Tumor microenvironment (TME)-responsive drug delivery systems that deliver a drug in spatial-, temporal- and dosage-controlled patterns have become a promising way to realized tumor-specific treatment. We have designed and prepared a series of biodegradable dendritic polymers for multiple stimuli-responsive drug delivery. These nano-agents are shown that exhibit good biocompatibility and significant antitumor efficacy. Furthermore, these nano-platforms conjugated doxorubicin, gemcitabine, paclitaxel and oxaliplatin through pH-sensitive hydrazone bond, N, O-coordination and enzyme-sensitive GFLG linker to prepare a series of TME-responsive nanoscale drug delivery systems. Through the systemic delivery of dendronized PEG-platinum (II), 25-fold higher tumor platinum uptake at 36 h post-injection was seen observed due to the enhanced permeability and retention (EPR) effect, which are much higher than the reported TME-responsive drug delivery systems. Then we designed and prepared a series of TME-responsive branched HPMA nano-platforms via reversible addition-fragmentation chain transfer (RAFT) polymerization, Gd(III) chelating, drug conjugation and cRGDyK  functionalization for magnetic resonance imaging and targeted therapy. Finally, we explored systematically the relationship between the structure and their behaviors for drug delivery, and found that amphiphilic dendronized polymers with a moderate HLB value display enhanced stability and highly efficient tumor retention. These high-performance TME-responsive dendritic polymers based nano-platforms may be employed as a safe and efficient multiple stimuli-responsive drug delivery systems for cancer therapy.

Keywords: Tumor microenvironment; Drug delivery systems; Dendritic polymers; Nanomedicines