Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles

Pun, Suzie H.; Tack, Frederik; Bellocq, Nathalie C.; Cheng, Jianjun; Grubbs, Brendan H.; Jensen, Gregory C.; Davis, Mark E.; Brewster, Marcus E.; Janicot, Michel; Janssens, Boudewijn; Floren, Wim; Bakker, Annette

doi:10.4161/cbt.3.7.918

Cited by 185 publications

(82 citation statements)

References 40 publications

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“…DNAzymes packaged in polyplex formulations are concentrated and retained in tumor tissue and other organs, whereas unformulated DNAzyme is eliminated from the body within 24 hours post-injection. 20 These ways would be enhancing stability and effective into the target cells of DNAzymes. In this study, for the sake of improve the stability of DNAzyme in vivo or in vitro, two bases of each end modified by phosphorothioate.…”

Section: Discussionmentioning

confidence: 99%

Effect of DNAzymes targeting Akt1 on cell proliferation and apoptosis in nasopharyngeal carcinoma

Yang¹,

Xiao²,

Ma³

et al. 2009

Cancer Biology & Therapy

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The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is important in nasopharyngeal carcinoma (NPC) pathogenesis. Activated PI3K and its downstream target Akt are concernful signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis and oncogenesis. The protein kinase Akt1, one of the Akt family members, is involved in several signaling pathways for tumor development and progression, suggesting that Akt1 might be an interesting target for a molecular tumor therapy. DNAzyme is a single-stranded DNA catalyst that can be engineered to bind to their complementary sequence in the target mRNA and cleave the mRNA. In this study, based on the analysis of sequences, thermodynamics and site distribution within the Akt1 gene, five DNAzymes were designed. We found that the DNAzyme, namely Dz2, strongly inhibited Akt1 mRNA and protein expression in the NPC cell line CNE1-LMP1. It was showed that the inhibition of cell proliferation, stimulation of apoptosis and inhibition of xenograft growth in nude mice can also exerted by Dz2. Besides, the apoptosis was shown to be associated with the suppression of the Bcl-2 and increased expression of Bax. Thus, DNAzyme targeting Akt1, Dz2, can inhibit multiple key tumorigenic processes in vitro and in vivo and may serve as a useful anti-cancer agent in NPC.

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Section: Discussionmentioning

confidence: 99%

Effect of DNAzymes targeting Akt1 on cell proliferation and apoptosis in nasopharyngeal carcinoma

Yang¹,

Xiao²,

Ma³

et al. 2009

Cancer Biology & Therapy

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“…A review of this delivery system is available (32). By using in vivo, whole-body fluorescence imaging, this system has been shown to deliver fluorescently labeled ssDNA to tumor cells in s.c., tumor-bearing nude mice from tail-vein injections (35). Absence of the transferrin ligand on the particles still provided tumor localization, but no uptake in tumor cells was observed (33,35).…”

Section: Introductionmentioning

confidence: 99%

Sequence-Specific Knockdown of EWS-FLI1 by Targeted, Nonviral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's Sarcoma

et al. 2005

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The development of effective, systemic therapies for metastatic cancer is highly desired. We show here that the systemic delivery of sequence-specific small interfering RNA (siRNA) against the EWS-FLI1 gene product by a targeted, nonviral delivery system dramatically inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. The nonviral delivery system uses a cyclodextrin-containing polycation to bind and protect siRNA and transferrin as a targeting ligand for delivery to transferrin receptor-expressing tumor cells. Removal of the targeting ligand or the use of a control siRNA sequence eliminates the antitumor effects. Additionally, no abnormalities in interleukin-12 and IFN-A, liver and kidney function tests, complete blood counts, or pathology of major organs are observed from long-term, low-pressure, lowvolume tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted, nonviral siRNA delivery system. (Cancer Res 2005; 65(19): 8984-92)

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“…This targeted particle has been shown to reach tumors from an i.v. injection in mice (19,29) and give sequencespecific gene inhibition that leads to antitumor efficacy (19). The Tf receptor (TfR) has long been known to be up-regulated in malignant cells (30).…”

Section: Resultsmentioning

confidence: 99%

Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

Heidel

Liu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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362

227

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The results of administering escalating, i.v. doses of targeted nanoparticles containing a siRNA targeting the M2 subunit of ribonucleotide reductase to non-human primates are reported. The nanoparticles consist of a synthetic delivery system that uses a linear, cyclodextrin-containing polycation, transferrin (Tf) protein targeting ligand, and siRNA. When administered to cynomolgus monkeys at doses of 3 and 9 mg siRNA/kg, the nanoparticles are well tolerated. At 27 mg siRNA/kg, elevated levels of blood urea nitrogen and creatinine are observed that are indicative of kidney toxicity. Mild elevations in alanine amino transferase and aspartate transaminase at this dose level indicate that the liver is also affected to some extent. Analysis of complement factors does not reveal any changes that are clearly attributable to dosing with the nanoparticle formulation. Detection of increased IL-6 levels in all animals at 27 mg siRNA/kg and increased IFN-␥ in one animal indicate that this high dose level produces a mild immune response. Overall, no clinical signs of toxicity clearly attributable to treatment are observed. The multiple administrations spanning a period of 17-18 days enable assessment of antibody formation against the human Tf component of the formulation. Low titers of anti-Tf antibodies are detected, but this response is not associated with any manifestations of a hypersensitivity reaction upon readministration of the targeted nanoparticle. Taken together, the data presented show that multiple, systemic doses of targeted nanoparticles containing nonchemically modified siRNA can safely be administered to non-human primates.systemic administration ͉ RNA interference

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Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles

Cited by 185 publications

References 40 publications

Effect of DNAzymes targeting Akt1 on cell proliferation and apoptosis in nasopharyngeal carcinoma

Effect of DNAzymes targeting Akt1 on cell proliferation and apoptosis in nasopharyngeal carcinoma

Sequence-Specific Knockdown of EWS-FLI1 by Targeted, Nonviral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's Sarcoma

Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

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