Camptothecin analogs, as commonly used chemotherapy drugs, usually have poor water solubility which has limited their use in the clinic. In order to improve the water-solubility of camptothecin, a new dextran derivative Dex-Mal was synthesized and used in designing a dextran–camptothecin conjugate which contained a CTB-sensitive linker. This conjugate could efficiently release the therapeutic drug SN-38 in the presence of cathepsin B and the antiproliferative activity of the conjugate was similar to the approved drug Irinotecan hydrochloride. Furthermore, in the presence of dextran, the conjugate could self-assemble into nanoparticles in water, which could improve the targeting ability through the EPR effect. This provides a potential way to formulate a drug delivery system for camptothecin analogs or other drugs which have poor water solubility.