Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
25460144
DOI
10.1016/j.ejpb.2014.10.007
PII: S0939-6411(14)00306-3
Knihovny.cz E-zdroje
- Klíčová slova
- Acid-cleavable linkage, Chemical carcinogenesis, Controlled drug release, Dendrimer-derived polymer conjugate, EPR effect, HPMA polymer conjugate, Pirarubicin (THP),
- MeSH
- berberinové alkaloidy chemie farmakokinetika MeSH
- dendrimery chemie farmakokinetika MeSH
- doxorubicin analogy a deriváty chemie farmakokinetika farmakologie MeSH
- HeLa buňky MeSH
- lidé MeSH
- melanom experimentální MeSH
- methakryláty chemie farmakokinetika MeSH
- myši inbrední ICR MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie MeSH
- nosiče léků chemie farmakokinetika MeSH
- polymery chemie farmakokinetika MeSH
- protinádorové látky chemie farmakokinetika farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 2,3,10,11-tetrahydroxytetrahydroprotoberberine MeSH Prohlížeč
- berberinové alkaloidy MeSH
- dendrimery MeSH
- doxorubicin MeSH
- hydroxypropyl methacrylate MeSH Prohlížeč
- methakryláty MeSH
- nosiče léků MeSH
- PAMAM Starburst MeSH Prohlížeč
- pirarubicin MeSH Prohlížeč
- polymery MeSH
- protinádorové látky MeSH
Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (SP-THP). THP was conjugated to SP to form SP-THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h-72 h of SP-THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DSS-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopic/spontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon.
Citace poskytuje Crossref.org
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