Construction polyprodrugs by click-reactions and metal-coordination: pH-responsive release for magnetic resonance imaging guided chemotherapy

Abstract

It is a long-pursued goal to construct various smart theranostics nanoplatforms by facile and repeatable method for personalized tumor treatment. Herein, we employed novel alkyne-phenol and alkyne-amine click-reaction to fabricate responsively biodegradable and multimodal polymeric nanoplatforms for magnetic resonance imaging (MRI) guided effective chemotherapy. The antitumor drug doxorubicin (DOX) and some essential amino acid such as lysine could react with trimethylolpropane tripropiolate (TMP) in a quite mild conditions (room temperature and weak alkaline) by facile click-reactions to give polyprodrugs, the carboxyl and excess amino groups on LTD tended to further coordinate with Mn2+ to afforded metal-coordinated-polyprodrugs (termed as LTD@Mn2+). The resulting LTD@Mn2+ nanoparticles have high covalently drug loading ratio (up to 35%), and could effectively and responsively release DOX and Mn2+ in the acidic environment of tumor cells (extracellular pH ~6.8, endosomes and lysosomes pH ~5.0), because the resulting vinyl-ether and vinyl-amino bonds in LTD@Mn2+ are stable in neutral physiological environment but tend to be broken in acidic conditions. The smart LTD@Mn2+ nanoplatforms not only showed significant tumor inhibit efficiency and negligible damage to normal tissues both in vitro and in vivo due to the high drug loading ratio and controlled release properties, but also provided satisfied MRI quality for assessment the treatment effect because of the magnetic nature of Mn2+. Thus, the metal-ligated polyprodrug suggests a new strategy for the simple and repeatable preparation of polyprodrugs for precise and personalized treatment of tumors.