Design, Synthesis, and Bioevaluation of Novel Enzyme-Triggerable Cell Penetrating Peptide-Based Dendrimers for Targeted Delivery of Camptothecin and Cancer Therapy

Novel enzyme-triggerable cell penetrating peptide(ETCPP) dendrimers with a camptothecin (CPT) warhead weredesigned and synthesized based on an amphiphilic penetratingpeptide (FKKFFRKLL, discovered by us before). Among thenewly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT(a high-generation dendrimer) exhibited the highest activity withIC50s in the nanomolar range (31-747 nM) against a panel ofcancer cells, which is 3-10 times better than that of CPT. BL_Oc-SS-CPT remained intact during transit to target cells and in normaltissues with a plasma half-life of 4.2 h, 2.3-fold longer than that ofthe monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT gradually released CPT in the presence of excessive matrixmetalloproteinase-2/9 and GSH in cancer cells. Importantly,BL_Oc-SS-CPT exhibited excellent in vivo tumor targeting capability and antitumor efficacy with benign toxicity profiles. Thus, thenovel ETCPP dendrimer-based drug delivery system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy for targeted cancer therapy