Dendritic polymers-based unimolecular micelles with enhanced stability are attractive carriers. However, the preparation of dendrimers or dendrons with higher generation remains substantially synthetic challenge due to the increased steric hindrance, multistep and tedious preparation, and low yields. The adoption of Boltorn H40, a commercially available dendritic polymer of Boltorn family containing multiple hydroxyl groups with various functionalities as a dendrimer-based starting core template for the generation of hyperbranched polymers, offers a straightforward solution to address this problem. To develop universal strategies toward H40-based amphiphilic block copolymers, the grafting from and grafting to approaches were both applied in this study. The reduction-insensitive block copolymers, H40-b-poly(-caprolactone)-b-poly(oligo(ethylene glycol) monomethyl ether methacrylate) (H40-b-PCL-b-POEGMA), were synthesized by grafting from including sequential ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The core structure and the polymer composition of the nonreducible amphiphilic hyperbranched block copolymers were optimized toward better properties and performance for drug delivery applications, and H40-PCL15-b-POEGMA(23) was screened as the best polymer construct relative to H20-PCL15-b-POEGMA(23) and H40-PCL15-b-POEGMA(32) in terms of micelle stability and drug loading capacity. Therefore, the reducible H40-b-PCL-SS-POEGMA with an identical core and polymer composition to that of H40-PCL15-b-POEGMA(23) was further prepared by grafting to using click coupling between H40-PCL-azide and P(OEGMA)-alkyne. The delivery efficacy evaluated by an in vitro cytotoxicity study revealed that the resulting DOX-loaded reducible micelles of H40-PCL15-SS-POEGMA(23) produced greater cytotoxicity in cancer cells than in normal cells and macrophages, therefore, are promising carriers for anticancer drug delivery. (c) 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1383-1394