Development of a Bifunctional Aptamer Targeting the Transferrin Receptor and Epithelial Cell Adhesion Molecule (EpCAM) for the Treatment of Brain Cancer Metastases

Macdonald, Joanna; Henri, Justin; Goodman, Lynda; Xiang, Dongxi; Duan, Wei; Shigdar, Sarah

doi:10.1021/acschemneuro.6b00369

Cited by 84 publications

(96 citation statements)

References 37 publications

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“…To apply aptamers in brain diseases, a bifunctional aptamer was generated by fusing an anti‐EpCAM aptamer with an aptamer against transferrin receptor . Since transferrin receptor is highly expressed on the surface of the cells lining on the blood–brain barrier, the EpCAM aptamer can piggyback on transferrin aptamer to cross the blood–brain barrier, and therefore, delivering payload into the brain …”

Section: Aptamer Emerges As a Prominent Targeting Ligand For Nanodelimentioning

confidence: 99%

Exosomes and Nanoengineering: A Match Made for Precision Therapeutics

et al. 2019

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Intense efforts from both scientists and physicians across Australia have been devoted onward advancing studies to fill the gap in understanding the biology and pathogenesis underlying cancer development. Exosomes are membrane-bound bio-nanoparticles secreted or released by most cells into the extracellular space. There has been an increasing interest in such bio-nanoparticles over the past 10 years, evident from the publication number of only 324 papers in 2006 to a massive increase to 4603 publications in 2018 with the search term "exosome" based on title/abstract in PubMed. Among these studies, 151 articles published from 2007 to 2018 are from Australian institutions, with 33 papers published in 2018. Such a strong surge of interest is due to discoveries that exosomes play key roles in intercellular and intertissue communication mediated by virtue of cargos contained inside the membrane-confined space. Furthermore, exosome cargos, including proteins, mRNAs and miRNAs, are linked to the Targeted exosomal delivery systems for precision nanomedicine attract wide interest across areas of molecular cell biology, pharmaceutical sciences, and nanoengineering. Exosomes are naturally derived 50-150 nm nanovesicles that play important roles in cell-to-cell and/or cell-to-tissue communications and cross-species communication. Exosomes are also a promising class of novel drug delivery vehicles owing to their ability to shield their payload from chemical and enzymatic degradations as well as to evade recognition by and subsequent removal by the immune system. Combined with a new class of affinity ligands known as aptamers or chemical antibodies, molecularly targeted exosomes are poised to become the next generation of smartly engineered nanovesicles for precision medicine. Here, recent advances in targeted exosomal delivery systems engineered by aptamer for future strategies to promote human health using this class of human-derived nanovesicles are summarized.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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Section: Aptamer Emerges As a Prominent Targeting Ligand For Nanodelimentioning

confidence: 99%

Exosomes and Nanoengineering: A Match Made for Precision Therapeutics

et al. 2019

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“…Active tumor targeting by aptamers, while preserving a nity and speci city similar to mAbs, presents several advantages over them, including smaller size, higher stability, cheaper cost for synthesis, minimal inter-batch variability and lack of immunogenicity [61,[65][66][67]. While aptamers are generally functionalized with cytotoxic payloads for cancer therapy, it has been also demonstrated their ability to be antagonistic agents independent of drug conjugation, exerting signi cant potential as anti-cancer therapeutics [31,37,68].…”

Section: Discussionmentioning

confidence: 99%

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Camorani

Passariello

Agnello

et al. 2020

Preprint

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Background: Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC.Methods: The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. Results: We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8+T cells and reducing FOXP3+Treg cells. Conclusion: Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

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“…The bifunctional aptamers targeting the TfR and EpCAM (TEPP = TfR positive and EpCAM positive) and the nontargeting control (TENN = TfR negative and EpCAM negative) were purchased from Integrated DNA Technologies (IDT, Coralville, IA) [25]. All oligonucleotide sequences were labeled with a TYE665 fluorophore on the 3¢ end and high performance liquid chromatography (HPLC) purified.…”

Section: Aptamersmentioning

confidence: 99%

“…With the knowledge that the bifunctional aptamers are internalized intracellularly following 60 min of incubation at a physiologically relevant temperature [25], it was imperative to establish if DOX intercalation affected this ability. To do this, each aptamer-DOX conjugate was prepared at an equivalent DOX concentration of 1 mM and incubated with MDA-MB-231 and HEK293T cells for 60 or 120 min, followed by visualization using laser scanning confocal microscopy.…”

Section: Characterization Of Cellular Internalization and Retention Omentioning

confidence: 99%

“…We have recently described the generation of a bifunctional aptamer that binds both to TfR and a cell surface receptor, the epithelial cell adhesion molecule (EpCAM), on cancer cells. Preliminary studies demonstrated that this aptamer can cross the BBB and target cancer cells using both in vitro and in vivo models [25]. In this study, we capitalized on these properties to transform this bifunctional aptamer into a targeted drug delivery vehicle.…”

Section: Introductionmentioning

confidence: 99%

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Bifunctional Aptamer–Doxorubicin Conjugate Crosses the Blood–Brain Barrier and Selectively Delivers Its Payload to EpCAM-Positive Tumor Cells

Macdonald

Denoyer

Henri

et al. 2020

Nucleic Acid Therapeutics

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The prognosis for breast cancer patients diagnosed with brain metastases is poor, with survival time measured merely in months. This can largely be attributed to the limited treatment options capable of reaching the tumor as a result of the highly restrictive blood-brain barrier (BBB). While methods of overcoming this barrier have been developed and employed with current treatment options, the majority are highly invasive and nonspecific, leading to severe neurotoxic side effects. A novel approach to address these issues is the development of therapeutics targeting receptor-mediated transport mechanisms on the BBB endothelial cell membranes. Using this approach, we intercalated doxorubicin (DOX) into a bifunctional aptamer targeting the transferrin receptor on the BBB and epithelial cell adhesion molecule (EpCAM) on metastatic cancer cells. The ability of the DOXloaded aptamer to transcytose the BBB and selectively deliver the payload to EpCAM-positive tumors was evaluated in an in vitro model and confirmed for the first time in vivo using the MDA-MB-231 breast cancer metastasis model (MDA-MB-231Br). We show that colocalized aptamer and DOX are clearly detectable within the brain lesions 75 min postadministration. Collectively, results from this study demonstrate that through intercalation of a cytotoxic drug into the bifunctional aptamer, a therapeutic delivery vehicle can be developed for specific targeting of EpCAM-positive brain metastases.

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Development of a Bifunctional Aptamer Targeting the Transferrin Receptor and Epithelial Cell Adhesion Molecule (EpCAM) for the Treatment of Brain Cancer Metastases

Cited by 84 publications

References 37 publications

Exosomes and Nanoengineering: A Match Made for Precision Therapeutics

Exosomes and Nanoengineering: A Match Made for Precision Therapeutics

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Bifunctional Aptamer–Doxorubicin Conjugate Crosses the Blood–Brain Barrier and Selectively Delivers Its Payload to EpCAM-Positive Tumor Cells

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