Synthetic α-l-Threose Nucleic Acids Targeting BcL-2 Show Gene Silencing and in Vivo Antitumor Activity for Cancer Therapy.

We design and synthesize a sequence-defined α-l-threose nucleic acid (TNA) polymer, which is complementary to certain nucleotide sites of target anti-apoptotic proteins, BcL-2 involving in development and progression of tumors. Compared to scramble TNA, anti-BcL-2 TNA significantly suppresses target mRNA and protein expression in cancerous cells and shows antitumor activity in carcinoma xenografts, resulting in suppression of tumor cell growth and induction of tumor cell death. Together with good biocompatibility, very low toxicity, excellent specificity features, and strong binding affinity toward the complementary target RNAs, TNAs become new useful biomaterials and effective alternatives to traditional antisense oligonucleotides including locked nucleic acids, morpholino oligomers, and peptide nucleic acids in antisense therapy. Compared to conventional cancer therapy such as radiotherapy, surgery, and chemotherapy, we anticipate that this TNA-based polymeric system will work effectively in antisense cancer therapy and shortly start to play an important role in practical application.