442
H. Jin
14.5 Challenges for Aptamer in Medical Applications:
From Bench to Bedside
The aptamers have numbers of preclinical biotechnologically and medically relevant
applications as exemplified by the clinical trials tabulated in Table 14.4. Certain
problems that arise from the inherent characters of aptamers should be settled down
before aptamers become practical tools just like antibodies that have already been
used in the therapy treatments.
14.5.1 Stability in Biological Media
Degradation of aptamers in biological media especially in the blood is a critical
problem that hinders the practical application. In some clinical scenarios, it is very
important to continuously monitor the changes of biomarkers in the blood. For
example, the changes in cortisol levels in patients with pregnancy-related hypertension or hyperglycemia are linearly related to the dynamic changes in blood pressure and blood glucose during pregnancy. Persistent dynamic monitoring of cortisol
during pregnancy can help to identify and treat hypoglycemia and hypertension. The
strategies for enhancing the stability of aptamer mainly lie on chemical modification [240] either on the aptamer itself or during the process in SELEX containing
modified nucleotides [241], “mirror aptamers” (Spiegelmers) [242], or “aptamer
displacement screening” [243, 244]. The chemical modification of aptamers can
address the nuclease degradation, thermals, renal clearance, off-target binding, and
other specificity issues of aptamers as well as enhance binding to more demanding
targets.
14.5.2 Safety for Modified Aptamer
Clearing by the kidney is another bottleneck for aptamer due to its small size. Several
functional groups can be conjugated to aptamer to solve this problem, including
cholesterol, polyethylene glycol (PEG), diacylglycerol, and liposome-embedded
aptamers. Among them, PEG is a common one that is used in macugen, the only
approved VEGF-aptamer agent by FDA for the treatment of wet age-related macular
degeneration (AMD) [245]. 40 kDaPEG improved the plasma half-life of VEGFaptamer to 12 h in primates following intravenous (IV) and subcutaneous administration [246]; while in eyes, the half-life of VEGF-aptamer prolongs to 90–99 h
in rhesus monkeys following intravitreal (IVT) injection [247]. Fortunately, PEG
presents no immunogenicity in Macugen in a dose of 0.3 mg [248].
H. Jin
14.5 Challenges for Aptamer in Medical Applications:
From Bench to Bedside
The aptamers have numbers of preclinical biotechnologically and medically relevant
applications as exemplified by the clinical trials tabulated in Table 14.4. Certain
problems that arise from the inherent characters of aptamers should be settled down
before aptamers become practical tools just like antibodies that have already been
used in the therapy treatments.
14.5.1 Stability in Biological Media
Degradation of aptamers in biological media especially in the blood is a critical
problem that hinders the practical application. In some clinical scenarios, it is very
important to continuously monitor the changes of biomarkers in the blood. For
example, the changes in cortisol levels in patients with pregnancy-related hypertension or hyperglycemia are linearly related to the dynamic changes in blood pressure and blood glucose during pregnancy. Persistent dynamic monitoring of cortisol
during pregnancy can help to identify and treat hypoglycemia and hypertension. The
strategies for enhancing the stability of aptamer mainly lie on chemical modification [240] either on the aptamer itself or during the process in SELEX containing
modified nucleotides [241], “mirror aptamers” (Spiegelmers) [242], or “aptamer
displacement screening” [243, 244]. The chemical modification of aptamers can
address the nuclease degradation, thermals, renal clearance, off-target binding, and
other specificity issues of aptamers as well as enhance binding to more demanding
targets.
14.5.2 Safety for Modified Aptamer
Clearing by the kidney is another bottleneck for aptamer due to its small size. Several
functional groups can be conjugated to aptamer to solve this problem, including
cholesterol, polyethylene glycol (PEG), diacylglycerol, and liposome-embedded
aptamers. Among them, PEG is a common one that is used in macugen, the only
approved VEGF-aptamer agent by FDA for the treatment of wet age-related macular
degeneration (AMD) [245]. 40 kDaPEG improved the plasma half-life of VEGFaptamer to 12 h in primates following intravenous (IV) and subcutaneous administration [246]; while in eyes, the half-life of VEGF-aptamer prolongs to 90–99 h
in rhesus monkeys following intravitreal (IVT) injection [247]. Fortunately, PEG
presents no immunogenicity in Macugen in a dose of 0.3 mg [248].