Development of efficient acid cleavable multifunctional prodrugs derived from dendritic polyglycerol with a poly(ethylene glycol) shell.

In an attempt to explore the potential of dendritic systems for the development of effective anticancer drug delivery systems, we explored a simple modular approach of preparing polyglycerol doxorubicin prodrugs, with flexibility for drug loading using an acid-sensitive hydrazone linker and further post-modification with poly(ethylene glycol) shell. The resulting drug polymer conjugates showed optimal properties for in vitro and in vivo applications because of their high water solubility, an appropriate size for passive tumor targeting, a high stability at physiological conditions, pronounced acid-sensitive properties, cellular internalization, and a favorable toxicity profile. Doxorubicin polyglycerol conjugates with a high drug loading ratio showed clearly improved antitumor efficacy over doxorubicin in an ovarian xenograft tumor model (A2780) inducing transient complete remissions thus demonstrating the potential of developing efficient multifunctional dendritic drug delivery using our modular approach.