Construction of hyperbranched and pH-responsive polymeric nanocarriers by yne-phenol click-reaction for tumor synergistic chemotherapy.

In past decades, to improve the chemotherapeutic efficiency and reduce the systemic toxicity of small molecule anti-cancer drugs, polymer-based drug delivery systems (DDSs) have attracted great attention for tumor treatment due to their remarkable biocompatibility and responsive degradation in tumor microenvironment (TME). Herein, we developed a kind of pH-responsive and degradable hyperbranched polymeric nanocarriers via yne-phenol click-reaction of resveratrol (RSV) with bifunctional n-butyl dipropiolate (BDP) for efficient doxorubicin (DOX) delivery. The natural product RSV with three phenol groups has excellent antioxidant activity and synergetic enhancement for some anticancer drugs such as DOX. RSV tends to attack the alkynyl groups on BDP by nucleophilic addition in the presence of base as catalyst to afford hyperbranched polyprodrug (denoted as RB). PEGylated RB (termed as RBP) were further synthesized to improve the water solubility and prolong blood circulation by the click reaction of propiolate-terminated RB with amino terminated poly(ethylene glycol) (PEG-NH). Interestingly, the RBP have high DOX loading ratio (∼58.6 %) at neutral pH, but the vinyl-ether bonds in RB could break down at low pH conditions such as acidic TME (extracellular pH∼6.8, endosomes and lysosomes pH∼5.0) that leading to the targeting release of DOX and RSV. Therefore, the developed RBP@DOX nanoparticles exhibited high kill efficiency to tumor cells and slight damage to normal cells due to the effective delivery and release of DOX and RSV in tumor sites and the synergistic enhancement effect of two drugs.