Metformin bicarbonate-mediated efficient RNAi for precise targeting of TP53 deficiency in colon and rectal cancers

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. (C) 2022 Elsevier Ltd. All rights reserved.

Automated summary

Colon and rectal cancers are leading causes of cancer-related deaths in the United States. Genomic analyses reveal the frequent hemizygous deletion of TP53 gene, an important tumor suppressor, in both cancers. Targeting TP53 directly has been unsuccessful, but the co-deletion of POLR2A gene with TP53 in these cancers suggests RNA interference with POLR2A siRNA as a potential strategy. However, efficient delivery of siRNA into the cytosol is a major challenge. To overcome this barrier, pH-responsive MetC-nanoparticles with a bomb effect are developed for effective cytosolic delivery of POLR2A siRNA, enhancing therapeutic efficacy for TP53-deficient cancer.