TY - JOUR
T1 - Metformin bicarbonate-mediated efficient RNAi for precise targeting of TP53 deficiency in colon and rectal cancers
AU - Xu, Jiangsheng
AU - Liu, Yunhua
AU - Liu, Sheng
AU - Ou, Wenquan
AU - White, Alisa
AU - Stewart, Samantha
AU - Tkaczuk, Katherine H.R.
AU - Ellis, Lee M.
AU - Wan, Jun
AU - Lu, Xiongbin
AU - He, Xiaoming
N1 - Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/4
Y1 - 2022/4
N2 - Colon and rectal cancers are the leading causes of cancer-related deaths in the United States and effective targeted therapies are in need for treating them. Our genomic analyses show hemizygous deletion of TP53, an important tumor suppressor gene, is highly frequent in both cancers, and the 5-year survival of patients with the more prevalent colon cancer is significantly reduced in the patients with the cancer harboring such deletion, although such reduction is not observed for rectal cancer. Unfortunately, direct targeting TP53 has been unsuccessful for cancer therapy. Interestingly, POLR2A, a gene essential for cell survival and proliferation, is almost always deleted together with TP53 in colon and rectal cancers. Therefore, RNA interference (RNAi) with small interfering RNAs (siRNAs) to precisely target/inhibit POLR2A may be an effective strategy for selectively killing cancer cells with TP53 deficiency. However, the difficulty of delivering siRNAs specifically into the cytosol where they perform their function, is a major barrier for siRNA-based therapies. Here, metformin bicarbonate (MetC) is synthesized to develop pH-responsive MetC-nanoparticles with a unique “bomb” effect for effective cytosolic delivery of POLR2A siRNA, which greatly facilitates its endo/lysosomal escape into the cytosol and augments its therapeutic efficacy of cancer harboring TP53 deficiency. Moreover, the MetC-based nanoparticles without functional siRNA show notable therapeutic effect with no evident systemic toxicity or immunogenicity.
AB - Colon and rectal cancers are the leading causes of cancer-related deaths in the United States and effective targeted therapies are in need for treating them. Our genomic analyses show hemizygous deletion of TP53, an important tumor suppressor gene, is highly frequent in both cancers, and the 5-year survival of patients with the more prevalent colon cancer is significantly reduced in the patients with the cancer harboring such deletion, although such reduction is not observed for rectal cancer. Unfortunately, direct targeting TP53 has been unsuccessful for cancer therapy. Interestingly, POLR2A, a gene essential for cell survival and proliferation, is almost always deleted together with TP53 in colon and rectal cancers. Therefore, RNA interference (RNAi) with small interfering RNAs (siRNAs) to precisely target/inhibit POLR2A may be an effective strategy for selectively killing cancer cells with TP53 deficiency. However, the difficulty of delivering siRNAs specifically into the cytosol where they perform their function, is a major barrier for siRNA-based therapies. Here, metformin bicarbonate (MetC) is synthesized to develop pH-responsive MetC-nanoparticles with a unique “bomb” effect for effective cytosolic delivery of POLR2A siRNA, which greatly facilitates its endo/lysosomal escape into the cytosol and augments its therapeutic efficacy of cancer harboring TP53 deficiency. Moreover, the MetC-based nanoparticles without functional siRNA show notable therapeutic effect with no evident systemic toxicity or immunogenicity.
KW - Endosomal escape
KW - Gene delivery
KW - Metformin
KW - POLR2A
KW - Targeted therapy
UR - http://www.scopus.com/inward/record.url?scp=85123870413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123870413&partnerID=8YFLogxK
U2 - 10.1016/j.nantod.2022.101406
DO - 10.1016/j.nantod.2022.101406
M3 - Article
C2 - 35251293
AN - SCOPUS:85123870413
SN - 1748-0132
VL - 43
JO - Nano Today
JF - Nano Today
M1 - 101406
ER -