Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25460144
DOI
10.1016/j.ejpb.2014.10.007
PII: S0939-6411(14)00306-3
Knihovny.cz E-resources
- Keywords
- Acid-cleavable linkage, Chemical carcinogenesis, Controlled drug release, Dendrimer-derived polymer conjugate, EPR effect, HPMA polymer conjugate, Pirarubicin (THP),
- MeSH
- Berberine Alkaloids chemistry pharmacokinetics MeSH
- Dendrimers chemistry pharmacokinetics MeSH
- Doxorubicin analogs & derivatives chemistry pharmacokinetics pharmacology MeSH
- HeLa Cells MeSH
- Humans MeSH
- Melanoma, Experimental MeSH
- Methacrylates chemistry pharmacokinetics MeSH
- Mice, Inbred ICR MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Neoplasms drug therapy MeSH
- Drug Carriers chemistry pharmacokinetics MeSH
- Polymers chemistry pharmacokinetics MeSH
- Antineoplastic Agents chemistry pharmacokinetics pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2,3,10,11-tetrahydroxytetrahydroprotoberberine MeSH Browser
- Berberine Alkaloids MeSH
- Dendrimers MeSH
- Doxorubicin MeSH
- hydroxypropyl methacrylate MeSH Browser
- Methacrylates MeSH
- Drug Carriers MeSH
- PAMAM Starburst MeSH Browser
- pirarubicin MeSH Browser
- Polymers MeSH
- Antineoplastic Agents 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.
References provided by Crossref.org
Structure-to-Efficacy Relationship of HPMA-Based Nanomedicines: The Tumor Spheroid Penetration Study
