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Oligonucleotide aptamers: new tools for targeted cancer therapy.

Sun H, Zhu X, Lu PY, Rosato RR, Tan W, Zu Y - Mol Ther Nucleic Acids (2014)

Bottom Line: Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed "chemical antibodies." In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties.Hence, they are more suitable for the development of novel clinical applications.Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.

ABSTRACT
Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed "chemical antibodies." In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy.

No MeSH data available.


Related in: MedlinePlus

Aptamer-based biotherapy. (a) Schema showing receptor oligomerization-inducing downstream signaling. CD30-associated signaling is activated by its ligand through trimerization of the receptor, leading to varied outcomes that range from apoptosis to proliferation. (b) CD30-positive and -negative cells were incubated without any treatment or in the presence of control streptavidin, monomeric aptamer, and multimeric aptamer. Following 72-hour incubation, the multivalent CD30 aptamer induced cell death in the CD30-positive lymphoma cells, but had no effect on the CD30-negative control cells. Ratio of the dead/live cells was calculated by costaining the cells with Hoechst 33342 (live cells) and propidium iodide (dead cells).
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fig6: Aptamer-based biotherapy. (a) Schema showing receptor oligomerization-inducing downstream signaling. CD30-associated signaling is activated by its ligand through trimerization of the receptor, leading to varied outcomes that range from apoptosis to proliferation. (b) CD30-positive and -negative cells were incubated without any treatment or in the presence of control streptavidin, monomeric aptamer, and multimeric aptamer. Following 72-hour incubation, the multivalent CD30 aptamer induced cell death in the CD30-positive lymphoma cells, but had no effect on the CD30-negative control cells. Ratio of the dead/live cells was calculated by costaining the cells with Hoechst 33342 (live cells) and propidium iodide (dead cells).

Mentions: Many cell surface receptors and biomarkers play a role in specific cellular functions, such as signaling transduction pathways. Therefore, their interaction with aptamers could confer agonistic or antagonistic effects on their specific biologic functions, resulting in cancer cell death. In a therapeutic setting, monovalent aptamers, especially those targeted to cell surface biomarkers, are usually unable to activate the downstream signaling pathways. Conversely, multivalent aptamers induce receptor multimerization, thus triggering downstream signaling. Recently, Mahlknecht et al. reported development of a trimeric HER2 aptamer for biotherapy in a human gastric cancer model. This trimeric HER2 aptamer significantly inhibited in vitro and in vivo proliferation of tumor cells, as compared to the monomeric HER2 aptamer.115 When compared against a HER2 monoclonal antibody, the trimeric HER2 aptamer increased the antitumor efficacy by twofold. The molecular mechanism involved internalization and cytoplasmic translocation of the HER2 receptor induced by the aptamer binding, followed by their degradation in the lysosomes.115 In a similar approach, our group developed a highly stable DNA aptamer specific for CD30. We conjugated a biotinylated CD30 aptamer with a streptavidin connector to form multivalent aptamers (Figure 6).23 Our results show that the addition of multivalent aptamers into cell culture induced CD30 oligomerization and subsequently triggered lymphoma apoptosis, up to sixfold higher than that observed in the control group.23 Together, these results demonstrate the feasibility of using aptamers as a biotherapeutics and warrant their further evaluation in the clinical arena.


Oligonucleotide aptamers: new tools for targeted cancer therapy.

Sun H, Zhu X, Lu PY, Rosato RR, Tan W, Zu Y - Mol Ther Nucleic Acids (2014)

Aptamer-based biotherapy. (a) Schema showing receptor oligomerization-inducing downstream signaling. CD30-associated signaling is activated by its ligand through trimerization of the receptor, leading to varied outcomes that range from apoptosis to proliferation. (b) CD30-positive and -negative cells were incubated without any treatment or in the presence of control streptavidin, monomeric aptamer, and multimeric aptamer. Following 72-hour incubation, the multivalent CD30 aptamer induced cell death in the CD30-positive lymphoma cells, but had no effect on the CD30-negative control cells. Ratio of the dead/live cells was calculated by costaining the cells with Hoechst 33342 (live cells) and propidium iodide (dead cells).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4221593&req=5

fig6: Aptamer-based biotherapy. (a) Schema showing receptor oligomerization-inducing downstream signaling. CD30-associated signaling is activated by its ligand through trimerization of the receptor, leading to varied outcomes that range from apoptosis to proliferation. (b) CD30-positive and -negative cells were incubated without any treatment or in the presence of control streptavidin, monomeric aptamer, and multimeric aptamer. Following 72-hour incubation, the multivalent CD30 aptamer induced cell death in the CD30-positive lymphoma cells, but had no effect on the CD30-negative control cells. Ratio of the dead/live cells was calculated by costaining the cells with Hoechst 33342 (live cells) and propidium iodide (dead cells).
Mentions: Many cell surface receptors and biomarkers play a role in specific cellular functions, such as signaling transduction pathways. Therefore, their interaction with aptamers could confer agonistic or antagonistic effects on their specific biologic functions, resulting in cancer cell death. In a therapeutic setting, monovalent aptamers, especially those targeted to cell surface biomarkers, are usually unable to activate the downstream signaling pathways. Conversely, multivalent aptamers induce receptor multimerization, thus triggering downstream signaling. Recently, Mahlknecht et al. reported development of a trimeric HER2 aptamer for biotherapy in a human gastric cancer model. This trimeric HER2 aptamer significantly inhibited in vitro and in vivo proliferation of tumor cells, as compared to the monomeric HER2 aptamer.115 When compared against a HER2 monoclonal antibody, the trimeric HER2 aptamer increased the antitumor efficacy by twofold. The molecular mechanism involved internalization and cytoplasmic translocation of the HER2 receptor induced by the aptamer binding, followed by their degradation in the lysosomes.115 In a similar approach, our group developed a highly stable DNA aptamer specific for CD30. We conjugated a biotinylated CD30 aptamer with a streptavidin connector to form multivalent aptamers (Figure 6).23 Our results show that the addition of multivalent aptamers into cell culture induced CD30 oligomerization and subsequently triggered lymphoma apoptosis, up to sixfold higher than that observed in the control group.23 Together, these results demonstrate the feasibility of using aptamers as a biotherapeutics and warrant their further evaluation in the clinical arena.

Bottom Line: Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed "chemical antibodies." In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties.Hence, they are more suitable for the development of novel clinical applications.Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.

ABSTRACT
Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed "chemical antibodies." In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy.

No MeSH data available.


Related in: MedlinePlus