemie metabolismus MeSH
- systémy cílené aplikace léků * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- akrylamidy MeSH
- galektin 3 MeSH
- galektiny MeSH
- glykokonjugáty MeSH
- krevní proteiny MeSH
- LGALS3 protein, human MeSH Prohlížeč
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nosiče léků MeSH
The delivery of nitric oxide (NO) specifically to solid tumours was explored in this study as a strategy to augment the passive accumulation of nanomedicines in tumours induced by the Enhanced Permeability and Retention (EPR) effect. An increase in accumulation was achieved by the binding of the chemical precursor of NO, based on an organic nitrate, to a water-soluble synthetic polymer drug carrier. Four structurally different N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer NO donors were synthesized. Depending on their chemical structure, two of these donors were hydrolytically stable, while two rapidly released the parent nitrate under acidic conditions, mimicking the intracellular environment. The polymer NO donors were shown to overcome the drawbacks related to low-molecular-weight NO releasing compounds, namely systemic toxicity, lack of site specificity, and fast blood clearance. The NO donors showed intracellular NO release upon incubation with tumour cells. In vivo, they potentiated the EPR effect, resulting in an increased accumulation of polymer-bound cytotoxic drug doxorubicin (Dox) in EL4 T-cell lymphoma inoculated in mice. This led to a better therapeutic outcome in the treatment of lymphoma with the high-molecular-weight polymer conjugates carrying Dox but not in the treatment with the free Dox. The localized augmentation of the EPR effect via the tumour-specific NO delivery system can be viewed as a promising strategy to potentiate polymer-based tumour therapy without increasing systemic toxicity.
- Klíčová slova
- Enhanced permeability and retention effect, HPMA, Nitric oxide donor, Polymer-based cytotoxic drugs, Solid tumour treatment, T-cell lymphoma,
- MeSH
- antibiotika antitumorózní aplikace a dávkování MeSH
- buněčné linie MeSH
- donory oxidu dusnatého aplikace a dávkování MeSH
- doxorubicin aplikace a dávkování MeSH
- lidé MeSH
- lymfom T-buněčný farmakoterapie MeSH
- myši inbrední C57BL MeSH
- nosiče léků aplikace a dávkování MeSH
- polymery aplikace a dávkování MeSH
- synergismus léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antibiotika antitumorózní MeSH
- donory oxidu dusnatého MeSH
- doxorubicin MeSH
- nosiče léků MeSH
- polymery MeSH
