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Z. Liu and Y. Liu
is to attach therapeutic agents with cell-specific targeting ligands that can selectively deliver cargos to diseased cells, minimizing the toxicity and side effects to
normal cells [2, 3]. Therefore, exploiting ideal ligands for pathologic cells, especially
cancerous cells, is of great significance.
Aptamers are a class of single-stranded DNA or RNA, evolved from an in vitro
selection method called systematic evolution of ligands by exponential enrichment (SELEX) [4]. The screened aptamers can form specific secondary or threedimensional structures to specifically interact with targets via different forces such as
hydrophobic interaction, electrostatic interaction, hydrogen bonding, van der Waals
forces, π–π stacking and even shape matching [5]. The unique interactions between
aptamers and their targets endow the binding with high affinity and specificity.
Compared with the most widely utilized antibodies, aptamers own unique advantages, such as easy synthesis, low cost, little immunogenicity, reversible conformational changes, considerable thermal stability, fast tissue penetration and easy
modification, making aptamers become promising candidates as targeting ligands
[6–8]. Since first reported in 1990, over 900 aptamers have been selected for a range
of targets, including metal ions, proteins, nucleic acids, cells and even tissues [9].
However, traditional selection methods are usually time consuming, due to multiple
rounds of screening. To solve this problem, more automated and smarter selection
protocols, such as capillary electrophoresis-SELEX, non-SELEX, and SOMAmerbased SELEX, have been established, which vastly shortened the selection period
to even a few days [10]. In addition, the advances in high-throughput sequencing,
bioinformatic analysis and chemical oligonucleotides synthesis/modification also
benefit the aptamer screening. In the last two decades, great progress has been made
in aptamer selection, and plenty of aptamers that can specifically bind with cell
membrane proteins have been generated, including epithelial cell adhesion molecules
(EpCAM) [11], human epidermal growth factor receptor 2 (HER2) [12], mucin 1
protein (MUC1) [13], prostate-specific membrane antigen (PSMA) [14], protein tyrosine kinase 7 (PTK7) [15] and immunoglobin heavy mu chain (IGHM) [16], which
are all important cancer protein biomarkers. All these features guarantee aptamers
as ideal ligands to guide targeted drug delivery.
Through the specific interactions with target proteins of living cells, aptamers
can directly regulate the cellular biological functions to acquire therapeutic effects,
or serve as targeting ligands to guide selective drug delivery to targeted cells via
receptor-mediated endocytosis. Herein, aptamer-based drug delivery systems are
generally divided into three types: (1) aptamers as therapeutic agents, (2) aptamerdrug conjugates (ApDCs) and (3) aptamer-functionalized nanoparticle drug delivery
systems.
4.2 Aptamers as Therapeutic Agents
Aptamers can regulate the cellular signal pathways by inhibiting or activating their
pathological targets, thus making them potential therapeutic agent candidates for
Z. Liu and Y. Liu
is to attach therapeutic agents with cell-specific targeting ligands that can selectively deliver cargos to diseased cells, minimizing the toxicity and side effects to
normal cells [2, 3]. Therefore, exploiting ideal ligands for pathologic cells, especially
cancerous cells, is of great significance.
Aptamers are a class of single-stranded DNA or RNA, evolved from an in vitro
selection method called systematic evolution of ligands by exponential enrichment (SELEX) [4]. The screened aptamers can form specific secondary or threedimensional structures to specifically interact with targets via different forces such as
hydrophobic interaction, electrostatic interaction, hydrogen bonding, van der Waals
forces, π–π stacking and even shape matching [5]. The unique interactions between
aptamers and their targets endow the binding with high affinity and specificity.
Compared with the most widely utilized antibodies, aptamers own unique advantages, such as easy synthesis, low cost, little immunogenicity, reversible conformational changes, considerable thermal stability, fast tissue penetration and easy
modification, making aptamers become promising candidates as targeting ligands
[6–8]. Since first reported in 1990, over 900 aptamers have been selected for a range
of targets, including metal ions, proteins, nucleic acids, cells and even tissues [9].
However, traditional selection methods are usually time consuming, due to multiple
rounds of screening. To solve this problem, more automated and smarter selection
protocols, such as capillary electrophoresis-SELEX, non-SELEX, and SOMAmerbased SELEX, have been established, which vastly shortened the selection period
to even a few days [10]. In addition, the advances in high-throughput sequencing,
bioinformatic analysis and chemical oligonucleotides synthesis/modification also
benefit the aptamer screening. In the last two decades, great progress has been made
in aptamer selection, and plenty of aptamers that can specifically bind with cell
membrane proteins have been generated, including epithelial cell adhesion molecules
(EpCAM) [11], human epidermal growth factor receptor 2 (HER2) [12], mucin 1
protein (MUC1) [13], prostate-specific membrane antigen (PSMA) [14], protein tyrosine kinase 7 (PTK7) [15] and immunoglobin heavy mu chain (IGHM) [16], which
are all important cancer protein biomarkers. All these features guarantee aptamers
as ideal ligands to guide targeted drug delivery.
Through the specific interactions with target proteins of living cells, aptamers
can directly regulate the cellular biological functions to acquire therapeutic effects,
or serve as targeting ligands to guide selective drug delivery to targeted cells via
receptor-mediated endocytosis. Herein, aptamer-based drug delivery systems are
generally divided into three types: (1) aptamers as therapeutic agents, (2) aptamerdrug conjugates (ApDCs) and (3) aptamer-functionalized nanoparticle drug delivery
systems.
4.2 Aptamers as Therapeutic Agents
Aptamers can regulate the cellular signal pathways by inhibiting or activating their
pathological targets, thus making them potential therapeutic agent candidates for