Properties of Native High‐Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles

McMahon, Kaylin M.; Plebanek, Michael P.; Thaxton, C. Shad

doi:10.1002/adfm.201602600

Cited by 47 publications

(50 citation statements)

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“…http://dx.doi.org/10.1101/247429 doi: bioRxiv preprint first posted online Jan. 12, 2018; We were wondering whether the super toxic TNR-based siRNAs could be used for cancer therapy. We decided to deliver the siRNAs to cancer cells in vivo using templated lipoprotein (TLP) nanoparticles [26].…”

Section: Super Toxic Tnr-derived Sirnas Kill Cells By Targeting Tnr Smentioning

confidence: 99%

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Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Murmann

Gao

Putzbach

et al. 2018

Preprint

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Synopsis Bullet points• CAG and CUG trinucleotide repeat (TNR) derived siRNAs are super toxic to cancer cells.• Super toxic siRNA duplexes kill cancer cells via RNAi by targeting survival genes with sequence complementarity.• Super toxic siRNAs reduce tumor growth in a murine cancer model without affecting normal tissues. Synopsis blurbTrinucleotide repeat disorders like Huntington's disease show severe neurological pathologies, but are also characterised by reduced cancer susceptibility. siRNAs based on trinucleotide repeats show specific toxicity against cancer cells, explaining the low cancer incidence in triple repeat diseases.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/247429 doi: bioRxiv preprint first posted online Jan. 12, 2018; peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/247429 doi: bioRxiv preprint first posted online Jan. 12, 2018; 2 Abstract Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complimentary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the 6 members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anti-cancer reagents.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/247429 doi: bioRxiv preprint first posted online Jan. 12, 2018; 3 IntroductionTrinucleotide repeat (TNR) expansions are the cause of a large number of degenerative disease syndromes characterized by amplification of DNA triplet motifs [1]. They include spinocerebellar ataxias (SCAs), spinobulbar muscular atrophy (SBMA), myotonic dystrophy type 1 (DM1), and Huntington's disease (HD) [1,2]. HD is a dominantly inherited neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin (HTT) gene. It has been shown that the resulting glutamine expansions (polyQ) in HTT are toxic to cells [3,4] and that the length of the CAG amplifications determines severity and onset of the disease...

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Section: Super Toxic Tnr-derived Sirnas Kill Cells By Targeting Tnr Smentioning

confidence: 99%

“…We decided to deliver the siRNAs to cancer cells in vivo using templated lipoprotein (TLP) nanoparticles [26].…”

mentioning

confidence: 99%

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Murmann

Gao

Putzbach

et al. 2018

Preprint

Self Cite

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“…12 Recently, the co-delivery of chemotherapeutic drugs and siRNA has gained increasing attention owing to enhanced antitumor efficacy over single administration. 13,14 Previous studies showed that simultaneously delivering chemotherapeutic drugs and siRNA via a single targeted vector was more effective in treating some cancers than sequential administration of two separate vectors with one drug in each. 15 This finding indicates that simultaneous delivery of chemotherapeutic drugs and suitable amount of siRNA into the same tumor plays an important role in the cancer treatments.…”

Section: Introductionmentioning

confidence: 99%

Novel functionalized nanoparticles for tumor-targeting co-delivery of doxorubicin and siRNA to enhance cancer therapy

Xia

Wang

et al. 2017

IJN

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Human homeobox protein (Nanog) is highly expressed in most cancer cells and has gradually emerged as an excellent target in cancer therapy, owing to its regulation of cancer cell proliferation, metastasis and apoptosis. In this study, we prepared tumor-targeting functionalized selenium nanoparticles (RGDfC-SeNPs) to load chemotherapeutic doxorubicin (DOX) and Nanog siRNA. Herein, RGDfC peptide was used as a tumor-targeting moiety which could specifically bind to α v β 3 integrins overexpressed on various cancer cells. The sizes of RGDfC-SeNPs@DOX nanoparticles (~12 nm) were confirmed by both dynamic light scattering and transmission electron microscopy. The chemical structure of RGDfC-SeNPs@DOX was characterized via Fourier-transform infrared spectroscopy. The RGDfC-SeNPs@DOX was compacted with siRNA (anti-Nanog) by electrostatic interaction to fabricate the RGDfC-SeNPs@DOX/siRNA complex. The RGDfC-SeNPs@DOX/siRNA complex nanoparticles could efficiently enter into HepG2 cells via clathrin-associated endocytosis, and showed high gene transfection efficiency that resulted in enhanced gene silencing. The in vivo biodistribution experiment indicated that RGDfC-SeNPs@DOX/siRNA nanoparticles were capable of specifically accumulating in the tumor site. Furthermore, treatment with RGDfC-SeNPs@DOX/siRNA resulted in a more significant anticancer activity than the free DOX, RGDfC-SeNPs@DOX or RGDfC-SeNPs/siRNA in vitro and in vivo. In summary, this study shows a novel type of DOX and siRNA co-delivery system, thereby providing an alternative route for cancer treatment.

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“…We first demonstrated that DISE induction works in an in vivo model whereby mice harbor xenografted ovarian cancer cells expressing a CD95L derived shRNA (shL3). We then delivered two siRNAs derived from CD95L (siL2 and siL3) to mice with ovarian cancer xenografts using a nanoparticle platform demonstrated previously to deliver siRNA in vivo [11,12]. Templated lipoprotein particles (TLP) stabilize siRNA and are dependent upon SR-B1 expression for efficient siRNA delivery.…”

Section: Introductionmentioning

confidence: 99%

Induction of DISE in ovarian cancer cellsin vivo

Murmann¹,

McMahon²,

Haluck-Kangas³

et al. 2017

Preprint

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The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. shRNAs and siRNAs derived from CD95 or CD95 ligand (CD95L) are highly toxic to most cancer cells. We recently found that these sh/siRNAs kill cancer cells in the absence of the target by targeting the 3'UTRs of critical survival genes through canonical RNAi. We have named this unique form of off-target effect DISE (for death induced by survival gene elimination). DISE preferentially kills transformed cells and cancer stem cells. We demonstrate that DISE induction occurs in cancer cells in vivo after introducing a lentiviral CD95L derived shRNA (shL3) into HeyA8 ovarian cancer cells grown as i.p. xenografts in mice, when compared to a scrambled shRNA. To demonstrate the possibility of therapeutically inducing DISE, we coupled siRNAs to templated lipoprotein nano particles (TLP). In vitro, TLPs loaded with a CD95L derived siRNA (siL3) selectively silenced a biosensor comprised of Venus and CD95L ORF and killed ovarian cancer cells. In vivo, two siRNA-TLPs (siL2-TLP and siL3-TLP) reduced tumor growth similarly as observed for cells expressing the shL3 vector. These data suggest that it is possible to kill ovarian cancer cells in vivo via DISE induction using siRNA-TLPs.

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Properties of Native High‐Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles

Cited by 47 publications

References 54 publications

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Novel functionalized nanoparticles for tumor-targeting co-delivery of doxorubicin and siRNA to enhance cancer therapy

Induction of DISE in ovarian cancer cellsin vivo

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