Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB–siRNA conjugates

Cuellar, Trinna; Barnes, Debra A.; Nelson, Christopher G.; Tanguay, Joshua; Yu, Shang‐Fan; Wen, Xiaohui; Scales, Suzie J.; Gesch, Julie; Davis, Donald W.; Smith, Anja van Brabant; Leake, Devin; Vandlen, Richard; Siebel, Christian W.

doi:10.1093/nar/gku1362

Cited by 165 publications

(159 citation statements)

References 37 publications

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“…The accumulation of both targeted and non-targeted nanoparticles in the liver and kidney has also been reported in previous studies 37,38 . The liver accumulation of silica is expected as a result of particle uptake by macrophages in the reticuloendothelial system 39 .…”

Section: Discussionsupporting

confidence: 77%

Targeted drug delivery using genetically engineered diatom biosilica

et al. 2015

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The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

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Section: Discussionsupporting

confidence: 77%

Targeted drug delivery using genetically engineered diatom biosilica

et al. 2015

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“…In addition to overcoming complex biology, a clinically viable delivery solution must meet pharmaceutical criteria: stability, scalability, and amenability to good manufacturing practices (GMP). Classes of RNAi delivery formulations that have been investigated as cancer therapeutics either preclinically or clinically include cyclodextrin-based polymers (20), chitosan particles (21), antibody-linked conjugates (22), carbon nanotubes (23), and lipid nanoparticles (LNPs) (13, 24–26). …”

Section: Introductionmentioning

confidence: 99%

Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin

Ganesh

Koser

Cyr

et al. 2016

Molecular Cancer Therapeutics

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The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level, and therefore can be applied to previously-undruggable targets. Lipid nanoparticles (LNPs) represent an elegant solution for delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDx) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens and identify efficacious combinations with standard-of-care therapeutics.

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“…In most studies up to now, efforts have been made separately to improve either specific targeting or efficiency of intracellular delivery, reviewed by Lares MR. 26 Antibody-directed delivery was first experimented to guide anti-cancer drugs and used for specific delivery of siRNA as well. 27,28 In recent years, nucleic acid aptamers have showed new promise as specific ligands for diagnostic or therapeutic use. 29 Aptamers have the advantages of being highly specific, relatively small in size, and easily synthesized, which could be regarded as a chemical equivalent of antibodies.…”

Section: Discussionmentioning

confidence: 99%

A specific aptamer-cell penetrating peptides complex delivered siRNA efficiently and suppressed prostate tumor growthin vivo

Yanjun

Liu

et al. 2016

Cancer Biology & Therapy

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Specific and efficient delivery of siRNA into intended tumor cells remains as a challenge, even though RNAi has been exploited as a new strategy for prostate cancer therapy. This work aims to address both specificity and efficiency of SURVIVIN-siRNA delivery by constructing a therapeutic complex using combinatorial strategies. A fusion protein STD was first expressed to serve as a backbone, consisting of streptavidin, a cell-penetrating peptide called Trans-Activator of Transcription (TAT) and a doublestranded RNA binding domain. A biotinylated Prostate Specific Membrane Antigen (PSMA) specific aptamer A10 and SURVIVIN-siRNA were then linked to STD protein to form the therapeutic complex. This complex could specifically targeted PSMA C tumor cells. Compared to lipofectamine and A10-siRNA chimera, it demonstrated higher efficiency in delivering siRNA into target cells by 19.2% and 59.9%, and increased apoptosis by 16.8% and 26.1% respectively. Upon systemic administration, this complex also showed significant efficacy in suppressing tumor growth in athymic mice (p <0.001). We conclude that this therapeutic complex could specifically and efficiently deliver SURVIVIN-siRNA to target cells and suppressed tumor growth in vivo, which indicates its potential to be used as a new strategy in prostate cancer therapy

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Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB–siRNA conjugates

Cited by 165 publications

References 37 publications

Targeted drug delivery using genetically engineered diatom biosilica

Targeted drug delivery using genetically engineered diatom biosilica

Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin

A specific aptamer-cell penetrating peptides complex delivered siRNA efficiently and suppressed prostate tumor growthin vivo

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