-
Something wrong with this record ?
HPMA copolymer conjugates with reduced anti-CD20 antibody for cell-specific drug targeting. I. Synthesis and in vitro evaluation of binding efficacy and cytostatic activity
T. Etrych, J. Strohalm, L. Kovář, M. Kabešová, B. Říhová, K. Ulbrich
Language English Country Netherlands
Document type Evaluation Study, Research Support, Non-U.S. Gov't
NLK
ScienceDirect (archiv)
from 1993-01-01 to 2009-12-31
- MeSH
- Acrylamides chemistry MeSH
- Burkitt Lymphoma drug therapy metabolism MeSH
- Models, Chemical MeSH
- Cytostatic Agents metabolism MeSH
- Doxorubicin chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Drug Delivery Systems MeSH
- Humans MeSH
- Lymphoma, T-Cell drug therapy metabolism MeSH
- Methacrylates chemistry MeSH
- Molecular Weight MeSH
- Antibodies, Monoclonal immunology MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Drug Carriers chemical synthesis chemistry MeSH
- Polymers chemistry MeSH
- Drug Evaluation, Preclinical MeSH
- Antibiotics, Antineoplastic chemistry MeSH
- Solubility MeSH
- Water chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Evaluation Study MeSH
- Research Support, Non-U.S. Gov't MeSH
Synthesis, physicochemical and biological properties and preliminary anticancer activity of new star-shaped polymer-doxorubicin (DOX) conjugates targeted with anti-CD20 monoclonal antibody were investigated. Mild reduction of antibody (Ab) with dithiothreitol (DTT) resulted in introduction of thiol groups into Ab. Polymer precursors used for the synthesis of the conjugates were based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with a functional group at the polymer chain end. The copolymers were linked to the thiol groups of the reduced Ab via one-point attachment forming a star-shaped structure with central antibody surrounded by hydrophilic polymer chains. Neither reduction nor polymer modification of Ab influenced binding activity of the Ab to its specific cancer cell membrane antigen as it was confirmed in vitro by standard flow cytometry. The anticancer drug DOX was attached to the HPMA copolymer chain in an Ab-polymer system via a pH-labile hydrazone linkage or via an oligopeptide sequence degradable by lysosomal enzymes. Such Ab-polymer-DOX conjugates were fairly stable in aqueous solution at pH 7.4 and the drug was readily released in mildly acid environment at pH 5-5.5 by hydrolysis of hydrazone bond or more slowly by enzymolysis with lysosomal enzymes. The cytostatic activity of the anti-CD20 monoclonal Ab-targeted conjugates tested on several CD20-positive or negative human and mouse cancer cell lines confirmed considerable targeting capacity of the monoclonal Ab after its binding to the polymer carrier. New method of synthesis of star antibody-targeted polymer-drug conjugates with pH-controlled drug release described in this paper opens new perspectives for development of new therapeutics intended for cancer therapy.
- 000
- 03970naa 2200565 a 4500
- 001
- bmc11022205
- 003
- CZ-PrNML
- 005
- 20121129101036.0
- 008
- 110729s2009 ne e eng||
- 009
- AR
- 040 __
- $a ABA008 $b cze $c ABA008 $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a ne
- 100 1_
- $a Etrych, Tomáš $7 xx0068504
- 245 10
- $a HPMA copolymer conjugates with reduced anti-CD20 antibody for cell-specific drug targeting. I. Synthesis and in vitro evaluation of binding efficacy and cytostatic activity / $c T. Etrych, J. Strohalm, L. Kovář, M. Kabešová, B. Říhová, K. Ulbrich
- 314 __
- $a Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic. etrych@imc.cas.cz
- 520 9_
- $a Synthesis, physicochemical and biological properties and preliminary anticancer activity of new star-shaped polymer-doxorubicin (DOX) conjugates targeted with anti-CD20 monoclonal antibody were investigated. Mild reduction of antibody (Ab) with dithiothreitol (DTT) resulted in introduction of thiol groups into Ab. Polymer precursors used for the synthesis of the conjugates were based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with a functional group at the polymer chain end. The copolymers were linked to the thiol groups of the reduced Ab via one-point attachment forming a star-shaped structure with central antibody surrounded by hydrophilic polymer chains. Neither reduction nor polymer modification of Ab influenced binding activity of the Ab to its specific cancer cell membrane antigen as it was confirmed in vitro by standard flow cytometry. The anticancer drug DOX was attached to the HPMA copolymer chain in an Ab-polymer system via a pH-labile hydrazone linkage or via an oligopeptide sequence degradable by lysosomal enzymes. Such Ab-polymer-DOX conjugates were fairly stable in aqueous solution at pH 7.4 and the drug was readily released in mildly acid environment at pH 5-5.5 by hydrolysis of hydrazone bond or more slowly by enzymolysis with lysosomal enzymes. The cytostatic activity of the anti-CD20 monoclonal Ab-targeted conjugates tested on several CD20-positive or negative human and mouse cancer cell lines confirmed considerable targeting capacity of the monoclonal Ab after its binding to the polymer carrier. New method of synthesis of star antibody-targeted polymer-drug conjugates with pH-controlled drug release described in this paper opens new perspectives for development of new therapeutics intended for cancer therapy.
- 590 __
- $a bohemika - dle Pubmed
- 650 _2
- $a akrylamidy $x chemie $7 D000178
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a protinádorová antibiotika $x chemie $7 D000903
- 650 _2
- $a monoklonální protilátky $x imunologie $7 D000911
- 650 _2
- $a Burkittův lymfom $x farmakoterapie $x metabolismus $7 D002051
- 650 _2
- $a nádorové buněčné linie $7 D045744
- 650 _2
- $a cytostatické látky $x metabolismus $7 D054697
- 650 _2
- $a doxorubicin $x chemie $7 D004317
- 650 _2
- $a nosiče léků $x chemická syntéza $x chemie $7 D004337
- 650 _2
- $a lékové transportní systémy $7 D016503
- 650 _2
- $a preklinické hodnocení léčiv $7 D004353
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a koncentrace vodíkových iontů $7 D006863
- 650 _2
- $a lymfom T-buněčný $x farmakoterapie $x metabolismus $7 D016399
- 650 _2
- $a mužské pohlaví $7 D008297
- 650 _2
- $a methakryláty $x chemie $7 D008689
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a chemické modely $7 D008956
- 650 _2
- $a molekulová hmotnost $7 D008970
- 650 _2
- $a polymery $x chemie $7 D011108
- 650 _2
- $a rozpustnost $7 D012995
- 650 _2
- $a voda $x chemie $7 D014867
- 655 _2
- $a hodnotící studie $7 D023362
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Strohalm, Jiří $7 xx0109134
- 700 1_
- $a Kovář, Lubomír $7 xx0126758
- 700 1#
- $a Kabešová, Martina. $7 _AN067038
- 700 1_
- $a Říhová, Blanka, $d 1942- $7 jo20000073671
- 700 1_
- $a Ulbrich, Karel, $d 1947- $7 jo2004259877
- 773 0_
- $t Journal of Controlled Release $w MED00002621 $g Roč. 140, č. 1 (2009), s. 18-26
- 910 __
- $a ABA008 $b x $y 2
- 990 __
- $a 20110729094053 $b ABA008
- 991 __
- $a 20121129101104 $b ABA008
- 999 __
- $a ok $b bmc $g 867038 $s 732098
- BAS __
- $a 3
- BMC __
- $a 2009 $x MED00002621 $b 140 $c 1 $d 18-26 $m Journal of controlled release $n J Controlled Release
- LZP __
- $a 2011-4B09/jvme