Starlike vs. classic macromolecular prodrugs: two different antibody-targeted HPMA copolymers of doxorubicin studied in vitro and in vivo as potential anticancer drugs.
OBJECTIVE
Two different monoclonal antibody-targeted HPMA copolymer-doxorubicin conjugates, classic and starlike, were synthesized to be used for site-specific cancer therapy. The anti-mouse Thy-1.2 (IgG3) and two anti-human CD71/A (IgG1) and CD71/B (IgG2a) monoclonal antibodies were used as targeting structures.


METHODS
Their binding and cytotoxic activity in vitro, body distribution, and anticancer activity in vivo were evaluated.


RESULTS
The results of flow cytometric analysis showed comparable binding of classic and starlike conjugates to the target cells. The in vitro cytotoxic effect was 10-fold higher if cancer cells were exposed to the starlike conjugate compared to the classic one. Biodistribution studies showed that the starlike conjugate remained in a relatively high concentration in blood, whereas the classic conjugate was found in a 6.5-times lower amount. In contrast to the low antitumor activity of free doxorubicin and nontargeted HPMA copolymer-doxorubicin conjugate, both anti-Thy-1.2 targeted conjugates (classic and starlike) cured all mice bearing T-cell lymphoma EL4. On the other hand, starlike conjugates containing anti-CD71/A or anti-CD71/B monoclonals as targeting structures were more effective against human colorectal cancer SW 620 than the classic one.


CONCLUSIONS
We have shown that the starlike conjugates are more effective systems for targeted drug delivery and cancer treatment than classic conjugates.
Jelínková
Markéta
M
Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídenská 1083, 142 20 Prague 4, Czech Republic.
Strohalm
Jirí
J
Etrych
Tomás
T
Ulbrich
Karel
K
Ríhová
Blanka
B
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D016399:Lymphoma, T-Cell / Q000188:drug therapy; D008689:Methacrylates / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D008689:Methacrylates; D011355:Prodrugs; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate