198
M. Irfan et al.
10 min in human plasma [127–129]. Similar effect was shown for R9D-14 T, an
RNA aptamer that binds prothrombin and thrombin pro/exosite I, by using antidote
oligonucleotides [130].
7.4 Gaps-Issues to be Considered
In the era of personalized medicine, targeted therapy has become an integral part
of disease treatment and interestingly, aptamers are well suited for this job. Despite
continuous research and breakthroughs, several major challenges still remain that
hinder the rapid transition of aptamer-mediated targeting technology from the
research laboratory benchtop to the clinical settings [131]. The pharmacokinetics of
a therapeutic agent is determined by their chemical and physical properties including
the stability (as in the case of aptamers, nuclease/protease-resistance), the uptake and
bio-distribution in tissue, and the half-life at physiological conditions [120, 132].
As rivals of aptamers, antibodies have no threat of nuclease degradation. Furthermore, antibodies contain better pharmacokinetic properties due to their large size
which prevent the renal filtration and extend their circulating half-life. Aptamers are
single-stranded polynucleotides with relatively smaller size (30–45 nt) and molecular
weight (10–15 kDa) as compared to antibodies. Moreover, aptamers are susceptible
to nuclease-mediated degradation, fast bio-distribution from the plasma to tissues
compartments, and rapid renal filtration. Appropriate chemical modifications of
aptamers can improve their pharmacokinetics for clinical application [133, 134].
It is very necessary to choose the chemical modification carefully and incorporate
it precisely to achieve the required goal. Keeping in mind the function of aptamer
mostly depends upon nucleotide sequence and secondary structure. So, aptamers
should preserve their native folding properties after chemical modification. With
respect to improving the bioavailability and circulating half-life of aptamers in vivo,
they have been conjugated to cholesterol or PEG. Macugen is 40 kDa PEGylated
chemically modified aptamer against vascular endothelial growth factor, and the
pharmacokinetics study reported its half-life in plasma as 9.3 h after intravenous and
12 h after subcutaneous injection and 94 h in vitreous humor. As per the consideration
of chemical modifications of aptamers, incorporating protective groups, such as thiolphosphate, 2
-fluoro, 2
-amino, 2
-OMe, and so on, in the phosphate backbone or
2
-position of the ribose sugar enhances their nuclease resistance [135].
Despite the increasing number of published studies demonstrating advances in
the development of aptamers applied to different diseases, we have observed a very
slow progress in the utilization of this knowledge in clinical practice so far. The
aforementioned areas need more attention in terms of more in vivo data, which may
help aptamers to become the key players in modern personalized medicines.
M. Irfan et al.
10 min in human plasma [127–129]. Similar effect was shown for R9D-14 T, an
RNA aptamer that binds prothrombin and thrombin pro/exosite I, by using antidote
oligonucleotides [130].
7.4 Gaps-Issues to be Considered
In the era of personalized medicine, targeted therapy has become an integral part
of disease treatment and interestingly, aptamers are well suited for this job. Despite
continuous research and breakthroughs, several major challenges still remain that
hinder the rapid transition of aptamer-mediated targeting technology from the
research laboratory benchtop to the clinical settings [131]. The pharmacokinetics of
a therapeutic agent is determined by their chemical and physical properties including
the stability (as in the case of aptamers, nuclease/protease-resistance), the uptake and
bio-distribution in tissue, and the half-life at physiological conditions [120, 132].
As rivals of aptamers, antibodies have no threat of nuclease degradation. Furthermore, antibodies contain better pharmacokinetic properties due to their large size
which prevent the renal filtration and extend their circulating half-life. Aptamers are
single-stranded polynucleotides with relatively smaller size (30–45 nt) and molecular
weight (10–15 kDa) as compared to antibodies. Moreover, aptamers are susceptible
to nuclease-mediated degradation, fast bio-distribution from the plasma to tissues
compartments, and rapid renal filtration. Appropriate chemical modifications of
aptamers can improve their pharmacokinetics for clinical application [133, 134].
It is very necessary to choose the chemical modification carefully and incorporate
it precisely to achieve the required goal. Keeping in mind the function of aptamer
mostly depends upon nucleotide sequence and secondary structure. So, aptamers
should preserve their native folding properties after chemical modification. With
respect to improving the bioavailability and circulating half-life of aptamers in vivo,
they have been conjugated to cholesterol or PEG. Macugen is 40 kDa PEGylated
chemically modified aptamer against vascular endothelial growth factor, and the
pharmacokinetics study reported its half-life in plasma as 9.3 h after intravenous and
12 h after subcutaneous injection and 94 h in vitreous humor. As per the consideration
of chemical modifications of aptamers, incorporating protective groups, such as thiolphosphate, 2
-fluoro, 2
-amino, 2
-OMe, and so on, in the phosphate backbone or
2
-position of the ribose sugar enhances their nuclease resistance [135].
Despite the increasing number of published studies demonstrating advances in
the development of aptamers applied to different diseases, we have observed a very
slow progress in the utilization of this knowledge in clinical practice so far. The
aforementioned areas need more attention in terms of more in vivo data, which may
help aptamers to become the key players in modern personalized medicines.