Quantum dots (QDs) are potential probes for cell labeling and tracking. But the design of safe and tumor cell-sensitive probes together with high luminescent efficiency is still challenging. In this study, a novel class of biodegradable amphiphilic centipede-like copolymers was synthesized for QDs surface modification, which transformed hydrophobic QDs into hydrophilic ones. A systematic study was carried out to find how poly(ethyleneglycol) (PEG) chain density of the polymer coating influenced the properties of QDs nanocomposites, including particle size, optical properties and morphology. Results indicated that when the PEG grafting level was 40%, QDs nanocomposites showed the smallest size (105 nm), and simultaneously exhibited superior fluorescent properties among all the nanocomposites. These shell–core spherical structural nanoparticles were well dispersed in water, and did not form large aggregates. Apparently, a polymer with a PEG chain density of 40% was the optimum surface coating for QDs. These nanocomposites with outstanding capabilities can be further designed to target liver cancer cells with vascular endothelial growth factor receptor (VEGFR) overexpressed. We have evaluated QD-anti-vascular endothelial growth factor (VEGF) bioconjugates and QDs nanocomposites without anti-VEGF in live cell imaging experiments and results showed that the targeting capability to HepG2 cells of QD-anti-VEGF bioconjugates was more significant than that of non-anti-VEGF QDs. Our results provide a basis for the optimization of the polymer coating of QDs and are important for the design and development of nanoprobes for optical detection and bio-imaging of tumor cells.