The permeability and responsiveness of polymer membranes are absolutely relevant in the design of polymersomes for cargo delivery. Accordingly, we herein correlate the structural features, permeability, and responsiveness of doxorubicin-loaded (DOX-loaded) nonresponsive and stimuli-responsive polymersomes with their in vitro and in vivo antitumor performance. Polymer vesicles were produced using amphiphilic block copolymers containing a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) segment linked to poly[N-(4-isopropylphenylacetamide)ethyl methacrylate] (PPPhA, nonresponsive block), poly[4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)benzyl methacrylate] [PbAPE, reactive oxygen species (ROS)-responsive block], or poly[2-(diisopropylamino)ethyl methacrylate] (PDPA, pH-responsive block). The PDPA-based polymersomes demonstrated outstanding biological performance with antitumor activity notably enhanced compared to their counterparts. We attribute this behavior to a fast-triggered DOX release in acidic tumor environments as induced by pH-responsive polymersome disassembly at pH < 6.8. Possibly, an insufficient ROS concentration in the selected tumor model attenuates the rate of ROS-responsive vesicle degradation, whereas the nonresponsive nature of the PPPhA block remarkably impacts the performance of such potential nanomedicines.
- MeSH
- akrylamidy chemie farmakologie MeSH
- antibiotika antitumorózní farmakologie chemie MeSH
- antitumorózní látky farmakologie chemie MeSH
- doxorubicin * farmakologie chemie MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemie MeSH
- permeabilita buněčné membrány účinky léků MeSH
- polymery chemie farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- akrylamidy MeSH
- antibiotika antitumorózní MeSH
- antitumorózní látky MeSH
- doxorubicin * MeSH
- nosiče léků MeSH
- polymery MeSH
- reaktivní formy kyslíku MeSH
Reconfiguring the structure and selectivity of existing chemotherapeutics represents an opportunity for developing novel tumor-selective drugs. Here, as a proof-of-concept, the use of high-frequency sound waves is demonstrated to transform the nonselective anthracycline doxorubicin into a tumor selective drug molecule. The transformed drug self-aggregates in water to form ≈200 nm nanodrugs without requiring organic solvents, chemical agents, or surfactants. The nanodrugs preferentially interact with lipid rafts in the mitochondria of cancer cells. The mitochondrial localization of the nanodrugs plays a key role in inducing reactive oxygen species mediated selective death of breast cancer, colorectal carcinoma, ovarian carcinoma, and drug-resistant cell lines. Only marginal cytotoxicity (80-100% cell viability) toward fibroblasts and cardiomyocytes is observed, even after administration of high doses of the nanodrug (25-40 µg mL-1 ). Penetration, cytotoxicity, and selectivity of the nanodrugs in tumor-mimicking tissues are validated by using a 3D coculture of cancer and healthy cells and 3D cell-collagen constructs in a perfusion bioreactor. The nanodrugs exhibit tropism for lung and limited accumulation in the liver and spleen, as suggested by in vivo biodistribution studies. The results highlight the potential of this approach to transform the structure and bioactivity of anticancer drugs and antibiotics bearing sono-active moieties.
- Klíčová slova
- cancer therapy, mitochondria, nanodrugs, ultrasound,
- MeSH
- antibiotika antitumorózní chemie MeSH
- doxorubicin chemie farmakologie MeSH
- lidé MeSH
- nádory vaječníků * MeSH
- nanočástice * chemie MeSH
- tkáňová distribuce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibiotika antitumorózní MeSH
- doxorubicin MeSH
BACKGROUND: Ferritin is a globular intracellular protein that acts as the main reservoir for iron. Malignancies are associated with increased plasma ferritin concentrations. A number of studies show that tumor cells express high levels of transferrin receptors (TfR). Increased TfR expression was observed in prostate carcinoma. Apoferritin (APO) can be used as a protein nanotransporter into which a suitable medicinal substance can be encapsulated. Nanoparticles increase the permeability of tumor cells to nanotransporters and have a photothermal effect. The aim of this study was to encapsulate doxorubicin (DOX) into APO and to modify the resulting APO/DOX with gold (AuNPs) and silver nanoparticles prepared by green synthesis (AgNPsGS). METHODS: APO was characterized using 10% sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) - 120 V, 60 min, 24 mM Tris, 0.2 M glycine, 3 mM SDS. DOX fluorescence (Ex 480 nm; Em 650 nm) was observed, with a typical absorption maximum at 560 nm. Electrochemical measurement was performed in Brdicka solution (three-electrode setup). AgNPsGS were prepared by green synthesis using clover (Trifolium pratense L.). RESULTS: An electrophoretic study of APO and APO/DOX (5-100 μg/mL) was performed and the behavior of APO and APO/DOX (10 μM) as a function of pH was monitored. In an acidic environment, APO forms subunits of about 20 kDa; in an alkaline medium, it forms a globular protein of about 450 kDa. A change in APO/DOX mobility (about by 10%) was observed. A film of gold nanoparticles was applied to the APO/DOX surface. APO/DOX-AuNPs were washed with ultra-pure water. pH-dependent release of DOX a was monitored. The amount of DOX analyzed was increased by up to 50%. Furthermore, an AgNPsGS-DOX complex (1 mg AgNPsGS/100 μM DOX) was generated and prepared. Subsequently, the AgNPsGS-DOX complex was encapsulated into APO. To further improve therapeutic efficacy, the APO/AgNPsGS-DOX complex was coated with an Au layer. APO/AgNPsGS-DOX/AuNPs were stable and DOX was released from the complex after physical parameters had changed. CONCLUSION: APO nanocomplexes were prepared and modified to increase therapeutic efficacy against tumors. Tumor cell targeting was achieved by binding to TfR and via increased tumor cell permeability and retention. Release of the drug was made possible due to a pH change and photothermal activation that will now be tested. This work was supported by COST European Cholangiocarcinoma Network CA18122 and International Collaboration Project of The European Technology Platform for Nanomedicine. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 3. 2019 Accepted: 14. 5. 2019.
- Klíčová slova
- apoferritin nanotransporter, gold nanoparticles, malignant tumors, nanomedicine, prostate tumors, silver nanoparticles, targeted therapy, transferin receptors,
- MeSH
- antibiotika antitumorózní chemie farmakologie MeSH
- apoferritiny chemie MeSH
- doxorubicin analogy a deriváty chemie farmakologie MeSH
- koncentrace vodíkových iontů MeSH
- kovové nanočástice chemie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- receptory transferinu metabolismus MeSH
- stříbro chemie MeSH
- uvolňování léčiv MeSH
- zlato chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibiotika antitumorózní MeSH
- apoferritin doxorubicin MeSH Prohlížeč
- apoferritiny MeSH
- doxorubicin MeSH
- receptory transferinu MeSH
- stříbro MeSH
- zlato MeSH
Multiwall carbon nanotubes (MWCNTs) are among the frequently studied carbon materials, particularly because of their physical and chemical properties and high potential for application in materials chemistry, industry, and medicine. MWCNTs are very promising as transporters of bioactive molecules because of their π electrons and large surface area, which can be easily modified, mostly by the application of inorganic acids for the introduction of carboxylic moieties on the surface. In the present study, we designed an oxidised MWCNTs (oMWCNTs) transporter for the targeted delivery of doxorubicin (Dox). The modification of oMWCNTs with prostate-homing peptide (SMSIARL) promotes increased cytotoxicity for prostate cancer cells. Using advanced analytical techniques, we studied the loading efficiency, stability, and release kinetics of Dox from a oMWCNTs-Dox-Pep nanoconstruct. We show that pH strictly drives Dox release, and imitating the pH of intracellular acidic compartments, 60% of Dox is released from oMWCNTs-Dox-Pep, while in plasma conditions, only a 14% release of Dox was found during 24h. The nanoconstruct displayed no cytotoxicity in non-malignant prostate cells (PNT1A), while in metastatic prostate cancer cells (LNCaP), the cytotoxic effects were close to the cytotoxicity of free Dox. This indicates that peptide modification promotes interactions with malignant cells, resulting in efficient internalisation into the intracellular region. Overall, we show that oMWCNTs are exceptional platforms for simple and stable non-covalent modification with bioactive molecules.
- Klíčová slova
- Carbon nanomaterial, Drug delivery, Nanomedicine, Prostate-homing peptide,
- MeSH
- antibiotika antitumorózní chemie MeSH
- doxorubicin chemie MeSH
- kinetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nanotrubičky uhlíkové * MeSH
- prostata metabolismus MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibiotika antitumorózní MeSH
- doxorubicin MeSH
- nanotrubičky uhlíkové * MeSH
New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rh of approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.
- Klíčová slova
- EPR effect, HPMA copolymer, Micellar drug conjugate, Multidrug resistance, P-glycoprotein inhibitor, Poly(propylene oxide),
- MeSH
- akrylamidy aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- antibiotika antitumorózní aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- chemorezistence účinky léků MeSH
- doxorubicin aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- hydrofobní a hydrofilní interakce MeSH
- lidé MeSH
- micely * MeSH
- mnohočetná léková rezistence účinky léků MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie metabolismus patologie MeSH
- nosiče léků aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- polymery aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- propylenglykoly aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- tumor burden účinky léků MeSH
- uvolňování léčiv MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- akrylamidy MeSH
- antibiotika antitumorózní MeSH
- doxorubicin MeSH
- micely * MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nosiče léků MeSH
- polymery MeSH
- polypropylene glycol MeSH Prohlížeč
- propylenglykoly MeSH
Many conjugates of water-soluble polymers with biologically active molecules were developed during the last two decades. Although, therapeutic effects of these conjugates are affected by the properties of carriers, the properties of the attached drugs appear more important than the same carrier polymer in this case. Pirarubicin (THP), a tetrahydropyranyl derivative of doxorubicin (DOX), demonstrated more rapid cellular internalization and potent cytotoxicity than DOX. Here, we conjugated the THP or DOX to N-(2-hydroxypropyl)methacrylamide copolymer via a hydrazone bond. The polymeric prodrug conjugates, P-THP and P-DOX, respectively, had comparable hydrodynamic sizes and drug loading. Compared with P-DOX, P-THP showed approximately 10 times greater cellular uptake during a 240 min incubation and a cytotoxicity that was more than 10 times higher during a 72-h incubation. A marginal difference was seen in P-THP and P-DOX accumulation in the liver and kidney at 6 h after drug administration, but no significant difference occurred in the tumor drug concentration during 6-24 h after drug administration. Antitumor activity against xenograft human pancreatic tumor (SUIT2) in mice was greater for P-THP than for P-DOX. To sum up, the present study compared the biological behavior of two different drugs, each attached to an N-(2-hydroxypropyl)methacrylamide copolymer carrier, with regard to their uptake by tumor cells, body distribution, accumulation in tumors, cytotoxicity, and antitumor activity in vitro and in vivo. No differences in the tumor cell uptake of the polymer-drug conjugates, P-THP and P-DOX, were observed. In contrast, the intracellular uptake of free THP liberated from the P-THP was 25-30 times higher than that of DOX liberated from P-DOX. This finding indicates that proper selection of the carrier, and especially conjugated active pharmaceutical ingredient (API) are most critical for anticancer activity of the polymer-drug conjugates. THP, in this respect, was found to be a more preferable API for polymer conjugation than DOX. Hence the treatment based on enhanced permeability and retention (EPR) effect that targets more selectively to solid tumors can be best achieved with THP, although both polymer conjugates of DOX and THP exhibited the EPR effects and drug release profiles in acidic pH similarly.
- Klíčová slova
- EPR effect, HPMA polymer conjugate, acid-cleavable linkage, doxorubicin (DOX), pirarubicin (THP),
- MeSH
- akrylamidy chemie MeSH
- antibiotika antitumorózní chemie farmakologie MeSH
- antitumorózní látky chemie farmakologie MeSH
- doxorubicin analogy a deriváty chemie farmakologie MeSH
- experimentální sarkom farmakoterapie metabolismus patologie MeSH
- lidé MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- nosiče léků aplikace a dávkování chemie MeSH
- polymery aplikace a dávkování chemie MeSH
- proliferace buněk účinky léků MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- akrylamidy MeSH
- antibiotika antitumorózní MeSH
- antitumorózní látky MeSH
- doxorubicin MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nosiče léků MeSH
- pirarubicin MeSH Prohlížeč
- polymery MeSH
Water-soluble N-(2-hydroxypropyl)methacrylamide copolymer conjugates bearing the anticancer drugs doxorubicin (Dox) or pirarubicin (THP), P-gp inhibitors derived from reversin 121 (REV) or ritonavir (RIT)), or both anticancer drug and P-gp inhibitor were designed and synthesized. All biologically active molecules were attached to the polymer carrier via pH-sensitive spacer enabling controlled release in mild acidic environment modeling endosomes and lysosomes of tumor cells. The cytotoxicity of the conjugates against three sensitive and Dox-resistant neuroblastoma (NB) cell lines, applied alone or in combination, was studied in vitro. All conjugates containing THP displayed higher cytotoxicity against all three Dox-resistant NB cell lines compared with the corresponding Dox-containing conjugates. Furthermore, the cytotoxicity of conjugates containing both drug and P-gp inhibitor was up to 10 times higher than that of the conjugate containing only drug. In general, the polymer-drug conjugates showed higher cytotoxicity when conjugates containing inhibitors were added 8 or 16h prior to treatment compared with conjugates bearing both the inhibitor and the drug. The difference in cytotoxicity was more pronounced at the 16-h time point. Moreover, higher inhibitor:drug ratios resulted in higher cytotoxicity. The cytotoxicity of the polymer-drug used in combination with polymer P-gp inhibitor was up to 84 times higher than that of the polymer-drug alone.
- Klíčová slova
- Doxorubicin, Multidrug resistance, N-(2-hydroxypropyl)methacrylamide copolymers, Neuroblastoma, P-glycoprotein inhibitors, Pirarubicin, Reversin 121, Ritonavir,
- MeSH
- antibiotika antitumorózní aplikace a dávkování chemie farmakologie MeSH
- chemorezistence účinky léků MeSH
- doxorubicin aplikace a dávkování analogy a deriváty chemie farmakologie MeSH
- lidé MeSH
- methakryláty aplikace a dávkování chemie MeSH
- mnohočetná léková rezistence účinky léků MeSH
- nádorové buněčné linie MeSH
- neuroblastom genetika metabolismus MeSH
- oligopeptidy aplikace a dávkování chemie farmakologie MeSH
- P-glykoprotein antagonisté a inhibitory genetika metabolismus MeSH
- ritonavir aplikace a dávkování chemie farmakologie MeSH
- uvolňování léčiv MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibiotika antitumorózní MeSH
- doxorubicin MeSH
- hydroxypropyl methacrylate MeSH Prohlížeč
- methakryláty MeSH
- oligopeptidy MeSH
- P-glykoprotein MeSH
- pirarubicin MeSH Prohlížeč
- reversin 121 MeSH Prohlížeč
- ritonavir MeSH
Polymer drug carriers that are based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been widely used in the development and synthesis of high-molecular-weight (HMW) drug delivery systems for cancer therapy. In this study, we compared linear (Mw ~27kDa, Rh ~4nm) and non-degradable star (Mw ~250kDa, Rh ~13nm) HPMA copolymer conjugates bearing anthracycline antibiotic doxorubicin (DOX) bound via pH-sensitive hydrazone bond. We determined the in vitro and in vivo toxicity of both conjugates and their maximum tolerated dose (MTD). We also compared their anti-tumour activity in mouse B-cell leukaemia (BCL1) and a mouse T-cell lymphoma (EL4) model. We found that MTD was higher for the linear conjugate (85mgDOX/kg) and lower for the star conjugate (22.5mgDOX/kg). An evaluation of the intestinal barrier integrity using FITC-dextran as a gut permeability tracer proved that no pathology was caused by the MTD of either conjugate. However, free DOX showed some damage to the gut barrier. The therapy of BCL1 leukaemia by both of the polymeric conjugates using the MTD or its fraction (i.e., equitoxic dosage) showed better results in the case of the star conjugate. On the other hand, treatment of EL4 lymphoma seemed to be more efficient when the linear conjugate was used. We suppose that the anti-cancer treatment of solid tumours and leukaemias requires different types of drug conjugates. We hypothesise that the most suitable HPMA copolymer-DOX conjugate for the treatment of solid tumours should have an HMW structure with increased Rh that would be stable for three to four days after the conjugate administration and then rapidly disintegrate in the short polymer chains, which are excretable from the body by glomerular filtration. On the other hand, the treatment of leukaemia requires a drug conjugate with a long circulation half-life. This would provide an active drug, whilst slowly degrading to excretable fragments.
- Klíčová slova
- Anti-tumour activity, Doxorubicin, HPMA, Structure, Toxicity,
- MeSH
- akrylamidy chemie farmakokinetika terapeutické užití toxicita MeSH
- antibiotika antitumorózní * chemie farmakokinetika terapeutické užití toxicita MeSH
- dendrimery chemie farmakokinetika terapeutické užití toxicita MeSH
- doxorubicin chemie farmakokinetika terapeutické užití toxicita MeSH
- játra účinky léků patologie MeSH
- kostní dřeň účinky léků patologie MeSH
- maximální tolerovaná dávka MeSH
- molekulová hmotnost MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory krev farmakoterapie metabolismus MeSH
- nosiče léků * chemie farmakokinetika terapeutické užití toxicita MeSH
- slezina účinky léků patologie MeSH
- střevní sliznice metabolismus MeSH
- vztahy mezi strukturou a aktivitou 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
- antibiotika antitumorózní * MeSH
- dendrimery MeSH
- doxorubicin MeSH
- N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate MeSH Prohlížeč
- nosiče léků * MeSH
- PAMAM Starburst MeSH Prohlížeč
Increased oxidative stress is indisputably an important mechanism of doxorubicin side effects, especially its cardiotoxicity. To prevent impairment of non-tumorous tissue and to improve the specificity in targeting the tumor tissue, new drug nanotransporters are developed. In many cases preclinical therapeutic advantage has been shown when compared with the administration of conventional drug solution. Three forms of doxorubicin--conventional (DOX), encapsulated in liposomes (lipoDOX) and in apoferritin (apoDOX) were applied to Wistar rats. After 24 h exposition, the plasma level of 4-hydroxy-2-nonenal (4-HNE) as a marker of lipoperoxidation and tissue gene expression of thioredoxin reductase 2 (TXNRD2) and aldehyde dehydrogenase 3A1 (ALDH3A1) as an important part of antioxidative system were determined. Only conventional DOX significantly increases the level of 4-HNE; encapsulated forms on the other hand show significant decrease in plasma levels of 4-HNE in comparison with DOX. They also cause significant decrease in gene expression of ALDH3A1 and TXNRD2 in liver as a main detoxification organ, and a mild influence on the expression of these enzymes in left heart ventricle as a potential target of toxicity. Thus, 4-HNE seems to be a good potential biomarker of oxidative stress induced by various forms of doxorubicin.
- MeSH
- aldehyddehydrogenasa genetika metabolismus MeSH
- aldehydy krev MeSH
- antibiotika antitumorózní aplikace a dávkování chemie toxicita MeSH
- apoferritiny aplikace a dávkování chemie toxicita MeSH
- biologické markery krev MeSH
- chemie farmaceutická MeSH
- down regulace MeSH
- doxorubicin aplikace a dávkování analogy a deriváty chemie toxicita MeSH
- játra účinky léků enzymologie MeSH
- oxidační stres účinky léků MeSH
- peroxidace lipidů účinky léků MeSH
- polyethylenglykoly aplikace a dávkování chemie toxicita MeSH
- potkani Wistar MeSH
- regulace genové exprese enzymů MeSH
- thioredoxinreduktasa 2 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- 4-hydroxy-2-nonenal MeSH Prohlížeč
- aldehyddehydrogenasa MeSH
- aldehydy MeSH
- antibiotika antitumorózní MeSH
- apoferritin doxorubicin MeSH Prohlížeč
- apoferritiny MeSH
- biologické markery MeSH
- doxorubicin MeSH
- liposomal doxorubicin MeSH Prohlížeč
- polyethylenglykoly MeSH
- thioredoxinreduktasa 2 MeSH
- Txnrd2 protein, rat MeSH Prohlížeč
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
- antibiotika antitumorózní chemie farmakokinetika farmakologie 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
- tkáňová distribuce MeSH
- volné radikály chemie MeSH
- xenogenní modely - testy antitumorózní 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
- Názvy látek
- antibiotika antitumorózní MeSH
- doxorubicin MeSH
- hydroxypropyl methacrylate MeSH Prohlížeč
- léky s prodlouženým účinkem MeSH
- methakryláty MeSH
- nosiče léků MeSH
- polymery MeSH
- volné radikály MeSH