6 Aptamers for Targeted Therapy
159
drug resistance, and nucleic acid aptamers are considered to be new therapeutic
molecules with the potential to overcome the limitations of existing EGFR inhibitors.
NaLi et al. [225] reported a 2
-F-Py-modified RNA aptamer E07 (K D = ∼2.4 nM)
of EGFR, which competes with EGF to bind EGFR, and can bind to the deletion
mutant EGFRvIII, which is common in breast and lung cancer. The results showed
that E07 could block the phosphorylation of EGFR and further inhibit the proliferation of A431 cells in three-dimensional matrix. In addition, like EGF and cetuximab,
E07 can induce EGFR internalization, indicating that E07 can be used as a cytotoxic
delivery agent to target EGFR or EGFRvIII overexpression cells. Esposito et al. [234]
screened the nuclease-resistant RNA aptamer CL4 (K D = ∼10 nM) of EGFR. CL4
blocks the downstream signal transduction of EGFR by inhibiting ErbB2 or ErbB3
of homodimer and heterodimer of EGFR. At low doses, CL4 can induce apoptosis of
tolerant cells of EGFR inhibitors (gefitinib or cetuximab) and inhibit tumor growth
in human non-small cell lung cancer (NSCLC) mice xenotransplantation model.
In addition, cetuximab combined with CL4 had synergistic induction of apoptosis
in vivo and in vitro. Wang et al. [237] obtained methyl modified 27 nt RNA and
DNA aptamer CL-4RNV616, which effectively recognized and inhibited the proliferation of human hepatoma cell line Huh-7, breast cancer cell line MDA-MB-231,
and glioblastoma cell line U87MG with positive epidermal growth factor receptor,
and their IC50 values are 258.9, 413.7, and 567.9 nM, respectively. In addition, the
immunostaining test of clinical breast cancer biopsy showed that the detection effect
of CL4RNV616 in EGFR positive breast cancer was similar to that of commercial
antibodies.
ErbB-2/HER2
The overexpression of ErbB-2/HER2 protein is present in 15% of breast cancer
cells and 20% of breast cancer cells, which is associated with invasive diseases
and poor prognosis of patients [238]. Trastuzumab (Herceptin ®, Genentech) is a
monoclonal antibody against ErbB-2/HER2 that has been approved for the treatment
of ErbB-2/HER2-positive early breast cancer, metastatic breast cancer, and metastatic
cancer at the gastric or gastroesophageal junction [239, 240]. However, only onethird of patients responded to trastuzumab, and most of those who responded would
eventually relapse. In addition, resistance to trastuzumab is a major problem [241].
Aptamers provide a potential source of alternative targeting molecules for existing
ErbB2/HER2 antibody therapy.
Liu et al. [39] identified the aptamer HB5 (K D = ∼18.9 nM) binding to the extracellular domain (ECD) of ErbB-2/HER2 and inserted Dox into HB5, to prepare
an aptamer adriamycin complex (HB5-Dox). HB5-Dox complex can selectively
transfer Dox to ErbB-2/HER2 positive breast cancer cells in vitro and reduce the
drug intake of ErbB-2/HER2 negative cells. HB5-Dox retained the killing effect of
Dox on ErbB-2/HER2-positive breast cancer cells, but decreased the killing effect on
ErbB-2/HER2-negative breast cancer cells. Moosavian et al. [242] screened ErbB2/HER2 aptamers with high affinity for breast cancer cells against HER2 overexpressed TUBO cells via Cell-SELEX. Gijs et al. [243] identified a 40 nt DNA
aptamers HeA2_1 and HeA2_3, which targeted to human breast cancer adherent
159
drug resistance, and nucleic acid aptamers are considered to be new therapeutic
molecules with the potential to overcome the limitations of existing EGFR inhibitors.
NaLi et al. [225] reported a 2
-F-Py-modified RNA aptamer E07 (K D = ∼2.4 nM)
of EGFR, which competes with EGF to bind EGFR, and can bind to the deletion
mutant EGFRvIII, which is common in breast and lung cancer. The results showed
that E07 could block the phosphorylation of EGFR and further inhibit the proliferation of A431 cells in three-dimensional matrix. In addition, like EGF and cetuximab,
E07 can induce EGFR internalization, indicating that E07 can be used as a cytotoxic
delivery agent to target EGFR or EGFRvIII overexpression cells. Esposito et al. [234]
screened the nuclease-resistant RNA aptamer CL4 (K D = ∼10 nM) of EGFR. CL4
blocks the downstream signal transduction of EGFR by inhibiting ErbB2 or ErbB3
of homodimer and heterodimer of EGFR. At low doses, CL4 can induce apoptosis of
tolerant cells of EGFR inhibitors (gefitinib or cetuximab) and inhibit tumor growth
in human non-small cell lung cancer (NSCLC) mice xenotransplantation model.
In addition, cetuximab combined with CL4 had synergistic induction of apoptosis
in vivo and in vitro. Wang et al. [237] obtained methyl modified 27 nt RNA and
DNA aptamer CL-4RNV616, which effectively recognized and inhibited the proliferation of human hepatoma cell line Huh-7, breast cancer cell line MDA-MB-231,
and glioblastoma cell line U87MG with positive epidermal growth factor receptor,
and their IC50 values are 258.9, 413.7, and 567.9 nM, respectively. In addition, the
immunostaining test of clinical breast cancer biopsy showed that the detection effect
of CL4RNV616 in EGFR positive breast cancer was similar to that of commercial
antibodies.
ErbB-2/HER2
The overexpression of ErbB-2/HER2 protein is present in 15% of breast cancer
cells and 20% of breast cancer cells, which is associated with invasive diseases
and poor prognosis of patients [238]. Trastuzumab (Herceptin ®, Genentech) is a
monoclonal antibody against ErbB-2/HER2 that has been approved for the treatment
of ErbB-2/HER2-positive early breast cancer, metastatic breast cancer, and metastatic
cancer at the gastric or gastroesophageal junction [239, 240]. However, only onethird of patients responded to trastuzumab, and most of those who responded would
eventually relapse. In addition, resistance to trastuzumab is a major problem [241].
Aptamers provide a potential source of alternative targeting molecules for existing
ErbB2/HER2 antibody therapy.
Liu et al. [39] identified the aptamer HB5 (K D = ∼18.9 nM) binding to the extracellular domain (ECD) of ErbB-2/HER2 and inserted Dox into HB5, to prepare
an aptamer adriamycin complex (HB5-Dox). HB5-Dox complex can selectively
transfer Dox to ErbB-2/HER2 positive breast cancer cells in vitro and reduce the
drug intake of ErbB-2/HER2 negative cells. HB5-Dox retained the killing effect of
Dox on ErbB-2/HER2-positive breast cancer cells, but decreased the killing effect on
ErbB-2/HER2-negative breast cancer cells. Moosavian et al. [242] screened ErbB2/HER2 aptamers with high affinity for breast cancer cells against HER2 overexpressed TUBO cells via Cell-SELEX. Gijs et al. [243] identified a 40 nt DNA
aptamers HeA2_1 and HeA2_3, which targeted to human breast cancer adherent