Nejvíce citovaný článek - PubMed ID 12204597
Immunomodulating activities of soluble synthetic polymer-bound drugs
To avoid the side effects of the anti-cancer drug doxorubicin (Dox), we conjugated this drug to a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone. Dox was conjugated via an amide bond (Dox-HPMA(AM), PK1) or a hydrazone pH-sensitive bond (Dox-HPMA(HYD)). In contrast to Dox and Dox-HPMA(HYD), Dox-HPMA(AM) accumulates within the cell's intracellular membranes, including those of the Golgi complex and endoplasmic reticulum, both involved in protein glycosylation. Flow cytometry was used to determine lectin binding and cell death, immunoblot to characterize the presence of CD7, CD43, CD44, and CD45, and high-performance anion exchange chromatography with pulsed amperometric detector analysis for characterization of plasma membrane saccharide composition. Incubation of EL4 cells with Dox-HPMA(AM) conjugate, in contrast to Dox or Dox-HPMA(HYD), increased the amounts of membrane surface-associated glycoproteins, as well as saccharide moieties recognized by peanut agglutinin, Erythrina cristagalli, or galectin-1 lectins. Only Dox-HPMA(AM) increased expression of the highly glycosylated membrane glycoprotein CD43, while expression of others (CD7, CD44, and CD45) was unaffected. The binding sites for galectin-1 are present on CD43 molecule. Furthermore, we present that EL4 treated with Dox-HPMA(AM) possesses increased sensitivity to galectin-1-induced apoptosis. In this study, we demonstrate that Dox-HPMA(AM) treatment changes glycosylation of the EL4 T cell lymphoma surface and sensitizes the cells to galectin-1-induced apoptosis.
- MeSH
- amidy chemie MeSH
- antibiotika antitumorózní farmakologie MeSH
- antigeny CD43 metabolismus MeSH
- apoptóza MeSH
- doxorubicin analogy a deriváty farmakologie MeSH
- endoplazmatické retikulum metabolismus MeSH
- galektin 1 metabolismus MeSH
- glykosylace MeSH
- Golgiho aparát metabolismus MeSH
- kyseliny polymethakrylové farmakologie MeSH
- lymfom T-buněčný farmakoterapie metabolismus patologie MeSH
- myši MeSH
- nádorové buněčné linie účinky léků MeSH
- nosiče léků MeSH
- proliferace buněk MeSH
- průtoková cytometrie MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- amidy MeSH
- antibiotika antitumorózní MeSH
- antigeny CD43 MeSH
- doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate MeSH Prohlížeč
- doxorubicin MeSH
- galektin 1 MeSH
- kyseliny polymethakrylové MeSH
- nosiče léků MeSH
PURPOSE: In vivo efficacy and safety of HPMA-based copolymers armed with doxorubicin via a spacer containing pH-sensitive linkage that can be prepared within a broad range of attached drug contents (1) was tested in murine tumor models. METHODS: Mice bearing T cell lymphoma EL4 or B cell lymphoma 38C13 were treated with a single dose of the conjugate (15, 25, and 75 mg Dox eq./kg i.v.) in a therapeutic regime. Anti-tumor resistance of the cured animals was proved by a second challenge with a lethal dose of tumor cells without additional treatment. RESULTS: The content of drug bound to the polymer is an important parameter in relation to the conjugate therapeutic efficacy. The best anti-tumor effects were produced by conjugates with 10 - 13 wt% of bound doxorubicin. Free doxorubicin up to 4.6% relative to total drug content had no impact on the treatment efficacy and acute toxicity. The conjugates induced a complete cure of mice and regular treatment-dependent development of specific anti-tumor resistance. No myelosuppression or organ damage was observed. CONCLUSIONS: A well-defined HPMA copolymer-doxorubicin conjugate with pH-sensitive drug release is a good candidate for clinical trials as it has remarkable anti-tumor efficacy and a favorable safety profile.
- MeSH
- antibiotika antitumorózní farmakokinetika farmakologie MeSH
- doxorubicin analogy a deriváty chemická syntéza farmakokinetika farmakologie MeSH
- imunomodulace účinky léků MeSH
- koncentrace vodíkových iontů MeSH
- kyseliny polymethakrylové chemická syntéza farmakokinetika farmakologie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemická syntéza farmakokinetika farmakologie MeSH
- polymery * chemická syntéza farmakokinetika farmakologie MeSH
- proliferace buněk účinky léků MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antibiotika antitumorózní MeSH
- doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate MeSH Prohlížeč
- doxorubicin MeSH
- kyseliny polymethakrylové MeSH
- nosiče léků MeSH
- polymery * MeSH