Amphiphilic block copolymers consisting of hydrophilic poly(ethylene glycol) and hydrophobic polyester bearing pendent cyclic ketals were synthesized by ring-opening copolymerization of ε-caprolactone (CL) and 1,4,8-trioxaspiro-[4,6]-9-undecanone (TSU) using α-hydroxyl, ω-methoxy, polyethylene glycol as the initiator and stannous octoate as the catalyst. Compositional analyses indicate that TSU was randomly distributed in the hydrophobic blocks. When the TSU content in the copolymers increased, the polymer crystallinity decreased progressively and the glass transition temperature increased accordingly. Hydrophobic, anticancer drug, camptothecin (CPT), was successfully encapsulated in the block copolymer nanoparticles. The CPT encapsulation efficiency and release kinetics were strongly dependent on the copolymer composition and crystallinity. CPT release from nanoparticles constructed from copolymers containing 0, 39 and 100 mol% TSU in the hydrophobic block followed the same trend, with an initial burst of ~40% within one day followed by a moderate and slow release lasting up to 7 days. At a TSU content of 14 mol%, CPT was released in a continuous and controlled fashion with a reduced initial burst and a 73% cumulative release by day 7. In vitro cytoxicity assay showed that the blank nanoparticles were not toxic to the cultured bone metastatic prostate cancer cells (C4-2B). Compared to the free drug, the encapsulated CPT was more effective in inducing apoptotic responses in C4-2B cells. Modulating the physical characteristics of the amphiphilic copolymers via copolymerization offers a facile method for controlling the bioavailability of anticancer drugs ultimately increasing effectiveness and minimizing toxicity.