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.