160
G. Yang and Y. Huang
cells SKBR3, with highly specific binding to ErbB-2/HER2 overexpression cells
and ErbB-2/HER2 positive tumor tissue samples.
Shen et al. [244] designed a novel HER2 aptamer functionalized pH sensitive cyclodextrin (poly-CD) encapsulated doxorubicin (DOX) mesoporous silica
nanoparticles (MSN-BM/CD-HApt@DOX) for targeted delivery and selective
targeting of HER2 positive cells. The results showed that MSN-BM/CDHApt@DOX could release pH-sensitive adriamycin and accept endocytosis mediated by HER2. It showed better uptake and stronger growth inhibition in SKBR3
cells. Ma et al. [196] reported an intelligent nanorobot HApttFNA, based on DNA
framework for selective lysosome degradation of tumor-specific proteins on cancer
cells. They specifically located the HER2 aptamer HApt on a tetrahedral frame
nucleic acid (tFNA). HApt-tFNA can target HER2 positive breast cancer cells and
specifically induce lysosome degradation of cell membrane protein HER2. When
the DNA nanorobot was injected into the mice model, it was found that the presence
of tFNA enhanced the stability of HApt and enabled HER2 to degrade lysosomes
efficiently. The triggered HER2-mediated lysosomal swallowing and digestion effectively reduced the content of HER2 on the cell surface. Increased HER2 digestion
further induced apoptosis and inhibited the growth of cells. This new type of DNA
nanorobot provides a new idea for accurate targeted protein degradation in breast
cancer therapy.
Mahlknecht et al. [245] screened a 14 nt DNA aptamer of ErbB-2/HER2 and
developed a 42 nt aptamer trimer. The aptamer trimer reduced the tumor growth rate
of human gastric cancer cells xenografted in mice, and the inhibitory effect was twice
as much as that of ErbB-2/HER2 monoclonal antibody. Immunofluorescence and
biochemical analysis showed that DNA aptamer targeting ErbB-2/HER2 may delay
the tumor growth of gastric cancer by accelerating the degradation of oncoprotein
lysosomes.
Zhu et al. [139] obtained HER2 targeting DNA aptamers Heraptamer1 and Heraptamer2, through in vitro and in vivo screening. The aptamers were modified with
alkynes and labeled with
18 F radiolabeling for PET imaging of ovarian cancer HER2.
Kim et al. [246] successfully demonstrated target-specific radioisotope uptake in
HER2 overexpressed tumors using
18 F-labeled PET images of HER2 aptamer SH1194-35. The PET images of BT474 tumor-bearing mice showed a reliable tumorto-background ratio, indicating that the aptamer recognized the HER2 target in vivo.
However, there are still some problems to be solved when HER2 aptamers are used
in PET imaging. Compared with HER2-negative cell tumors,
18 F-labeled HER2
aptamer heteroaptamers significantly entered the tumor (p = 0.033), but physiological intestinal uptake still played a dominant role in whole body images. One possible
solution is to carry out chemical modifications, such as PEG modification, to prolong
the half-life of aptamers to form delayed images and weaken the background effects
of intestinal uptake.
ErbB-3/HER3
Human epidermal growth factor receptor-3 (HER3) is a member of type I receptor
tyrosine kinase family. Unlike epidermal growth factor receptor (HER2), HER3 can
G. Yang and Y. Huang
cells SKBR3, with highly specific binding to ErbB-2/HER2 overexpression cells
and ErbB-2/HER2 positive tumor tissue samples.
Shen et al. [244] designed a novel HER2 aptamer functionalized pH sensitive cyclodextrin (poly-CD) encapsulated doxorubicin (DOX) mesoporous silica
nanoparticles (MSN-BM/CD-HApt@DOX) for targeted delivery and selective
targeting of HER2 positive cells. The results showed that MSN-BM/CDHApt@DOX could release pH-sensitive adriamycin and accept endocytosis mediated by HER2. It showed better uptake and stronger growth inhibition in SKBR3
cells. Ma et al. [196] reported an intelligent nanorobot HApttFNA, based on DNA
framework for selective lysosome degradation of tumor-specific proteins on cancer
cells. They specifically located the HER2 aptamer HApt on a tetrahedral frame
nucleic acid (tFNA). HApt-tFNA can target HER2 positive breast cancer cells and
specifically induce lysosome degradation of cell membrane protein HER2. When
the DNA nanorobot was injected into the mice model, it was found that the presence
of tFNA enhanced the stability of HApt and enabled HER2 to degrade lysosomes
efficiently. The triggered HER2-mediated lysosomal swallowing and digestion effectively reduced the content of HER2 on the cell surface. Increased HER2 digestion
further induced apoptosis and inhibited the growth of cells. This new type of DNA
nanorobot provides a new idea for accurate targeted protein degradation in breast
cancer therapy.
Mahlknecht et al. [245] screened a 14 nt DNA aptamer of ErbB-2/HER2 and
developed a 42 nt aptamer trimer. The aptamer trimer reduced the tumor growth rate
of human gastric cancer cells xenografted in mice, and the inhibitory effect was twice
as much as that of ErbB-2/HER2 monoclonal antibody. Immunofluorescence and
biochemical analysis showed that DNA aptamer targeting ErbB-2/HER2 may delay
the tumor growth of gastric cancer by accelerating the degradation of oncoprotein
lysosomes.
Zhu et al. [139] obtained HER2 targeting DNA aptamers Heraptamer1 and Heraptamer2, through in vitro and in vivo screening. The aptamers were modified with
alkynes and labeled with
18 F radiolabeling for PET imaging of ovarian cancer HER2.
Kim et al. [246] successfully demonstrated target-specific radioisotope uptake in
HER2 overexpressed tumors using
18 F-labeled PET images of HER2 aptamer SH1194-35. The PET images of BT474 tumor-bearing mice showed a reliable tumorto-background ratio, indicating that the aptamer recognized the HER2 target in vivo.
However, there are still some problems to be solved when HER2 aptamers are used
in PET imaging. Compared with HER2-negative cell tumors,
18 F-labeled HER2
aptamer heteroaptamers significantly entered the tumor (p = 0.033), but physiological intestinal uptake still played a dominant role in whole body images. One possible
solution is to carry out chemical modifications, such as PEG modification, to prolong
the half-life of aptamers to form delayed images and weaken the background effects
of intestinal uptake.
ErbB-3/HER3
Human epidermal growth factor receptor-3 (HER3) is a member of type I receptor
tyrosine kinase family. Unlike epidermal growth factor receptor (HER2), HER3 can