HPMA polymers Dotaz Zobrazit nápovědu
HPMA copolymers are one of the most promising drug carriers as their biophysical and biochemical properties, including their immunocompatibility, are very favorable. So far, there is no evidence that HPMA copolymers can interact with the immune system in a way that would lead either to suppression of some of its crucial functions or to inappropriate activation with possible serious side-effects and thus we can conclude that HPMA copolymers are convincingly proved to be "immunologically" safe. Moreover, it was shown both in mice and humans that HPMA copolymer-bound doxorubicin (DOX-HPMA) conjugates possess besides powerful anti-tumor effect also various immunomodulatory properties and exert significantly decreased side-toxicities, minimized bone marrow toxicity and cardiotoxicity being the most important ones. The possibility to induce potent and long-lasting tumor-specific immunity during the treatment with these compounds which is capable to provide protection against minimal residual disease is one of the most important and therapeutically valuable features of these conjugates.
- MeSH
- akrylamidy chemie imunologie terapeutické užití MeSH
- antitumorózní látky chemie terapeutické užití MeSH
- chemorezistence imunologie MeSH
- imunologické faktory chemie imunologie terapeutické užití MeSH
- lidé MeSH
- nádory farmakoterapie imunologie MeSH
- polymery chemie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
N-(2-Hydroxypropyl)methacrylamide (HPMA) co-polymers containing disulfide and carbonyl thiazolidine-2-thione (TT) reactive groups in their side-chains (pHPMA-TT) were used as reductively removable chemical modification of the surface of cowpea mosaic viruses (CPMV). CPMV was used in this study as a model particle for viral gene delivery. The co-polymer reaction with CPMV surfaces carried out in aqueous solution was evaluated by monitoring the changes in the weight-average molecular weight and hydrodynamic size of the viruses using light scattering methods. The reaction conditions were optimized. The surface modification of CPMV with pHPMA-TT under selected conditions (concentrations of a coating polymer (c(p)) and NaCl) has not influenced the size distribution of the viral particles. The uncharged polymers bound to the viral surface via biodegradable S-S bonds can be fully removed by the exchange reaction with reductive dithiothreitol. To achieve optimal covering of viral surfaces, the positively charged reactive polymers (with or without biodegradable S-S bonds) should be applied at low concentrations (c(p)=0.1-0.5 mg/ml) and in presence of NaCl (0.15 M).
- MeSH
- biokompatibilní materiály chemická syntéza chemie MeSH
- biomimetika MeSH
- Comovirus chemie MeSH
- disulfidy chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- intracelulární prostor metabolismus MeSH
- methakryláty chemie MeSH
- polymery chemická syntéza chemie MeSH
- povrchové vlastnosti MeSH
- thiazolidiny chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Synthesis and physico-chemical behavior of new polymer-drug conjugates intended for the treatment of cancer were investigated. In the polymer conjugate with the expected dual therapeutic activity, two drugs, a cytostatic agent doxorubicin (DOX) and anti-inflammatory drug dexamethason (DEX) were covalently attached to the same polymer backbone via hydrolytically labile pH-sensitive hydrazone bonds. The precursor, a copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) bearing hydrazide groups randomly distributed along the polymer chain, was conjugated with DOX (through its C13 keto group) or with a keto ester (DEX). Two derivatives of DEX, 4-oxopentanoate and 4-(2-oxopropyl)benzoate esters, were synthesized and employed for conjugation reaction. As a control, also a few polymer conjugates containing only a single drug (DOX or DEX) attached to the polymer carrier were synthesized. Physico-chemical properties of the polymer conjugates strongly depend on the attached drug, spacer structure and the drug content. Polymer-drug conjugates incubated in buffers modeling intracellular environment released the drug (DOX) or a drug derivatives (DEX) at the rate significantly exceeding the release rate observed under conditions mimicking situation in the blood stream. Incubation of the DEX conjugates in a buffer containing carboxyesterase resulted in complete ester hydrolysis thus demonstrating susceptibility of the system to release free active drug in the two-step release profile.
- MeSH
- antibiotika antitumorózní aplikace a dávkování chemie MeSH
- doxorubicin aplikace a dávkování chemie MeSH
- fixní kombinace léků MeSH
- karboxylesterasa chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- methakryláty chemická syntéza chemie MeSH
- polymery MeSH
- pomocné látky MeSH
- spektrofotometrie ultrafialová MeSH
- Publikační typ
- práce podpořená grantem 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.
New biodegradable star polymer-doxorubicin (Dox) conjugates designed for passive tumor targeting were investigated and the present study described their synthesis, physico-chemical characterization, drug release and biodegradation. In the conjugates the core formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin attached by hydrazone bonds, which enabled intracellular pH-controlled drug release, or by a GFLG sequence, which was susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic copolymer precursors facilitated preparation of biodegradable polymer conjugates in a broad range of molecular weights (110-295 kDa) while still maintaining low polydispersity (∼1.7). The polymer grafts were attached to the dendrimers either through stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high molecular weight polymer carrier to products that were able to be excreted from the body by glomerular filtration. Biodegradability tests showed that the rate of degradation was much faster for reductively degradable conjugates (completed within 4 h) than the degradation of conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (within 72 h). This finding was likely due to the difference in steric hindrance for the small molecule glutathione and the enzyme cathepsin B. As for drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin either under mild acidic conditions or in the presence of lysosomal enzyme cathepsin B, both of which modeled the tumor cell microenvironment.
- MeSH
- antibiotika antitumorózní aplikace a dávkování chemie MeSH
- biokompatibilní materiály chemická syntéza chemie MeSH
- dendrimery chemie MeSH
- doxorubicin aplikace a dávkování chemie MeSH
- methakryláty chemie MeSH
- molekulární struktura MeSH
- nosiče léků chemická syntéza chemie MeSH
- rozpustnost MeSH
- stabilita léku MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Synthetic strategies and chemical and structural aspects of the synthesis of HPMA copolymer conjugates with various drugs and other biologically active molecules are described and discussed in this chapter. The discussion is held from the viewpoint of design and structure of the polymer backbone and biodegradable spacer between a polymer and drug, structure and methods of attachment of the employed drugs to the carrier and structure and methods of conjugation with targeting moieties. Physicochemical properties of the water-soluble polymer-drug conjugates and polymer micelles including mechanisms of drug release are also discussed. Detailed description of biological behavior of the polymer-drug conjugates as well as application of the copolymers for surface modification and targeting of gene delivery vectors are not included, they are presented and discussed in separate chapters of this issue.
- MeSH
- akrylamidy aplikace a dávkování chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- nosiče léků aplikace a dávkování chemie MeSH
- polymery aplikace a dávkování chemie MeSH
- systémy cílené aplikace léků metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Herein, new biodegradable star polymer-doxorubicin conjugates designed for passive tumor targeting were investigated, and their synthesis, physico-chemical characterization, drug release, biodegradation, biodistribution and in vivo anti-tumor efficacy are described. In the conjugates, the core formed by poly(amidoamine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin (Dox) attached by hydrazone bonds, which enabled intracellular pH-controlled drug release. The described synthesis facilitated the preparation of biodegradable polymer conjugates in a broad range of molecular weights (200-1000g/mol) while still maintaining low polydispersity (~1.7). The polymer grafts were attached to the dendrimers through either stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high-molecular-weight polymer carrier to excretable products. Biodegradability tests in suspensions of EL4 T-cell lymphoma cells showed that the rate of degradation was much faster for reductively degradable conjugates (close to completion within 24h of incubation) than for conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (slow degradation taking several days). This finding was likely due to the differences in steric hindrance in terms of the accessibility of the small molecule glutathione and the bulky enzyme cathepsin B to the polymer substrate. Regarding drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin under mild acidic conditions that model the tumor cell microenvironment. The star polymer-Dox conjugates exhibited significantly prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice, indicating the important role of the EPR effect in its anti-cancer activity. The star polymer conjugates showed prominently higher in vivo anti-tumor activities than the free drug or linear polymer conjugate when tested in mice bearing EL4 T-cell lymphoma, with a significant number of long-term surviving (LTS). Based on the results, we conclude that a M(w) of HPMA copolymers of 200,000 to 600,000g/mol is optimal for polymer carriers designed for the efficient passive targeting to solid tumors. In addition, an expressive therapy-dependent stimulation of the immune system was observed.
- MeSH
- antibiotika antitumorózní chemie metabolismus farmakokinetika terapeutické užití MeSH
- biokompatibilní materiály chemie metabolismus MeSH
- dendrimery chemie metabolismus MeSH
- doxorubicin chemie metabolismus farmakokinetika terapeutické užití MeSH
- lidé MeSH
- lymfom farmakoterapie MeSH
- methakryláty chemie metabolismus MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Here, we present the synthesis, physicochemical, and preliminary biological characterization of micellar polymer-betulinic acid (BA) conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers, enabling the controlled release of cytotoxic BA derivatives in solid tumors or tumor cells. Various HPMA copolymer conjugates differing in the structure of the spacer between the drug and the carrier were synthesized, all designed for pH-triggered drug release in tumor tissue or tumor cells. The high molecular weight of the micellar conjugates should improve the uptake of the drug in solid tumors due to the Enhanced permeability and retention (EPR) effect. Nevertheless, only the conjugate containing BA with methylated carboxyl groups enabled pH-dependent controlled release in vitro. Moreover, drug release led to the disassembly of the micellar structure, which facilitated elimination of the water-soluble HPMA copolymer carrier from the body by renal filtration. The methylated BA derivative and its polymer conjugate exhibited high cytostatic activity against DLD-1, HT-29, and HeLa carcinoma cell lines and enhanced tumor accumulation in HT-29 xenograft in mice.
- MeSH
- biologicky odbouratelné plasty chemie MeSH
- doxorubicin aplikace a dávkování chemie MeSH
- lidé MeSH
- methakryláty aplikace a dávkování chemie MeSH
- micely MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie MeSH
- nosiče léků aplikace a dávkování chemie MeSH
- polymery aplikace a dávkování chemie MeSH
- proliferace buněk účinky léků MeSH
- triterpeny aplikace a dávkování chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Novel star polymer-doxorubicin conjugates designed for passive tumor targeting have been developed and their potential for treatment of cancer has been investigated. In the present study the synthesis, physico-chemical characterization, drug release, bio-distribution and preliminary data of in vivo efficacy of the conjugates are described. In the water-soluble conjugates the core of a molecule formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin (Dox) attached by hydrazone bonds enabling intracellular pH-controlled hydrolytic drug release, or by GFLG sequence susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic copolymer precursors facilitated preparation of polymer conjugates in a broad range of molecular weights (1.1-3.0·10(5) g/mol). In contrast to free drug or linear conjugates the star polymer-Dox conjugates exhibited prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice indicating important role of the EPR effect. The star polymer-Dox conjugates showed significantly higher anti-tumor activity in vivo than Dox?HCl or its linear or graft polymer conjugates, if treated with a single dose 15 or 5 mg Dox eq./kg. Method of tumor initialization (acute or chronic experimental tumor models) significantly influenced effectiveness of the treatment with much lower success in treatment of mice bearing chronic tumors.
- MeSH
- akrylamidy chemie MeSH
- antibiotika antitumorózní aplikace a dávkování chemie farmakokinetika MeSH
- dendrimery chemie MeSH
- doxorubicin aplikace a dávkování chemie farmakokinetika MeSH
- koncentrace vodíkových iontů MeSH
- léky s prodlouženým účinkem MeSH
- lymfom T-buněčný farmakoterapie patologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nosiče léků chemie MeSH
- rozpustnost MeSH
- systémy cílené aplikace léků MeSH
- tkáňová distribuce MeSH
- voda chemie 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
In this work, design and synthesis of high-molecular-weight N-(2-hydroxypropyl)methacrylamide-based polymer drug delivery systems tailored for cancer therapy is summarized. Moreover, the influence of their architecture on tumor accumulation and in vivo anti-cancer efficacy is discussed. Mainly, the high-molecular-weight delivery systems, such as branched, grafted, multi-block, star-like or micellar systems, with molecular weights greater than the renal threshold are discussed and reviewed in detail.
