Novel amphiphilic PEG-hydroxycamptothecin conjugates as glutathione-responsive prodrug nanocapsules for cancer chemotherapy

A series of novel hydroxycamptothecin (HCPT) conjugates (13a–14d), which contained a polyethylene glycol moiety and disulfide bond, were designed and synthesized in five to six steps, with overall yields of 20–39%. The anticancer activities and toxicities of these new conjugates were evaluated using an in vitro MTT assay in K562, HepG2, and HT-29 cell lines and HUVECs. The conjugates displayed enhanced antitumor activity and reduced toxicity in comparison with their parent molecule, HCPT. Among these conjugates, compound 13a exhibited 100-fold better selectivity to the tumor cells than to HUVECs. TEM and DLS experiments demonstrated that 13a formed nanosized micelles with a diameter of approximately 200 nm in aqueous solution and that the conjugate could undergo glutathione-responsive degradation to release HCPT at the tumor site. The improved potency and reduced toxicity of these conjugates may be caused by the enhanced permeation and retention (EPR) effect of nanoparticles.