Abstract
In a previous study, we reported on the development of a synthetic polymer conjugate of pirarubicin (THP) that was formed via an acid-labile hydrazone bond between the polymer and the THP. However, the synthetic polymer itself was non-biodegradable, which could lead to unexpected adverse effects. Human serum albumin (HSA), which has a high biocompatibility and good biodegradability, is also a potent carrier for delivering antitumor drugs. The objective of this study was to develop pH-sensitive HSA conjugates of THP (HSA-THP), and investigate the release of THP and the cytotoxicity under acidic conditions in vitro for further clinical development. HSA-THP was synthesized by conjugating maleimide hydrazone derivatives of THP with poly-thiolated HSA using 2-iminothiolane, via a thiol-maleimide coupling reaction. We synthesized two types of HSA-THP that contained different amounts of THP (HSA-THP2 and HSA-THP4). Free THP was released from both of the HSA conjugates more rapidly at an acidic pH, and the rates of release for HSA-THP2 and HSA-THP4 were similar. Moreover, both HSA-THPs exhibited a higher cytotoxicity at acidic pH than at neutral pH, which is consistent with the effective liberation of free THP under acidic conditions. These findings suggest that these types of HSA-THPs are promising candidates for further development.
Highlights
Pirarubicin (40 -O-tetrahydropyranyldoxorubicin, THP), a semi-synthetic derivative of doxorubicin [1], shows much more rapid intracellular uptake, more effective antitumor activity, and lesser cardiac toxicity, compared to doxorubicin [2,3,4,5]
It is known that macromolecular drugs exhibit insufficient therapeutic effects due to the low release of the active form of the free drug from the macromolecular drug in the tumor tissues [9,10,11,12]
We examined the behavior of the Human serum albumin (HSA)-THPs at different pH values
Summary
Pirarubicin (40 -O-tetrahydropyranyldoxorubicin, THP), a semi-synthetic derivative of doxorubicin [1], shows much more rapid intracellular uptake, more effective antitumor activity, and lesser cardiac toxicity, compared to doxorubicin [2,3,4,5]. Free THP, as well as free doxorubicin, is indiscriminately distributed to both tumor and normal healthy tissues. It is known that macromolecular drugs exhibit insufficient therapeutic effects due to the low release of the active form of the free drug from the macromolecular drug in the tumor tissues [9,10,11,12]. To address this limitation, we recently developed PHPMA conjugates of THP via the formation of a hydrazone bond resulting in a more effective release of free. THP in the acidic milieu of tumor tissues [13,14,15,16].
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