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M. Irfan et al.
7.3 Aptamer Systems for Targeted Drug Delivery
7.3.1 Target-Specific Delivery of siRNAs: Aptamer–siRNA
Conjugates
The RNAi molecules can be efficiently used to inhibit the expression of the complementary RNA transcripts in a highly specific and efficient fashion. The phenomenon
of RNA interference is increasingly used as emerging therapeutics for treatment
of complex diseases such as different types of cancer and AIDS. siRNAs degrade
the target mRNA via RNA-induced silencing complex, the RISC pathway. RNAi
molecules have been conjugated with aptamers and aptamer siRNA chimeras (AsiCs)
for their specific delivery to corresponding targets. The siRNAs and aptamers conjugates can be obtained either by chemical conjugation or through covalent bonding.
In 2006, the first AsiCs were synthesized and produced by two independent research
groups employing two different research themes. An antilamin siRNA and an
antiprostate-specific aptamer were linked via a modular streptavidin bridge. These
AsiCs could be directly added to cells and led to an efficient inhibition of gene
expression [99]. In another case, antiprostate-specific membrane antigen (PSMA)
RNA aptamer was linked with 21mer siRNA through covalent bonding, blocking the
functioning of polo-like kinase 1 (PLK1) and B-cell lymphoma 2 (BCL2) genes. In
this aforementioned AsiCs, the aptamer binds specifically to PSMA, whereas siRNA
hinders gene expression in cancer cells leading to reduced tumor growth [100, 101].
A concurrent delivery of specific shRNA and Dox by using anti PSMA A10 RNA
aptamer was also reported. This conjugate can efficiently deliver shRNA as well
as Dox to the PSMA positive cells via A10 RNA aptamer [102]. siRNA-aptamer
conjugates are reported to treat AID as well. For instance, a conjugate of anti-CD4
DNA aptamer with siRNA specific for HIV1 protease gene resulted in the inhibition of expression of HIV1 protease gene in CD4 positive T lymphocytes. Similarly,
the AsiCs consisting of anti-gp120 aptamer and siRNA exhibited significant activity
against HIV, since both the anti-gp120 aptamer as well as the siRNA have anti-HIV
activities. This kind of aptamer-mediated RNA components delivery system offers
several possible advantages as therapeutic agents; similarly, the ease of chemical
synthesis and lack of immunogenicity are added merits [103].
7.3.2 Aptamer-Drug Conjugates for Therapies
Lack of specificity and drug off-targeting poses a major setback in the form of
severe side effects in classical methods (such as chemo-, radio-, photodynamic, and
photothermal therapy) for disease treatment [104]. Due to these reasons, personalized
tailored therapies are attaining significant attention for the treatment of complex
diseases. The focal point of targeted therapy is to specifically maximize toxicity in
diseased tissues only, while minimizing toxicity in healthy cells [105]. Accordingly,
M. Irfan et al.
7.3 Aptamer Systems for Targeted Drug Delivery
7.3.1 Target-Specific Delivery of siRNAs: Aptamer–siRNA
Conjugates
The RNAi molecules can be efficiently used to inhibit the expression of the complementary RNA transcripts in a highly specific and efficient fashion. The phenomenon
of RNA interference is increasingly used as emerging therapeutics for treatment
of complex diseases such as different types of cancer and AIDS. siRNAs degrade
the target mRNA via RNA-induced silencing complex, the RISC pathway. RNAi
molecules have been conjugated with aptamers and aptamer siRNA chimeras (AsiCs)
for their specific delivery to corresponding targets. The siRNAs and aptamers conjugates can be obtained either by chemical conjugation or through covalent bonding.
In 2006, the first AsiCs were synthesized and produced by two independent research
groups employing two different research themes. An antilamin siRNA and an
antiprostate-specific aptamer were linked via a modular streptavidin bridge. These
AsiCs could be directly added to cells and led to an efficient inhibition of gene
expression [99]. In another case, antiprostate-specific membrane antigen (PSMA)
RNA aptamer was linked with 21mer siRNA through covalent bonding, blocking the
functioning of polo-like kinase 1 (PLK1) and B-cell lymphoma 2 (BCL2) genes. In
this aforementioned AsiCs, the aptamer binds specifically to PSMA, whereas siRNA
hinders gene expression in cancer cells leading to reduced tumor growth [100, 101].
A concurrent delivery of specific shRNA and Dox by using anti PSMA A10 RNA
aptamer was also reported. This conjugate can efficiently deliver shRNA as well
as Dox to the PSMA positive cells via A10 RNA aptamer [102]. siRNA-aptamer
conjugates are reported to treat AID as well. For instance, a conjugate of anti-CD4
DNA aptamer with siRNA specific for HIV1 protease gene resulted in the inhibition of expression of HIV1 protease gene in CD4 positive T lymphocytes. Similarly,
the AsiCs consisting of anti-gp120 aptamer and siRNA exhibited significant activity
against HIV, since both the anti-gp120 aptamer as well as the siRNA have anti-HIV
activities. This kind of aptamer-mediated RNA components delivery system offers
several possible advantages as therapeutic agents; similarly, the ease of chemical
synthesis and lack of immunogenicity are added merits [103].
7.3.2 Aptamer-Drug Conjugates for Therapies
Lack of specificity and drug off-targeting poses a major setback in the form of
severe side effects in classical methods (such as chemo-, radio-, photodynamic, and
photothermal therapy) for disease treatment [104]. Due to these reasons, personalized
tailored therapies are attaining significant attention for the treatment of complex
diseases. The focal point of targeted therapy is to specifically maximize toxicity in
diseased tissues only, while minimizing toxicity in healthy cells [105]. Accordingly,