Peptide dendrimers as potentiators of conventional chemotherapy in the treatment of pancreatic cancer in a mouse model.

Chemotherapy is the recommended treatment for patients with advanced pancreatic ductal adenocarcinoma (PDAC). However, efficacy of traditional chemotherapy is not satisfactory due to the presence of a dense dysplastic tumor stroma which prevents drug accumulation in and deep penetration into tumors. To overcome these obstacles, we designed and synthesized peptide dendrimers as potentiators of conventional chemotherapy. The dendrimers markedly promoted free doxorubicin accumulation and penetration deeply into 3D multicellular PDAC tumor cultures upon co-incubation. Co-administration of the dendrimer and doxorubicin into PDAC tumor xenograft-bearing mice greatly increased the doxorubicin concentration in the tumor. In addition, the dendrimer also promoted free doxorubicin internalization into PDAC cells upon co-incubation in media mimicking tumor microenvironment. Finally, a significant enhancement in the anticancer efficacy of doxorubicin and gemcitabine when either of the drugs was individually co-administered with the dendrimer into PDAC tumor xenograft-bearing mice was observed. This was especially pronounced for the combination treatment with the dendrimer and gemcitabine, resulting in a tumor weight decrease to 12.9% compared to the treatment with gemcitabine alone. This can be attributed to the combination of the multi-functionalities of the dendrimer, i.e., promoting free drug accumulation and penetration deeply into tumors and internalization into cancer cells.