A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy

Trinh, Thu Le; Zhu, Guizhi; Xiao, Xilin; Puszyk, William; Sefah, Kwame; Wu, Qiang-Sheng; Tan, Weihong; Liu, Chen

doi:10.1371/journal.pone.0136673

Cited by 71 publications

(43 citation statements)

References 45 publications

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“…58 In mice xenografts, AS1411-doxorubicin conjugation has shown a specific uptake/release of drug in hepatocellular carcinoma and reduced tumor formation. 59 We found combined nucleolin-specific AS1411 and doxorubicin or etoposide treatment significantly inhibited the survival and proliferation of DLBCL cells (Figure 6a and Supplementary Figure 5). Similar results were obtained when DLBCL cells were treated with nucleolin specific nucant N6L (Figure 6b and Supplementary Figure 6).…”

Section: Discussionmentioning

confidence: 82%

Targeting nucleolin for better survival in diffuse large B-cell lymphoma

Jain¹,

Zhu²,

Khashab³

et al. 2017

Leukemia

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Anthracyclines have been a cornerstone in the cure of diffuse large B-cell lymphoma (DLBCL) and other hematological cancers. The ability of anthracyclines to eliminate DLBCL depends on the presence of topoisomerase-II-alpha (TopIIA), a DNA repair enzyme complex. We identified nucleolin as a novel binding partner of TopIIA. Abrogation of nucleolin sensitized DLBCL cells to TopIIA targeting agents (doxorubicin/etoposide). Silencing nucleolin and challenging DLBCL cells with doxorubicin enhanced the phosphorylation of H2AX (γH2AX-marker of DNA damage) and allowed DNA fragmentation. Reconstitution of nucleolin expression in nucleolin-knockdown DLBCL cells prevented TopIIA targeting agent-induced apoptosis. Nucleolin binding to TopIIA was mapped to RNA binding domain 3 of nucleolin, and this interaction was essential for blocking DNA damage and apoptosis. Nucleolin silencing decreased TopIIA decatenation activity, but enhanced formation of TopIIA-DNA-cleavable complexes in the presence of etoposide. Moreover, combining nucleolin inhibitors: aptamer AS1411 or nucant N6L with doxorubicin reduced DLBCL cell survival. These findings are of clinical importance because low nucleolin levels versus high nucleolin levels in DLBCL predicted 90 month estimated survival of 70% versus 12% (P<0.0001) of patients treated with R-CHOP based therapy.

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Section: Discussionmentioning

confidence: 82%

Targeting nucleolin for better survival in diffuse large B-cell lymphoma

Jain¹,

Zhu²,

Khashab³

et al. 2017

Leukemia

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“…Human serum albumin nanoparticles loaded with paclitaxel were delivered with the nucleolin aptamer and shown to inhibit growth of glioma xenografts in mice relative to nontargeted nanoparticles (59). AS1411 conjugated directly to doxorubicin (Dox) was delivered intravenously in mice that had hepatocellular cancer xenografts, resulting in inhibition of tumor growth (60). Other groups have functionalized different drug carriers with AS1411 and demonstrated targeted delivery of chemotherapeutic agents in vitro (61, 62).…”

Section: Cancermentioning

confidence: 99%

Aptamers as Therapeutics

Nimjee

White

Becker

et al. 2017

Annu. Rev. Pharmacol. Toxicol.

433

308

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Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development. This review presents a short history of aptamers and SELEX, describes their pharmacological development and optimization, and reviews potential treatment of diseases including visual disorders, thrombosis, and cancer.

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“…In particular, several research groups have focused their attention on AS1411-based drug-delivery approaches, developing essentially three different kinds of systems: AS1411-drug, AS1411-drug-liposomes and AS1411-drugnanoparticle conjugates. For each of these systems some valuable examples are reported here [136][137][138][139][140].…”

Section: G4-based Aptamers As Drug Delivery Systemsmentioning

confidence: 99%

“…Le Trinh et al have crosslinked AS1411 with doxorubicin, a known chemotherapeutic agent [137]. In vivo tests in a murine xenograft model have shown that injection of the AS1411-doxorubicin adduct resulted in a reduced antitumor activity compared with free doxorubicin, but also in a significant reduction of the typical side effects associated to doxorubicin treatments, such as cardiotoxicity, nephrotoxicity and weight loss [137].…”

Section: G4-based Aptamers As Drug Delivery Systemsmentioning

confidence: 99%

G-quadruplex-based aptamers against protein targets in therapy and diagnostics

Platella

Riccardi

Montesarchio

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

137

116

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Nucleic acid aptamers are single-stranded DNA or RNA molecules identified to recognize with high affinity specific targets including proteins, small molecules, ions, whole cells and even entire organisms, such as viruses or bacteria. They can be identified from combinatorial libraries of DNA or RNA oligonucleotides by SELEX technology, an in vitro iterative selection procedure consisting of binding (capture), partitioning and amplification steps. Remarkably, many of the aptamers selected against biologically relevant protein targets are G-rich sequences that can fold into stable G-quadruplex (G4) structures. Aiming at disseminating novel inspiring ideas within the scientific community in the field of G4-structures, the emphasis of this review is placed on: 1) recent advancements in SELEX technology for the efficient and rapid identification of new candidate aptamers (introduction of microfluidic systems and next generation sequencing); 2) recurrence of G4 structures in aptamers selected by SELEX against biologically relevant protein targets; 3) discovery of several G4-forming motifs in important regulatory regions of the human or viral genome bound by endogenous proteins, which per se can result into potential aptamers; 4) an updated overview of G4-based aptamers with therapeutic potential and 5) a discussion on the most attractive G4-based aptamers for diagnostic applications. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.

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A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy

Cited by 71 publications

References 45 publications

Targeting nucleolin for better survival in diffuse large B-cell lymphoma

Targeting nucleolin for better survival in diffuse large B-cell lymphoma

Aptamers as Therapeutics

G-quadruplex-based aptamers against protein targets in therapy and diagnostics

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