Novel polymer micelles, prepared by self-assembling thermoresponsive poly(N-isopropylacrylamide)-graft-poly[N-(2-hydroxypropyl)methacrylamide] copolymers with hydrolytically degradable N-glycosylamine groups between the polymer blocks are proposed for delivery of diagnostic and therapeutic radionuclides into solid tumors. The micelles are formed by fast heating of an aqueous solution of the copolymer to 37 degrees C. They have a hydrodynamic diameter of 128 nm (measured using dynamic light scattering) and slowly degrade during incubation in aqueous buffer at pH = 7.4. Labeling with both (131)I and (90)Y proceeds with high yields (>85%). The unlabeled polymers are not cytotoxic for any of the tested murine and human cell lines.

• MeSH
• akrylamidy chemie   metabolismus   MeSH
• akrylové pryskyřice MeSH
• biokompatibilní materiály chemie   metabolismus   MeSH
• hydrolýza MeSH
• lidé MeSH
• micely * MeSH
• molekulární struktura MeSH
• nosiče léků * chemická syntéza   chemie   metabolismus   MeSH
• polymery * chemická syntéza   chemie   metabolismus   MeSH
• radionuklidy chemie   metabolismus   MeSH
• systémy cílené aplikace léků MeSH
• teplota * MeSH
• testování materiálů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• akrylové pryskyřice MeSH
• biokompatibilní materiály MeSH
• micely * MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků * MeSH
• poly-N-isopropylacrylamide MeSH Prohlížeč
• polymery * MeSH
• radionuklidy MeSH

In the present study, we describe the synthesis and physicochemical properties of a novel pH- and thermoresponsive micellar drug delivery system for an anticancer ellipticinium derivative based on the triblock copolymer poly(ethylene oxide)-block-[tert-butylacrylamide-co-6-(N-methacryloylamino)hexanoic acid hydrazide]-block-poly(ethylene oxide). The system was designed to meet the basic criteria required for drug carrier systems, namely, solubility in water (overcoming the insolubility of ellipticine), satisfactory drug loading, particle size suitable for an efficient enhanced permeability and retention effect and adequate stability in blood plasma (pH 7.4) followed by rapid drug release in tumors or tumor cell endosomes (pH<6.5). The copolymer in the form of a unimer can be eliminated by kidneys because the weight-average molecular weight of 21 kDa is sufficiently below the renal threshold. The half-life of drug release in a pH 5.0 buffer solution (pH of a late endosome) was ~45 h, but a negligible amount of the free ellipticine derivative was detected at pH 7.4 (pH of blood). Consequently, this supramolecular polymer conjugate is a good candidate for the delivery of ellipticine-based drugs and will therefore be subjected to more detailed studies.

• Klíčová slova
• Cancer treatment, block copolymers, ellipticine, experimental chemotherapy, micelles,
• MeSH
• antitumorózní látky aplikace a dávkování   krev   terapeutické užití   MeSH
• elipticiny aplikace a dávkování   krev   terapeutické užití   MeSH
• koncentrace vodíkových iontů MeSH
• micely * MeSH
• nádory farmakoterapie   MeSH
• poločas MeSH
• polymery chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• elipticiny MeSH
• ellipticine MeSH Prohlížeč
• micely * MeSH
• polymery MeSH

An effective chemotherapy for neoplastic diseases requires the use of drugs that can reach the site of action at a therapeutically efficacious concentration and maintain it at a constant level over a sufficient period of time with minimal side effects. Currently, conjugates of high-molecular-weight hydrophilic polymers or biocompatible nanoparticles with stimuli-releasable anticancer drugs are considered to be some of the most promising systems capable of fulfilling these criteria. In this work, conjugates of thermoresponsive diblock copolymers with the covalently bound cancerostatic drug pirarubicin (PIR) were synthesized as a reversible micelle-forming drug delivery system combining the benefits of the above-mentioned carriers. The diblock copolymer carriers were composed of hydrophilic poly[N-(2-hydroxypropyl)methacrylamide]-based block containing a small amount (∼ 5 mol %) of comonomer units with reactive hydrazide groups and a thermoresponsive poly[2-(2-methoxyethoxy)ethyl methacrylate] block. PIR was attached to the hydrophilic block of the copolymer through the pH-sensitive hydrazone bond designed to be stable in the bloodstream at pH 7.4 but to be degraded in an intratumoral/intracellular environment at pH 5-6. The temperature-induced conformation change of the thermoresponsive block (coil-globule transition), followed by self-assembly of the copolymer into a micellar structure, was controlled by the thermoresponsive block length and PIR content. The cytotoxicity and intracellular transport of the conjugates as well as the release of PIR from the conjugates inside the cells, followed by its accumulation in the cell nuclei, were evaluated in vitro using human colon adenocarcinoma (DLD-1) cell lines. It was demonstrated that the studied conjugates have a great potential to become efficacious in vivo pharmaceuticals.

• MeSH
• antitumorózní látky aplikace a dávkování   chemie   MeSH
• doxorubicin aplikace a dávkování   analogy a deriváty   chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• micely MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• nanočástice aplikace a dávkování   chemie   MeSH
• polymery aplikace a dávkování   chemie   MeSH
• systémy cílené aplikace léků * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• doxorubicin MeSH
• micely MeSH
• pirarubicin MeSH Prohlížeč
• polymery MeSH

We report kinetic studies of therapeutically highly potent polymer-drug conjugates consisting of amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based copolymers bearing the anticancer drug doxorubicin (Dox). Highly hydrophobic cholesterol moieties as well as the drug were attached to the polymer backbone by a pH-sensitive hydrazone bond. Moreover, the structure of the spacer between the polymer carrier and the cholesterol moiety differed in order to influence the release rate of the hydrophobic moiety, and thus the disintegration of the high-molecular-weight micellar nanoparticle structure. We performed time-dependent SAXS/SANS measurements after changing pH from a typical blood value (pH 7.2) to that of tumor cells (pH 5.0) to characterize the drug release and changes in particle size and shape. Nanoparticles composed of the conjugates containing Dox were generally larger than the drug-free ones. For most conjugates, nanoparticle growth or decay was observed in the time range of several hours. It was established that the growth/decay rate and the steady-state size of nanoparticles depend on the spacer structure. From analytical fitting, we conclude that the most probable structure of the nanoparticles was a core-shell or a core with attached Gaussian chains. We concluded that the spacer structure determined the fate of a cholesterol derivative after the pH jump. Fitting results for 5α-cholestan-3-onecholestan-3-one and cholesteryl-4-oxopentanoate (Lev-chol) implied that cholesterol moieties continuously escape from the core of the nanoparticle core and concentrate in the hydrophilic shell. In contrast, cholest-4-en-3-one spacer prevent cholesterol escaping. Dox moiety release was only observed after a change in pH. Such findings justify the model proposed in our previous paper. Lastly, the cholesteryl 4-(2-oxopropyl)benzoate (Opb-Chol) was a different case where after the release of hydrophobic Opb-Chol moieties, the core becomes more compact. The physicochemical mechanisms responsible for the scenarios of the different spacers are discussed.

• MeSH
• akrylamidy chemie   MeSH
• antitumorózní látky aplikace a dávkování   MeSH
• časové faktory MeSH
• cholesterol chemie   MeSH
• difrakce rentgenového záření MeSH
• doxorubicin aplikace a dávkování   MeSH
• hydrofobní a hydrofilní interakce MeSH
• hydrolýza MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• kyseliny polymethakrylové chemie   MeSH
• maloúhlový rozptyl MeSH
• micely * MeSH
• molekulární struktura MeSH
• neutronová difrakce MeSH
• povrchové vlastnosti MeSH
• systémy cílené aplikace léků * MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• antitumorózní látky MeSH
• cholesterol MeSH
• doxorubicin MeSH
• Duxon MeSH Prohlížeč
• kyseliny polymethakrylové MeSH
• methacrylamide MeSH Prohlížeč
• micely * MeSH

The study compared the physico-chemical and biological properties of a water-soluble star-like polymer nanomedicine with three micellar nanomedicines formed by self-assembly of amphiphilic copolymers differing in their hydrophobic part (statistical, block and thermosensitive block copolymers). All nanomedicines showed a pH-responsive release of the drug, independent on polymer structure. Significant penetration of all polymer nanomedicines into tumor cells in vitro was demonstrated, where the most pronounced effect was observed for statistical- or diblock copolymer-based micellar systems. Tumor accumulation in vivo was dependent on the stability of the nanomedicines in solution, being the highest for the star-like system, followed by the most stable micellar nanomedicines. The star-like polymer nanomedicine showed a superior therapeutic effect. Since the micellar systems exhibited slightly lower systemic toxicity, they may exhibit the same efficacy as the star-like soluble system when administered at equitoxic doses. In conclusion, treatment efficacy of studied nanomedicines was directly controlled by the drug pharmacokinetics, namely by their ability to circulate in the bloodstream for the time needed for effective accumulation in the tumor due to the enhanced permeability and retention (EPR) effect. Easy and scalable synthesis together with the direct reconstitution possibility for nanomedicine application made these nanomedicines excellent candidates for further clinical evaluation.

• Klíčová slova
• Anti-cancer therapy, Doxorubicin, Drug delivery, EPR effect, Polymer micelles, Star-like copolymers, pH-responsive release,
• MeSH
• doxorubicin * chemie   MeSH
• hydrodynamika MeSH
• micely * MeSH
• nanomedicína * MeSH
• nosiče léků MeSH
• polymery * MeSH
• voda MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• doxorubicin * MeSH
• micely * MeSH
• nosiče léků MeSH
• polymery * MeSH
• voda MeSH

Thermoresponsive polymer micelles are promising drug and radionuclide carriers with a strong passive targeting effect into solid tumors. We have synthesized ABA triblock copolymers poly[2-methyl-2-oxazoline-block-(2-isopropyl-2-oxazoline-co-2-butyl-2-oxazoline)-block-2-methyl-2-oxazoline]. These polymers are molecularly dissolved in aqueous millieu below the cloud point temperature (CPT) of the thermoresponsive central block and above CPT form polymer micelles at CMC 5-10 × 10(-5) g · mL(-1) with diameter ≈200 nm. The phenolic moiety introduced into the copolymer allowed radionuclide labeling with iodine-125 ongoing in good yield with sufficient in vitro stability under model conditions.

• MeSH
• hemolýza MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• micely * MeSH
• molekulová hmotnost MeSH
• oxazoly chemie   MeSH
• polymery chemie   MeSH
• radionuklidy aplikace a dávkování   MeSH
• teplota MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• micely * MeSH
• oxazoly MeSH
• poly(2-methyl-2-oxazoline-block-(2-isopropyl-2-oxazoline-co-2-butyl-2-oxazoline)-block-2-methyl-2-oxazoline) MeSH Prohlížeč
• polymery MeSH
• radionuklidy MeSH

To optimally exploit the potential of (tumor-) targeted nanomedicines, platform technologies are needed in which physicochemical and pharmaceutical properties can be tailored according to specific medical needs and applications. We here systematically customized the properties of core-crosslinked polymeric micelles (CCPM). The micelles were based on mPEG-b-pHPMAmLacn (i.e. methoxy poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate]), similar to the block copolymer composition employed in CriPec® docetaxel, which is currently in phase I clinical trials. The CCPM platform was tailored with regard to size (30 to 100nm), nanocarrier degradation (1month to 1year) and drug release kinetics (10 to 90% in 1week). This was achieved by modulating the molecular weight of the block copolymer, the type and density of the crosslinking agent, and the hydrolytic sensitivity of the drug linkage, respectively. The high flexibility of CCPM facilitates the development of nanomedicinal products for specific therapeutic applications.

• Klíčová slova
• Core-crosslinking, Drug release, Drug targeting, Nanomedicine, Polymeric micelles,
• MeSH
• akrylamidy chemie   MeSH
• docetaxel MeSH
• doxorubicin chemie   MeSH
• micely * MeSH
• molekulová hmotnost MeSH
• nosiče léků chemie   MeSH
• polymery chemie   MeSH
• reagencia zkříženě vázaná chemie   MeSH
• taxoidy chemie   MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• akrylamidy MeSH
• docetaxel MeSH
• doxorubicin MeSH
• micely * MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků MeSH
• polymery MeSH
• reagencia zkříženě vázaná MeSH
• taxoidy MeSH

Nanosized materials offer promising strategy for topical drug delivery due to their enhancing effect on drug percutaneous transport across the stratum corneum barrier. In this work, polymeric micelles made from hydrophobized hyaluronic acid (HA) were probed for skin delivery. Compared to non-polymeric micelle solutions containing similar drug amount, in vitro skin penetration analysis indicated 3 times larger deposition of drug in the epidermis and 6 times larger drug deposition in the dermis after 5h of topical treatment in Franz diffusion cells. The drug deposition was further increased with prolonged time of topical treatment. Laser confocal microscopy revealed the accumulation of both, the HA forming the vehicle and the payload, in the epidermis and dermis. Although fluorescent labeling of the HA would suggest co-transport of the HA and the drug, loading FRET pair dyes in the micellar core clearly demonstrated gradual micelle disruption with increasing skin depth. Transcellular penetration was the predominant pathway for the loaded drug. The HA polymeric micelles also demonstrated increased bioactivity of loaded compound in vitro and in vivo. In addition, the loaded micelles were found to be stable in cream formulations and thus they have great potential for topical applications for cosmetic and pharmaceutical purposes.

• Klíčová slova
• Hyaluronan, Polymeric micelle, Skin penetration,
• MeSH
• buněčné linie MeSH
• dospělí MeSH
• kožní absorpce * MeSH
• kyselina hyaluronová chemie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• micely * MeSH
• nosiče léků chemie   MeSH
• pleťový krém MeSH
• polymery MeSH
• prasata MeSH
• techniky in vitro MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyselina hyaluronová MeSH
• micely * MeSH
• nosiče léků MeSH
• polymery MeSH

Herein, the biodegradable micelle-forming amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer conjugates with the anticancer drug doxorubicin (Dox) designed for enhanced tumor accumulation were investigated, and the influence of their stability in the bloodstream on biodistribution, namely, tumor uptake, and in vivo antitumor efficacy were evaluated in detail. Dox was attached to the polymer carrier by a hydrazone bond enabling pH-controlled drug release. While the polymer-drug conjugates were stable in a buffer at pH 7.4 (mimicking bloodstream environment), Dox was released in a buffer under mild acidic conditions modeling the tumor microenvironment or cells. The amphiphilic polymer carriers differed in the structure of hydrophobic cholesterol derivative moieties bound to the HPMA copolymers via a hydrolyzable hydrazone bond, exhibiting different rates of micellar structure disintegration at various pH values. Considerable dependence of the studied polymer-drug conjugate biodistribution on the stability of the micellar structure was observed in neutral, bloodstream-mimicking, environment, showing that a faster rate of the micelle disintegration in pH 7.4 increased the conjugate blood clearance, decreased tumor accumulation, and significantly reduced the tumor:blood and tumor:muscle ratios. Similarly, the final therapeutic outcome was strongly affected by the stability of the micellar structure because the most stable micellar conjugate showed an almost similar therapeutic outcome as the water-soluble, nondegradable, high-molecular-weight starlike HPMA copolymer-Dox conjugate, which was highly efficient in the treatment of solid tumors in mice. Based on the results, we conclude that the bloodstream stability of micellar polymer-anticancer drug conjugates, in addition to their low side toxicity, is a crucial parameter for their efficient solid tumor accumulation and high in vivo antitumor activity.

• Klíčová slova
• HPMA copolymer, degradation, pH-controlled release, polymer micelles, solid tumor treatment,
• MeSH
• antitumorózní látky chemie   farmakokinetika   terapeutické užití   MeSH
• doxorubicin chemie   farmakokinetika   terapeutické užití   MeSH
• hydrofobní a hydrofilní interakce MeSH
• koncentrace vodíkových iontů MeSH
• lymfom krev   farmakoterapie   MeSH
• micely MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nosiče léků chemie   MeSH
• polymery chemie   MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• doxorubicin MeSH
• micely MeSH
• nosiče léků MeSH
• polymery MeSH

• MeSH
• micely * MeSH
• polymery aplikace a dávkování   MeSH
• radionuklidy aplikace a dávkování   MeSH
• systémy cílené aplikace léků * MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• micely * MeSH
• polymery MeSH
• radionuklidy MeSH