There has been an increasing interest to develop new types of stimuli-responsive drug delivery vehicles with high drug loading and controlled release properties for chemotherapeutics. An acid-labile poly(ethylene oxide)-block-polyphosphoester-graft -PTX drug conjugate (PEO-b-PPE-g-PTX G2) degradable, polymeric paclitaxel (PTX) conjugate containing ultra-high levels of PTX loading is improved significantly, in this second-generation development, which involves connection of each PTX molecule to the polymer backbone via a pH-sensitive -thiopropionate linkage. The PEO-b-PPE-g-PTX G2 forms well-defi ned nanoparticles in an aqueous solution, by direct dissolution into water, with a number-averaged hydrodynamic diameter of 11431 nm, and exhibits a PTX loading capacity as high as 53 wt%, with a maximum PTX concentration of 0.68 mg mL−1 in water (vs 1.7 g mL−1 for free PTX). The PEO-b-PPE-g-PTX G2 shows accelerated drug release under acidic conditions (50 wt% PTX released in 8 d) compared with neutral conditions (20 wt% PTX released in 8 d). Compared to previously reported polyphosphoester-based PTX drug conjugates, PEO-b-PPE-g-PTX G1 without the -thiopropionate linker, the PEO-b-PPE-g-PTX G2 shows pH-triggered drug release property and 5- to 8-fold enhanced in vitro cytotoxicity against two cancer cell lines.