Polymer cancerostatics Dotaz Zobrazit nápovědu
Cell-penetrating peptides (CPPs) are commonly used substances enhancing the cellular uptake of various cargoes that do not easily cross the cellular membrane. CPPs can be either covalently bound directly to the cargo or they can be attached to a transporting system such as a polymer carrier together with the cargo. In this work, several CPP-polymer conjugates based on copolymers of N-(2-hydroxypropyl)methacrylamide (pHPMA) with HIV-1 Tat peptide (TAT), a minimal sequence of penetratin (PEN), IRS-tag (RYIRS), and PTD4 peptide, and the two short hydrophobic peptides VPMLK and PFVYLI were prepared and characterized. Moreover, the biological efficacy of fluorescently labeled polymer carriers decorated with various CPPs was compared. The experiments revealed that the TAT-polymer conjugate and the PEN-polymer conjugate were internalized about 40 times and 15 times more efficiently than the control polymer, respectively. Incorporation of dodeca(ethylene glycol) spacer improved the cell penetration of both studied polymer-peptide conjugates compared to the corresponding spacer-free polymer conjugates, while the shorter tetra(ethylene glycol) spacer improved only the penetration of the TAT conjugate but it did not improve the penetration of the PEN conjugate. Finally, a significantly improved cytotoxic effect of the polymer conjugate containing anticancer drug pirarubicin and TAT attached via a dodeca(ethylene glycol) was observed when compared with the analogous polymer-pirarubicin conjugate without TAT.
- Klíčová slova
- HPMA copolymers, cancerostatics, cell-penetrating peptides, delivery systems, diagnostics, polymer carriers,
- Publikační typ
- časopisecké články MeSH
A tumor-targeting drug delivery system consists of a tumor recognition moiety and a directly linked cytotoxic agent or an agent attached to a water-soluble synthetic polymer carrier through a suitable linker. Conjugation of a drug with a polymer carrier can change its solubility, toxicity, biodistribution, blood clearance and therapeutic specificity. Increased therapeutic specificity of a polymer drug can be achieved by the attachment of a targeting moiety (e.g. a lectin, protein, antibody, or peptide) that specifically interacts with receptors on the target cells. A large number of tumor-specific peptides were described in recent years. After a short introduction, some important examples of peptide-targeted conjugates will be described and discussed.
- MeSH
- antitumorózní látky * MeSH
- cílená molekulární terapie MeSH
- lidé MeSH
- nádory farmakoterapie MeSH
- nosiče léků * MeSH
- peptidy * MeSH
- polymery * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antitumorózní látky * MeSH
- nosiče léků * MeSH
- peptidy * 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
A water-soluble polymer cancerostatic actively targeted against cancer cells expressing a disialoganglioside antigen GD2 was designed, synthesized and characterized. A polymer conjugate of an antitumor drug doxorubicin with a N-(2-hydroxypropyl)methacrylamide-based copolymer was specifically targeted against GD2 antigen-positive tumor cells using a recombinant single chain fragment (scFv) of an anti-GD2 monoclonal antibody. The targeting protein ligand was attached to the polymer-drug conjugate either via a covalent bond between the amino groups of the protein using a traditional nonspecific aminolytic reaction with a reactive polymer precursor or via a noncovalent but highly specific interaction between bungarotoxin covalently linked to the polymer and the recombinant scFv modified with a C-terminal bungarotoxin-binding peptide. The GD2 antigen binding activity and GD2-specific cytotoxicity of the targeted noncovalent polymer-scFv complex proved to be superior to the covalent polymer-scFv conjugate.
- MeSH
- antitumorózní látky aplikace a dávkování chemie farmakologie MeSH
- bungarotoxiny chemie MeSH
- buňky 3T3 MeSH
- doxorubicin aplikace a dávkování chemie farmakologie MeSH
- gangliosidy imunologie MeSH
- jednořetězcové protilátky chemie imunologie MeSH
- kyseliny polymethakrylové chemie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nanokonjugáty chemie MeSH
- proliferace buněk účinky léků MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- bungarotoxiny MeSH
- doxorubicin MeSH
- Duxon MeSH Prohlížeč
- ganglioside, GD2 MeSH Prohlížeč
- gangliosidy MeSH
- jednořetězcové protilátky MeSH
- kyseliny polymethakrylové MeSH
- nanokonjugáty MeSH
A BCL1 leukemia-cell-targeted polymer-drug conjugate with a narrow molecular weight distribution consisting of an N-(2-hydroxypropyl)methacrylamide copolymer carrier and the anticancer drug pirarubicin is prepared by controlled radical copolymerization followed by metal-free click chemistry. A targeting recombinant single chain antibody fragment (scFv) derived from a B1 monoclonal antibody is attached noncovalently to the polymer carrier via a coiled coil interaction between two complementary peptides. Two pairs of coiled coil forming peptides (abbreviated KEK/EKE and KSK/ESE) are used as linkers between the polymer-pirarubicin conjugate and the targeting protein. The targeted polymer conjugate with the coiled coil linker KSK/ESE exhibits 4× better cell binding activity and 2× higher cytotoxicity in vitro compared with the other conjugate. Treatment of mice with established BCL1 leukemia using the scFv-targeted polymer conjugate leads to a markedly prolonged survival time of the experimental animals compared with the treatment using the free drug and the nontargeted polymer-pirarubicin conjugate.
- Klíčová slova
- cancer therapy, coiled coil, drug targeting, hydrophilic polymer, scFv,
- MeSH
- akrylamidy chemie MeSH
- cílená molekulární terapie MeSH
- cyklin D1 antagonisté a inhibitory imunologie MeSH
- imunoglobuliny - fragmenty aplikace a dávkování imunologie MeSH
- imunokonjugáty aplikace a dávkování chemie MeSH
- leukemie imunologie patologie terapie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- monoklonální protilátky chemie imunologie MeSH
- myši MeSH
- nosiče léků aplikace a dávkování chemie MeSH
- peptidy chemie imunologie MeSH
- polymery aplikace a dávkování chemie MeSH
- syntetická chemie okamžité shody MeSH
- systémy cílené aplikace léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- akrylamidy MeSH
- cyklin D1 MeSH
- imunoglobuliny - fragmenty MeSH
- imunokonjugáty MeSH
- monoklonální protilátky MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nosiče léků MeSH
- peptidy MeSH
- polymery MeSH
Polymer nanomedicines with anti-tumor activity should exhibit sufficient stability during systemic circulation to the target tissue; however, they should release the active drug selectively in the tumor. Thus, choice of a tumor-specific stimuli-sensitive spacer between the drug and the carrier is critical. Here, a series of polymer conjugates of anti-cancer drugs doxorubicin and pirarubicin covalently bound to copolymers based on N-(2-hydroxypropyl)methacrylamide via various enzymatically cleavable oligopeptide spacers were prepared and characterized. The highest rate of the drug release from the polymer carriers in presence of the lysosomal protease cathepsin B was determined for the copolymers with Val-Cit-Aba spacer. Copolymers containing pirarubicin were more cytotoxic and showed higher internalization rate than the corresponding doxorubicin counterparts. The conjugates containing GFLG and Val-Cit-Aba spacers exhibited the highest anti-tumor efficacy in vivo against murine sarcoma S-180, the highest rate of the enzymatically catalyzed drug release, and the highest cytotoxicity in vitro.
- Klíčová slova
- Drug delivery, Enzymatic release, Polymer cancerostatics,
- MeSH
- antitumorózní látky * farmakologie terapeutické užití chemie MeSH
- doxorubicin farmakologie chemie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory * farmakoterapie MeSH
- nanomedicína MeSH
- nosiče léků chemie MeSH
- polymery chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky * MeSH
- doxorubicin MeSH
- nosiče léků MeSH
- pirarubicin MeSH Prohlížeč
- polymery MeSH
The tumor-specific targeting of cancerostatics using polymer drug carriers represents a potential strategy to achieve an effective treatment with reduced side toxicity. Synthetic water-soluble copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are carriers with tunable architecture and drug loading, tumor-specific accumulation of the drug, and its controlled release. We describe a combination treatment of murine EL4 T cell lymphoma with HPMA-based star conjugates (Mw 250,000gmol-1) of doxorubicin (Dox) or docetaxel (Dtx) designed for enhanced tumor accumulation and combination therapy. Although the combination of linear conjugates (Mw=28,000gmol-1) containing Dox or Dtx resulted in an additive effect in the treatment of the lymphoma, the opposite was observed in the combination of two star conjugates with Dox or Dtx, as the star Dtx conjugate decreased the treatment efficacy of the star Dox conjugate. The Dtx conjugate alone was virtually ineffective in the reduction of tumor growth or survival time extension; thus, a curative effect could be solely attributed to the Dox-containing conjugate. When Dtx was delivered to the tumor on the same polymer carrier as Dox, the efficacy of the Dox-induced treatment was reduced to a lesser extent. No reduction was found when Dtx was delivered by a linear polymer or applied as a free drug. The phenomenon was strictly related to the enhanced permeability and retention (EPR) effect, as it was not observed in BCL1 leukemia, a model without EPR. The diminished treatment outcome in the combination therapy with the two star conjugates was underlined by the significantly decreased accumulation of Dox in the tumor. The use of the drug-free polymer carrier instead of the Dtx-containing star conjugate did not reduce the treatment efficacy of the Dox conjugate. Thus, the physicochemical characteristics of the polymer carrier designed for tumor-specific drug delivery systems control the activity of the respective drug, leading to changes within the tumor microenvironment that can determine ultimate efficacy of the combination therapy.
- Klíčová slova
- Docetaxel, Doxorubicin, Drug delivery, EPR effect, HPMA, Tumor microenvironment,
- MeSH
- akrylamidy chemie MeSH
- antitumorózní látky aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- docetaxel MeSH
- doxorubicin aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- lidé MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie patologie MeSH
- nosiče léků chemie MeSH
- taxoidy aplikace a dávkování chemie farmakokinetika terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- akrylamidy MeSH
- antitumorózní látky MeSH
- docetaxel MeSH
- doxorubicin MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nosiče léků MeSH
- taxoidy MeSH
The derivative of protease inhibitor ritonavir (5-methyl-4-oxohexanoic acid ritonavir ester; RD) was recently recognized as a potent P-gp inhibitor and cancerostatic drug inhibiting the proteasome and STAT3 signaling. Therefore, we designed high-molecular-weight HPMA copolymer conjugates with a PAMAM dendrimer core bearing both doxorubicin (Dox) and RD (Star-RD + Dox) to increase the circulation half-life to maximize simultaneous delivery of Dox and RD into the tumor. Star-RD inhibited P-gp activity, potently sensitizing both low- and high-P-gp-expressing cancer cells to the cytostatic and proapoptotic activity of Dox in vitro. Star-RD + Dox possessed higher cytostatic and proapoptotic activities compared to Star-Dox and the equivalent mixture of Star-Dox and Star-RD in vitro. Star-RD + Dox efficiently inhibited STAT3 signaling and induced caspase-3 activation and DNA fragmentation in cancer cells in vivo. Importantly, Star-RD + Dox was found to have superior antitumor activity in terms of tumor growth inhibition and increased survival of mice bearing P-gp-expressing tumors.
- MeSH
- chemorezistence MeSH
- cytostatické látky * MeSH
- doxorubicin farmakologie MeSH
- inhibitory proteas farmakologie MeSH
- myši MeSH
- nádory * MeSH
- nanomedicína MeSH
- polymery MeSH
- ritonavir MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cytostatické látky * MeSH
- doxorubicin MeSH
- inhibitory proteas MeSH
- polymery MeSH
- ritonavir MeSH