6 Aptamers for Targeted Therapy
163
6.5.2.5 Thioaptamer Targeting E-Selectin
E-selectin is an adhesion molecule expressed on the luminal surface of inflamed
blood vessels which mediates hematogenous metastasis by assisting shear-resistant
adhesion of circulating tumor cells to the inflamed vessel surface under dynamic
blood flow. An E-selectin antagonistic thioaptamer (ESTA) identified from cellSELEX demonstrated the ability to inhibit adhesion of circulating cells to E-selectin
expressing endothelial cells with binding affinity and IC50 of 47 nM and 63–83 nM,
respectively. This accounts for > 10,000 times higher affinity and 1000 times lower
IC50 to its natural ligands (sLex, K D = ∼100–2000 μM; IC50 = 100–750 μM)
[258]. Accordingly, a single intravenous injection of ESTA effectively prevented
hematogenous metastasis of CD44 high breast cancer cells to a level equal to baseline
by abrogating their adhesion to E-selectin-expressing pre-metastatic vascular niches
in both syngeneic and xenogeneic forced breast cancer metastasis models [259].
Additionally, truncated ESTA conjugated with 10 kDa PEG extended its serum halflife and led to improvement of its anti-metastasis activity compared to parental ESTA
[260]. Additionally, twice weekly intravenous administration of PEGylated ESTA at
a 128 μg dose was well tolerated; no symptomatic changes in the ALT or AST levels,
C3a, C5a complement levels, inflammation, or tissue damage (kidney, lung, or heart)
were noted. Based on its E-selectin specific binding ability, ESTA was also used as a
targeting moiety for nano- and microparticles [261]. ESTA conjugation to liposome
enhanced tumor targeting in mouse models of breast cancer and conjugation of ESTA
to porous silicon microparticles allowed bone marrow targeting in mice [262]. This
exemplifies the versatile applications of aptamers as therapeutic agents and targeting
moieties.
6.6 Prospects of Aptamer-Based Targeted Therapy
In the era of precision medicine, targeted therapy has become a key and hot spot in the
field of disease treatment, and it has become an important part of chemotherapy, radiotherapy, phototherapy (photodynamic and photothermal therapy), immunotherapy,
and gene therapy. A variety of targeted therapeutic agents have been studied, developed, and put into clinical application. After 30 years of development, aptamers
have been believed to be a novel generation of targeted therapeutic agents because
of their high affinity, specificity, low immunogenicity, high tissue permeability, and
modification ease according to demand. Particularly, these screened single-stranded
oligonucleotides with spatial structure can target almost any substance, from small
metal molecules to tissues and organs and even the whole organism, and are very
suitable to be the targeted elements for specific targeting drugs or delivery. Aptamers
show promising efficacy and safety in four types of clinical studies of ophthalmopathy, blood coagulation, inflammation, and cancer, and there is an increasing
number of evidence to prove the clinical application potential of aptamers.
163
6.5.2.5 Thioaptamer Targeting E-Selectin
E-selectin is an adhesion molecule expressed on the luminal surface of inflamed
blood vessels which mediates hematogenous metastasis by assisting shear-resistant
adhesion of circulating tumor cells to the inflamed vessel surface under dynamic
blood flow. An E-selectin antagonistic thioaptamer (ESTA) identified from cellSELEX demonstrated the ability to inhibit adhesion of circulating cells to E-selectin
expressing endothelial cells with binding affinity and IC50 of 47 nM and 63–83 nM,
respectively. This accounts for > 10,000 times higher affinity and 1000 times lower
IC50 to its natural ligands (sLex, K D = ∼100–2000 μM; IC50 = 100–750 μM)
[258]. Accordingly, a single intravenous injection of ESTA effectively prevented
hematogenous metastasis of CD44 high breast cancer cells to a level equal to baseline
by abrogating their adhesion to E-selectin-expressing pre-metastatic vascular niches
in both syngeneic and xenogeneic forced breast cancer metastasis models [259].
Additionally, truncated ESTA conjugated with 10 kDa PEG extended its serum halflife and led to improvement of its anti-metastasis activity compared to parental ESTA
[260]. Additionally, twice weekly intravenous administration of PEGylated ESTA at
a 128 μg dose was well tolerated; no symptomatic changes in the ALT or AST levels,
C3a, C5a complement levels, inflammation, or tissue damage (kidney, lung, or heart)
were noted. Based on its E-selectin specific binding ability, ESTA was also used as a
targeting moiety for nano- and microparticles [261]. ESTA conjugation to liposome
enhanced tumor targeting in mouse models of breast cancer and conjugation of ESTA
to porous silicon microparticles allowed bone marrow targeting in mice [262]. This
exemplifies the versatile applications of aptamers as therapeutic agents and targeting
moieties.
6.6 Prospects of Aptamer-Based Targeted Therapy
In the era of precision medicine, targeted therapy has become a key and hot spot in the
field of disease treatment, and it has become an important part of chemotherapy, radiotherapy, phototherapy (photodynamic and photothermal therapy), immunotherapy,
and gene therapy. A variety of targeted therapeutic agents have been studied, developed, and put into clinical application. After 30 years of development, aptamers
have been believed to be a novel generation of targeted therapeutic agents because
of their high affinity, specificity, low immunogenicity, high tissue permeability, and
modification ease according to demand. Particularly, these screened single-stranded
oligonucleotides with spatial structure can target almost any substance, from small
metal molecules to tissues and organs and even the whole organism, and are very
suitable to be the targeted elements for specific targeting drugs or delivery. Aptamers
show promising efficacy and safety in four types of clinical studies of ophthalmopathy, blood coagulation, inflammation, and cancer, and there is an increasing
number of evidence to prove the clinical application potential of aptamers.