期刊
ACS APPLIED MATERIALS & INTERFACES
卷 -, 期 -, 页码 -出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.2c05841
关键词
colorectal cancer; oxaliplatin; nanodrug; tumor-associated macrophages; LDHA gene; autophagy
资金
- National Natural Science Foundation of China [82072038, 82001837, 82102194, 51933011]
- Key Areas Research and Development Program of Guangzhou [202007020006]
- Natural Science Foundation of Guangdong Province [2018A0303130070, 2020A1515111206]
- China Postdoctoral Science Foundation [2020M680119]
- Excellent Young Researchers Program of the 5th Affiliated Hospital of SYSU [WYYXQN-2021010]
- Core Talent Fund of the Fifth Affiliated Hospital of Sun Yat-sen University [310103050302-220904094228]
A polymer nanocomplex was prepared to deliver siRNA to silence the LDHA gene and inhibit lactic acid secretion and M2-like polarization of TAMs, while enhancing OXA-induced autophagy and inducing autophagic death. The combination treatment of OXA and nanocomplex showed a significantly increased chemotherapeutic effect on CC.
Oxaliplatin (OXA) is a first-line chemotherapeutic agent for treating colorectal cancer (CC). However, the chemotherapeutic effect of OXA on CC is limited by the M2-like polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) and protective autophagy of tumor cells. Here, a cationic polymer APEG-PAsp(PEI) (PAPEI) was prepared to deliver small-interfering RNA (siRNA) to silence the lactate dehydrogenase A (LDHA) gene (LDHA-siRNA) to enhance the chemotherapeutic effect of OXA on CC. The PAPEI/LDHA-siRNA nanocomplex effectively silenced the LDHA gene to inhibit the secretion of lactic acid from tumor cells, resulting in inhibition of the M2-like polarization of TAMs. In addition, the nanocomplex also amplified OXA-induced autophagy and transformed protective autophagy into autophagic death. Consequently, the combination treatment of OXA and PAPEI/LDHA-siRNA showed a dramatically increased chemotherapeutic effect on CC compared with the OXA-alone treatment, which also suggested its attractive potential for treating CC-like immune cold tumors.
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