Three-in-One Aptamer-siRNA Chimera Used to Target Breast Cancer in Mice
20%–30% of breast cancer is characterized by HER2 overexpression that correlates with poor prognosis, high aggressiveness, and extensive drug resistance. Resistance to HER2-targeted therapies is associated with increased levels of other HER family receptors; also, antibody combinations have their limitations, with high immunogenicity and high cost. Therefore, in a new study, researchers have developed a three-in-one nucleic acid aptamer-small interfering RNA (siRNA) chimera, which targets EGFR/HER2/HER3 in one molecule.
This chimera, created by a team at the Georgia Cancer Center, has the ability to simultaneously decrease the expression of three growth factors that are over-expressed in some cancers.
Lead researcher, Hongyan Liu, and team created their molecule to target HER family receptors EGFR, HER2, and HER3 all at once, since it is well-known that another HER family member can compensate for one that is blocked by a drug having a single target.
Each component of this tripartite molecule has potent anti-tumor activity. The molecule was designed such that the EGFR-targeting component is sandwiched between the HER2- and HER3-targeting components in what is known as a HER2 aptamer-EGFR siRNA-HER3 aptamer chimera.
In vivo tests in mice bearing HER2+HER3+ breast tumors demonstrated that administering
H2EH3 intravenously or intratumorally led to significant reductions in tumor size—again, the chimera was more effective than the three individual constructs administered as a mixture. There was no evidence of nonspecific accumulation of H2EH3 in other major organs following tail-vein injection, except in the intestine and stomach.Further immunohistochemical assays indicated that HE2EH3 administration reduced expression of EGFR, HER2, and HER3 and induced tumor cell-cycle arrest and apoptosis, “which is translated into significant suppression of tumor growth in mouse xenograft models.” Encouragingly, there was no evidence of any treatment-related toxicity, or that H2E3 triggered any unwanted immune responses.
The authors suggest that the large size of the three-in-one chimera could mean that the drug would, in addition, have a longer circulating lifetime than would each aptamer alone.
“Such a nucleic-acid-based aptamer-siRNA chimera is a unique class of targeting therapeutics that has potential for clinical translation,” the authors conclude. “The new RNA therapeutic with low immunogenicity and low toxicity will provide a potent addition to HER-targeting therapeutics for HER2-expressing breast cancer.…Compared with antibodies, aptamer–siRNA chimeras provide ease of large-scale production, low immunogenicity, ease of modification, high thermostability, and a small size, whereas antibodies are cell-based products, associated with high immunogenicity, are sensitive to temperature, and have a high cost in manufacturing.”
