Key Laboratory of Functional Polymer Materials (Ministry of Education), College of Chemistry, Nankai University, Tianjin 300071, China.
Key Laboratory of Functional Polymer Materials (Ministry of Education), College of Chemistry, Nankai University, Tianjin 300071, China; Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China.
Eur J Pharm Biopharm. 2022 Jan;170:121-132. doi: 10.1016/j.ejpb.2021.11.005. Epub 2021 Nov 18.
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.
化疗是治疗晚期胰腺导管腺癌 (PDAC) 患者的推荐治疗方法。然而，由于存在密集的发育不良肿瘤基质，传统化疗的疗效并不令人满意，因为这种基质会阻止药物在肿瘤中积累和深入渗透。为了克服这些障碍，我们设计并合成了肽树突作为传统化疗的增效剂。树突在共孵育时可显著促进游离阿霉素的积累，并深入渗透到 3D 多细胞 PDAC 肿瘤培养物中。将树突和阿霉素共同给药给携带 PDAC 肿瘤异种移植物的小鼠，大大增加了肿瘤中的阿霉素浓度。此外，当在模拟肿瘤微环境的培养基中与 PDAC 细胞共孵育时，树突还促进了游离阿霉素的内化。最后，当将药物中的任何一种与树突共同给药给携带 PDAC 肿瘤异种移植物的小鼠时，阿霉素和吉西他滨的抗癌疗效都显著增强。当与吉西他滨联合使用树突时，这种联合治疗的效果更为显著，与单独使用吉西他滨相比，肿瘤重量减少了 12.9%。这可以归因于树突的多功能性的结合，即促进游离药物在肿瘤中的积累和深入渗透以及进入癌细胞的内化。
