Glucose-regulated protein of 78 kDa (GRP78) has become an attractive and novel target for tumor therapy. Design and construction of powerful delivery systems that could efficiently transport doxorubicin (DOX) to a tumor-cell nucleus remains a formidable challenge for improving the tumor therapeutic index and mitigating side effects to normal tissues. Herein, a novel doxorubicin prodrug (NDP) with GRP78 recognition and nucleus-targeting ability was synthesized by a facile chemical route. NDP exhibited an enhanced antiproliferative activity against colorectal cancer cells and could efficiently enter the cell nucleus. Furthermore, it is inspiring to note that NDP displayed a much stronger inhibitory efficacy against the growth of colorectal cancer xenografts in nude mice than free DOX and showed superior in vivo safety. Together, the work provides a novel GRP78 and nucleus-targeting strategy, and the NDP holds great promise to be used as a potent and safe chemotherapeutic agent.
Keywords: GRP78; antitumor efficacy; bifunctional peptide; novel doxorubicin prodrug; nucleus targeting.