Synthesis, physicochemical behavior, tumor accumulation and preliminary anticancer activity of a new biodegradable graft copolymer-doxorubicin (DOX) conjugates designed for passive tumor targeting were investigated. In the graft high-molecular-weight conjugates the multivalent N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer was grafted with a similar but semitelechelic HPMA copolymer; both types of polymer chains were bearing doxorubicin attached by hydrazone bonds enabling intracellular pH-controlled drug release. The polymer grafts were attached to the main chain through spacers, degradable enzymatically or reductively, facilitating, after the drug release, intracellular degradation of the graft polymer carrier to short fragments excretable from the organism by glomerular filtration. The graft polymer-DOX conjugate exhibited prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice indicating the important role of the EPR effect in the anticancer activity. The graft polymer-DOX conjugates showed a significantly higher antitumor activity in vivo than DOX.HCl or the linear polymer conjugate when tested in mice bearing 38C13 B-cell or EL4 T-cell lymphoma, with a significant number of long-term-surviving (LTS) mice with EL4 T-cell lymphoma treated with a single dose 15 mg DOX equiv./kg on day 10.

• MeSH
• akrylamidy aplikace a dávkování   chemická syntéza   farmakokinetika   farmakologie   MeSH
• biologický transport MeSH
• buněčné linie MeSH
• doxorubicin aplikace a dávkování   chemická syntéza   farmakokinetika   farmakologie   MeSH
• farmaceutická chemie MeSH
• hydrolýza MeSH
• injekce intravenózní MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem MeSH
• lymfom farmakoterapie   metabolismus   patologie   MeSH
• molekulová hmotnost MeSH
• myši inbrední C3H MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nosiče léků * MeSH
• protinádorová antibiotika aplikace a dávkování   chemická syntéza   farmakokinetika   farmakologie   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• doxorubicin MeSH
• léky s prodlouženým účinkem MeSH
• N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate MeSH Prohlížeč
• nosiče léků * MeSH
• protinádorová antibiotika MeSH

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
• 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
• protinádorová antibiotika aplikace a dávkování   chemie   MeSH
• rozpustnost MeSH
• stabilita léku MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biokompatibilní materiály MeSH
• dendrimery MeSH
• doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• nosiče léků MeSH
• PAMAM Starburst MeSH Prohlížeč
• protinádorová antibiotika 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
• dendrimery chemie   MeSH
• doxorubicin aplikace a dávkování   chemie   farmakokinetika   MeSH
• koncentrace vodíkových iontů MeSH
• lékové transportní systémy * MeSH
• léky s prodlouženým účinkem MeSH
• lymfom T-buněčný farmakoterapie   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nosiče léků chemie   MeSH
• protinádorová antibiotika aplikace a dávkování   chemie   farmakokinetika   MeSH
• rozpustnost 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
• Názvy látek
• akrylamidy MeSH
• dendrimery MeSH
• doxorubicin MeSH
• léky s prodlouženým účinkem MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků MeSH
• PAMAM Starburst MeSH Prohlížeč
• protinádorová antibiotika MeSH
• voda 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
• 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
• protinádorová antibiotika chemie   metabolismus   farmakokinetika   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biokompatibilní materiály MeSH
• dendrimery MeSH
• doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• PAMAM Starburst MeSH Prohlížeč
• protinádorová antibiotika MeSH