6 Aptamers for Targeted Therapy
161
catalyze defective kinase domains. In the absence of ligands, HER3 tends to selfpolymerize. Overexpression of HER2 and HER3 was found in several cancers at the
same time [247]. In many cancers with overexpression of HER2, the increase in drug
resistance depended on increased levels of HER3 or EGFR [176]. In 2002, Chi-hong
B. Chen et al. [248] identified the RNA aptamer A30 for the oligomeric HER3ECD
of the extracellular domain of HER3 for the first time. The high affinity binding
of A30 inhibited the HRG-dependent tyrosine phosphorylation of HER2 and the
growth response of MCF7 cells induced by HRG. Nachreiner et al. [249] explored
the ability of a group of A30 chimeric cytotoxic siRNAs to inhibit the growth of
breast cancer cells. Among them, A30 is the targeting element, and siRNA targets
eukaryotic elongation factor 2 (EEF2), polo-like kinase 1 (PLK1), G protein-coupled
receptor kinase 4 (GRK4), and sphingosine kinase interacting protein (SKIP5). In
vitro results showed that targeting binding of highly specific HER3 aptamers to
cytotoxic siRNAs (EEF2, PLK1, GRK4, and SKIP5) could inhibit the activity of
HER3 positive breast cancer cells and ultimately inhibit their proliferation. Ali et al.
[250] attached HER3 aptamers to the surface of (MP) particles coated with sorafenib
prepared by biodegradable poly (D-l-lactic-glycolic acid) (PLGA) copolymers to
form MPS-APT. The inhibitory effects of MPS and MPS-APT without aptamer modification on breast cancer cell line MDA-MB-231 expressing ErbB3 were compared.
The results of in vitro experiments showed that MPS-APT significantly reduced the
survival rate of breast cancer cells in vitro and slowed down the metastasis of breast
cancer cells. In addition, the drug showed low toxicity in female BALB/c mice.
Therefore, HER3 aptamers or in combination with other therapies may be a valuable
supplement to cancer-targeted inhibitors that overexpress HER2.
ErbB family members are interdependent and functionally compensatory. Studies
have shown that the therapeutic effect of antibody combined with targeting
EGFR/HER2/HER3 is better than targeting a HER receptor. However, antibody
combinations have limitations, including high immunogenicity and high cost. Yu
et al. [251] developed a three-in-one aptamer-siRNA chimera to achieve simultaneous targeting of EGFR/HER2/HER3. The targeting elements of the chimeric
H2EH3 are HER2 and HER3 aptamers, while EGFRsiRNA is located between them.
HER2/HER3 aptamers induce internalization into HER2/HER3 expression cells. In
addition, HER2/HER3 aptamers have the antagonistic function of blocking both
HER2 and HER3 signaling pathways. The results showed that H2EH3 downregulated the expression of EGFR/HER2/HER3, which triggered apoptosis. In the mouse
model of breast cancer xeno-transplantation, H2EH3 binds to breast tumor with high
specificity and significantly inhibits tumor growth through systemic or intratumoral
administration. Because H2EH3 is based on nucleic acid and has the advantages of
low immunogenicity and easy preparation, it is a promising treatment for HER2+
breast cancer.
161
catalyze defective kinase domains. In the absence of ligands, HER3 tends to selfpolymerize. Overexpression of HER2 and HER3 was found in several cancers at the
same time [247]. In many cancers with overexpression of HER2, the increase in drug
resistance depended on increased levels of HER3 or EGFR [176]. In 2002, Chi-hong
B. Chen et al. [248] identified the RNA aptamer A30 for the oligomeric HER3ECD
of the extracellular domain of HER3 for the first time. The high affinity binding
of A30 inhibited the HRG-dependent tyrosine phosphorylation of HER2 and the
growth response of MCF7 cells induced by HRG. Nachreiner et al. [249] explored
the ability of a group of A30 chimeric cytotoxic siRNAs to inhibit the growth of
breast cancer cells. Among them, A30 is the targeting element, and siRNA targets
eukaryotic elongation factor 2 (EEF2), polo-like kinase 1 (PLK1), G protein-coupled
receptor kinase 4 (GRK4), and sphingosine kinase interacting protein (SKIP5). In
vitro results showed that targeting binding of highly specific HER3 aptamers to
cytotoxic siRNAs (EEF2, PLK1, GRK4, and SKIP5) could inhibit the activity of
HER3 positive breast cancer cells and ultimately inhibit their proliferation. Ali et al.
[250] attached HER3 aptamers to the surface of (MP) particles coated with sorafenib
prepared by biodegradable poly (D-l-lactic-glycolic acid) (PLGA) copolymers to
form MPS-APT. The inhibitory effects of MPS and MPS-APT without aptamer modification on breast cancer cell line MDA-MB-231 expressing ErbB3 were compared.
The results of in vitro experiments showed that MPS-APT significantly reduced the
survival rate of breast cancer cells in vitro and slowed down the metastasis of breast
cancer cells. In addition, the drug showed low toxicity in female BALB/c mice.
Therefore, HER3 aptamers or in combination with other therapies may be a valuable
supplement to cancer-targeted inhibitors that overexpress HER2.
ErbB family members are interdependent and functionally compensatory. Studies
have shown that the therapeutic effect of antibody combined with targeting
EGFR/HER2/HER3 is better than targeting a HER receptor. However, antibody
combinations have limitations, including high immunogenicity and high cost. Yu
et al. [251] developed a three-in-one aptamer-siRNA chimera to achieve simultaneous targeting of EGFR/HER2/HER3. The targeting elements of the chimeric
H2EH3 are HER2 and HER3 aptamers, while EGFRsiRNA is located between them.
HER2/HER3 aptamers induce internalization into HER2/HER3 expression cells. In
addition, HER2/HER3 aptamers have the antagonistic function of blocking both
HER2 and HER3 signaling pathways. The results showed that H2EH3 downregulated the expression of EGFR/HER2/HER3, which triggered apoptosis. In the mouse
model of breast cancer xeno-transplantation, H2EH3 binds to breast tumor with high
specificity and significantly inhibits tumor growth through systemic or intratumoral
administration. Because H2EH3 is based on nucleic acid and has the advantages of
low immunogenicity and easy preparation, it is a promising treatment for HER2+
breast cancer.