Due to the unique features of hyperbranched polymers (e.g., easy synthesis, presence of internal cavities, multiple end-groups, 3D structure), 145 hyperbranched polymer prodrugs based on Cpt have been developed by RDRP via the "grafting through" approach. Boltorn™ H40 (H40), a fourth generation hyperbranched polyester with hydroxyl terminal groups, was transformed into a H40-star-macro-RAFT agent followed by sequential polymerization of Cptbearing methacrylate (MA-ester-Cpt) and MPC leading to H40-star-P(MA-ester-Cpt)-b-PMPC multi-polymer prodrug-arm hyperbranched nanocarriers of 159 nm in diameter (Figure ). An Using hydrophobic drugs to confer amphiphilicity to a diblock copolymer is a convenient strategy to form polymer prodrug nanoparticles, as previously illustrated with P(MAA-co-DMAEMA)-b-P(SMA-ester-Dt) copolymers. This approach has also been applied to the hydrophobic drug podophyllotoxin (POD), an antimitotic cyclolignan with antitumor activity, but clinically limited due to its poor solubility and severe side effects. superior cytotoxicity on HeLa cells (5-fold higher compared to free POD) and higher cellular uptake efficacy.