To develop designed polymer-drug conjugates, where the rate of drug liberation and hepatoma cell targeting function could be rationally and widely controlled, we facilely synthesized a series of novel, galactose-functionalized polymer-acyclovir conjugates with different linkers and first reported the effect of the linker structure including the type of acyclovir-linked bond (an ester bond or an amide bond) and relative length of the linker between acyclovir and the polymer main chain on release rate and targeting ability of conjugates. In vitro release studies showed that the cumulative released acyclovir from these polymer-acyclovir conjugates was between 24 and 65% in pH 1.2 glycine solution after 7 days. The ester bond more easily underwent hydrolysis than the amide bond. The longer the relative linker length was, the faster the acyclovir was released. The cell recognition experiments visualized using confocal laser scanning microscopy exhibited that the resultant galactose-functionalized polymer-acyclovir conjugates had evident targeting to hepG2 cells, and targeting ability was also in connection with the relative length of linker. By choosing appropriate linker, cellular internalization of acyclovir could be well achieved. We consider these results to be helpful for the design of multifunctional polymeric prodrugs, in which the required release rate and targeting ability could be rationally controlled by predetermined molecular architecture. (c) 2007 Wiley Periodicals, Inc.