Development of therapeutic systems to treat glioblastoma, the most common and aggressive brain tumor, belongs to priority tasks in cancer research. We have synthesized colloidally stable magnetic nanoparticles (Dh =336 nm) coated with doxorubicin (Dox) conjugated copolymers of N,N-dimethylacrylamide and either N-acryloylglycine methyl ester or N-acryloylmethyl 6-aminohexanoate. The terminal carboxyl groups of the copolymers were reacted with alendronate by carbodiimide formation. Methyl ester groups were then transferred to hydrazides for binding Dox by a hydrolytically labile hydrazone bond. The polymers were subsequently bound on the magnetic nanoparticles through bisphosphonate terminal groups. Finally, the anticancer effect of the Dox-conjugated particles was investigated using the U-87 glioblastoma cell line in terms of particle internalization and cell viability, which decreased to almost zero at a concentration of 100 μg of particles per ml. These results confirmed that poly(N,N-dimethylacrylamide)-coated magnetic nanoparticles can serve as a solid support for Dox delivery to glioblastoma cells.
- Klíčová slova
- antitumor agents, cytotoxicity, drug delivery, magnetic properties, nanoparticles,
- MeSH
- akrylové pryskyřice chemická syntéza chemie MeSH
- antitumorózní látky chemie farmakologie MeSH
- doxorubicin chemie farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- magnetické nanočástice chemie MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemická syntéza chemie MeSH
- povrchové vlastnosti MeSH
- uvolňování léčiv MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- akrylové pryskyřice MeSH
- antitumorózní látky MeSH
- doxorubicin MeSH
- magnetické nanočástice MeSH
- nosiče léků MeSH
In this study, we compared the enhanced permeability and retention (EPR) effect, toxicity, and therapeutic effect of the conjugate of the linear polymer poly(N-(2-hydroxypropyl)methacrylamide) (HPMA) with pirarubicin with an Mw below the renal threshold (39g/mol) (named LINEAR) and the disulfide-linked tandem-polymeric dimer of the poly(HPMA)-pirarubicin conjugate with an Mw above the renal threshold (93g/mol) (named DIBLOCK). The DIBLOCK conjugate, which was susceptible to reductive degradation, showed both a better EPR effect (tumor delivery) (2.5 times greater at 24h) and a prolonged plasma half-life. In addition, DIBLOCK had a better antitumor effect, as judged by percent survival, than did LINEAR (80% vs 65% at 150days), without any apparent toxicity in an S180 tumor model. However, the LD50 value of LINEAR was slightly higher than that of DIBLOCK (50mg/kg vs 37.5mg/kg, respectively). DIBLOCK required a longer time than LINEAR to reach maximum accumulation in the tumor. DIBLOCK also showed a greater time-dependent increase in the concentration in the tumor compared with the plasma concentration.
- Klíčová slova
- EPR effect, PHPMA conjugate, Pirarubicin, Tandem-diblock PHPMA conjugate, Tumor drug targeting,
- MeSH
- antitumorózní látky škodlivé účinky chemie farmakologie MeSH
- biologická dostupnost MeSH
- biologický transport MeSH
- doxorubicin škodlivé účinky analogy a deriváty chemie farmakologie MeSH
- kyseliny polymethakrylové chemická syntéza MeSH
- lidé MeSH
- molekulová hmotnost MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemická syntéza MeSH
- poločas MeSH
- renální reabsorpce MeSH
- tkáňová distribuce MeSH
- uvolňování léčiv MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Názvy látek
- antitumorózní látky MeSH
- doxorubicin MeSH
- Duxon MeSH Prohlížeč
- kyseliny polymethakrylové MeSH
- nosiče léků MeSH
- pirarubicin MeSH Prohlížeč
Sponge-type nanocarriers (spongosomes) are produced upon dispersion of a liquid crystalline sponge phase formed by self-assembly of an amphiphilic lipid in excess aqueous phase. The inner organization of the spongosomes is built-up by randomly ordered bicontinuous lipid membranes and their surfaces are stabilized by alginate chains providing stealth properties and colloidal stability. The present study elaborates spongosomes for improved encapsulation of Brucea javanica oil (BJO), a traditional Chinese medicine that may strongly inhibit proliferation and metastasis of various cancers. The inner structural organization and the morphology characteristics of BJO-loaded nanocarriers at varying quantities of BJO were determined by cryogenic transmission electron microscopy (Cryo-TEM), small angle X-ray scattering (SAXS) and dynamic light scattering (DLS). Additionally, the drug loading and drug release profiles for BJO-loaded spongosome systems also were determined. We found that the sponge-type liquid crystalline lipid membrane organization provides encapsulation efficiency rate of BJO as high as 90%. In vitro cytotoxicity and apoptosis study of BJO spongosome nanoparticles with A549 cells demonstrated enhanced anti-tumor efficiency. These results suggest potential clinical applications of the obtained safe spongosome formulations.
- Klíčová slova
- Liquid crystalline nanocarriers, Nanosponges, Phytochemical anticancer nanomedicines, Self-assembly,
- MeSH
- antitumorózní látky fytogenní aplikace a dávkování chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- Brucea chemie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nanočástice chemie MeSH
- nosiče léků chemická syntéza chemie MeSH
- oleje aplikace a dávkování chemie farmakologie MeSH
- povrchové vlastnosti MeSH
- proliferace buněk účinky léků MeSH
- velikost částic MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antitumorózní látky fytogenní MeSH
- nosiče léků MeSH
- oleje MeSH
In this paper, we describe the synthesis, physicochemical characterization, drug release kinetics and preliminary biological evaluation of several N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer-retinoid conjugates designed for solid tumor immunotherapy. The conjugates are supposed to inhibit the immunosuppressive activity of myeloid-derived suppressor cells (MDSC) accumulated in the solid tumor microenvironment. All-trans retinoic acid (ATRA) was derivatized to hydrazide (AtrHy) and then attached to the polymer backbone via a spacer that is stable at the normal pH of blood (7.4) and hydrolytically degradable in mildly acidic environments (e.g. in endosomes or lysosomes, pH~5.0-6.5). Polymer-AtrHy conjugates were designed to achieve prolonged blood circulation and release of the immunomodulator intracellularly or extracellularly in solid tumor tissue. Three types of polymer precursors, differing in the structure of the keto acid-containing side chains, were synthesized. A linkage susceptible to hydrolytic cleavage was formed by the conjugation reaction of the carbonyl group-terminated side chains of the polymer precursors with the hydrazide group of a drug derivative. In vitro incubation of the conjugates in buffers resulted in much faster release of the drugs or their derivatives from the polymer at pH 5.0 than at pH 7.4, with the rate depending on the detailed structure of the spacer. Both the AtrHy derivative and its polymer conjugates showed the ability to induce the differentiation of retinoid-responsive HL-60 cells, thus demonstrating the required biological activity.
- MeSH
- antitumorózní látky farmakokinetika MeSH
- HL-60 buňky MeSH
- lidé MeSH
- methakryláty chemie MeSH
- nosiče léků chemická syntéza MeSH
- tretinoin farmakokinetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antitumorózní látky MeSH
- hydroxypropyl methacrylate MeSH Prohlížeč
- methakryláty MeSH
- nosiče léků MeSH
- tretinoin MeSH
Cytarabine is one of the most efficient drugs in the treatment of hematological malignancies. In this work, we describe the synthesis and characterization of two different polymer conjugates of cytarabine that were designed for the controlled release of cytarabine within the leukemia cells. Reactive copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) and 3-(3-methacrylamidopropa-noyl)thiazolidine-2-thione) or 3-(Nmethacryloylglycyl-phenylalanylleucylglycyl)thiazolidine-2-thione were used in the study as reactive polymer precursors for reaction with cytarabine. The enzymatic release of cytarabine from the conjugate containing a GFLG spacer utilizing cathepsin B was verified. In addition to enzymolysis, the pH-dependent hydrolysis of cytarabine from both copolymers was also confirmed. Approximately 40 % and 20 % of the drug was released by spontaneous hydrolysis at pH 7.4 within 72 h from the polymer conjugates with the GFLG and beta-Ala spacers, respectively. At pH 6.0, the spontaneous hydrolysis slowed down, and less than 10 % of the drug was liberated within 72 h. The results of the cytotoxicity evaluation of the polymer conjugates in vitro against various cell lines showed that the cytotoxicity of the polymer conjugates is approximately three times lower in comparison to free cytarabine.
- MeSH
- antimetabolity antitumorózní farmakokinetika MeSH
- cytarabin farmakokinetika MeSH
- lidé MeSH
- methakryláty chemie MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemická syntéza MeSH
- polymery chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antimetabolity antitumorózní MeSH
- cytarabin MeSH
- hydroxypropyl methacrylate MeSH Prohlížeč
- methakryláty MeSH
- nosiče léků MeSH
- polymery MeSH
This study describes a one-pot synthesis of superparamagnetic maghemite-based 4-aminobenzoic acid-coated spherical core-shell nanoparticles (PABA@FeNPs) as suitable nanocomposites potentially usable as magnetic carriers for drug delivery. The PABA@FeNPs system was subsequently functionalized by the activated species (1* and 2*) of highly in vitro cytotoxic cis-[PtCl2(3Claza)2] (1; 3Claza stands for 3-chloro-7-azaindole) or cis-[PtCl2(5Braza)2] (2; 5Braza stands for 5-bromo-7-azaindole), which were prepared by a silver(I) ion assisted dechlorination of the parent dichlorido complexes. The products 1*@PABA@FeNPs and 2*@PABA@FeNPs, as well as an intermediate PABA@FeNPs, were characterized by a combination of various techniques, such as Mössbauer, FTIR and EDS spectroscopy, thermal analysis, SEM and TEM. The results showed that the products consist of well-dispersed maghemite-based nanoparticles of 13 nm average size that represent an easily obtainable system for delivery of highly cytotoxic cisplatin-like complexes in oncological practice.
- MeSH
- antitumorózní látky chemie MeSH
- cisplatina aplikace a dávkování chemie MeSH
- indoly chemická syntéza chemie MeSH
- kyselina 4-aminobenzoová aplikace a dávkování chemická syntéza chemie MeSH
- lidé MeSH
- nádory farmakoterapie MeSH
- nanočástice chemie MeSH
- nosiče léků chemická syntéza chemie MeSH
- stříbro chemie MeSH
- systémy cílené aplikace léků * MeSH
- železité sloučeniny chemická syntéza chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 7-azaindole dimer MeSH Prohlížeč
- antitumorózní látky MeSH
- cisplatina MeSH
- ferric oxide MeSH Prohlížeč
- indoly MeSH
- kyselina 4-aminobenzoová MeSH
- nosiče léků MeSH
- stříbro MeSH
- železité sloučeniny MeSH
The synthesis, characterization and results of evaluation of the biological behavior of HPMA copolymer conjugates bearing anti-cancer drugs doxorubicin and mitomycin C are described. Two HPMA copolymer carrier types were synthesized: the linear copolymer and the biodegradable high-molecular-weight diblock copolymer containing a degradable disulfide bond. The polymer-drug conjugates incubated in buffers modeling the intracellular environment released the drugs more rapidly than those incubated in bloodstream conditions. Significant in vitro and in vivo antitumor synergistic activity of the conjugates in the treatment of EL-4 T-cell demonstrates their high potential for solid tumor treatment.
- Klíčová slova
- HPMA copolymers, Mitomycin C, combination therapy, doxorubicin, tumor treatment,
- MeSH
- akrylamidy chemie MeSH
- analýza přežití MeSH
- antitumorózní látky chemie farmakologie MeSH
- B-buněčný lymfom farmakoterapie mortalita patologie MeSH
- cytotoxiny chemie farmakologie MeSH
- disulfidy MeSH
- doxorubicin chemie farmakologie MeSH
- karcinom plic Lewisové farmakoterapie mortalita patologie MeSH
- karcinom farmakoterapie mortalita patologie MeSH
- kinetika MeSH
- kombinovaná farmakoterapie MeSH
- kyseliny levulové chemie MeSH
- lymfom T-buněčný farmakoterapie mortalita patologie MeSH
- mitomycin chemie farmakologie MeSH
- mléčné žlázy zvířat účinky léků patologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemická syntéza MeSH
- transplantace nádorů MeSH
- tumor burden účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- akrylamidy MeSH
- antitumorózní látky MeSH
- cytotoxiny MeSH
- disulfidy MeSH
- doxorubicin MeSH
- kyseliny levulové MeSH
- levulinic acid MeSH Prohlížeč
- mitomycin MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nosiče léků MeSH
Polymer conjugates of anticancer drugs have shown high potential for assisting in cancer treatments. The pH-labile spacers allow site-specific triggered release of the drugs. We synthesized and characterized model drug conjugates with hydrazide bond-containing poly[N-(2-hydroxypropyl)methacrylamide] differing in the chemical surrounding of the hydrazone bond-containing spacer to find structure-drug release rate relationships. The conjugate selected for further studies shows negligible drug release in a pH 7.4 buffer but released 50% of the ellipticinium drug within 24h in a pH 5.0 phosphate saline buffer. The ellipticinium drug retained the antiproliferative activity of the ellipticine.
- Klíčová slova
- Controlled release, Drug delivery, Ellipticine, Hydrazone, PolyHPMA,
- MeSH
- akrylamidy chemie MeSH
- antitumorózní látky chemie metabolismus toxicita MeSH
- buněčné linie MeSH
- DNA chemie metabolismus MeSH
- elipticiny chemie MeSH
- hydrazony chemie MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- nosiče léků chemická syntéza chemie MeSH
- proliferace buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- akrylamidy MeSH
- antitumorózní látky MeSH
- DNA MeSH
- elipticiny MeSH
- hydrazony MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nosiče léků MeSH
Acridines are potent DNA-intercalating anticancer agents with high in vivo anticancer effectiveness, but also severe side effects. We synthesized five 9-anilinoacridine-type drugs and their conjugates with biocompatible water-soluble hydrazide polymer carrier. All of the synthesized acridine drugs retained their in vitro antiproliferative properties. Their polymer conjugates were sufficiently stable at pH 7.4 (model of pH in blood plasma) while releasing free drugs at pH 5.0 (model of pH in endosomes). After internalization of the conjugates, the free drugs were released and are visible in cell nuclei by fluorescence microscopy. Their intercalation ability was proven using a competitive ethidium bromide displacement assay.
- MeSH
- amsakrin analogy a deriváty chemie MeSH
- antitumorózní látky chemická syntéza chemie toxicita MeSH
- buněčné jádro metabolismus MeSH
- buňky Hep G2 MeSH
- DNA metabolismus MeSH
- fluorescenční mikroskopie MeSH
- interkalátory chemická syntéza chemie toxicita MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemická syntéza chemie MeSH
- polymery chemická syntéza chemie MeSH
- viabilita buněk účinky léků MeSH
- voda chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 9-anilinoacridine MeSH Prohlížeč
- amsakrin MeSH
- antitumorózní látky MeSH
- calf thymus DNA MeSH Prohlížeč
- DNA MeSH
- interkalátory MeSH
- nosiče léků MeSH
- polymery MeSH
- voda MeSH
We have designed, synthesized, and characterized peptides containing four repeats of the sequences VAALEKE (peptide E) or VAALKEK (peptide K). While the peptides alone adopt in aqueous solutions a random coil conformation, their equimolar mixture forms heterodimeric coiled coils as confirmed by CD spectroscopy. 5-Azidopentanoic acid was connected to the N-terminus of peptide E via a short poly(ethylene glycol) spacer. The terminal azide group enabled conjugation of the peptide with a synthetic drug carrier based on the N-(2-hydroxypropyl)methacrylamide copolymer containing propargyl groups using "click" chemistry. When incorporated into the polymer drug carrier, peptide E formed a stable noncovalent complex with peptide K belonging to a recombinant single-chain fragment (scFv) of the M75 antibody. The complex thereby mediates a noncovalent linkage between the polymer drug carrier and the protein. The recombinant scFv antibody fragment was selected as a targeting ligand against carbonic anhydrase IX-a marker overexpressed by tumor cells of various human carcinomas. The antigen binding affinity of the polymer-scFv complex was confirmed by ELISA. This approach offers a well-defined, specific, and nondestructive universal method for the preparation of protein (antibody)-targeted polymer drug and gene carriers designed for cell-specific delivery.
- MeSH
- akrylamidy chemie MeSH
- antigeny nádorové imunologie metabolismus MeSH
- bakteriální transformace MeSH
- cirkulární dichroismus MeSH
- dimerizace MeSH
- ELISA MeSH
- Escherichia coli MeSH
- imunokonjugáty chemie imunologie farmakologie MeSH
- karboanhydrasa IX MeSH
- karboanhydrasy imunologie metabolismus MeSH
- karcinom farmakoterapie enzymologie imunologie patologie MeSH
- klonování DNA MeSH
- lidé MeSH
- molekulární konformace MeSH
- monoklonální protilátky chemie genetika imunologie MeSH
- nádorové biomarkery imunologie metabolismus MeSH
- nosiče léků chemická syntéza farmakologie MeSH
- oligopeptidy chemická syntéza imunologie farmakologie MeSH
- plazmidy MeSH
- polyethylenglykoly chemie MeSH
- rekombinantní proteiny chemie genetika imunologie MeSH
- syntetická chemie okamžité shody metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- akrylamidy MeSH
- antigeny nádorové MeSH
- CA9 protein, human MeSH Prohlížeč
- imunokonjugáty MeSH
- karboanhydrasa IX MeSH
- karboanhydrasy MeSH
- M75 monoclonal antibody MeSH Prohlížeč
- monoklonální protilátky MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nádorové biomarkery MeSH
- nosiče léků MeSH
- oligopeptidy MeSH
- polyethylenglykoly MeSH
- rekombinantní proteiny MeSH
