Current issues of RNAi therapeutics delivery and development

Haussecker, Dirk

doi:10.1016/j.jconrel.2014.07.056

Cited by 184 publications

(167 citation statements)

References 42 publications

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“…A major challenge in applying this technology is to effectively deliver the small interfering RNAs (siRNAs) to the tumor in vivo. Enzymatic degradation, removal from circulation by renal excretion or mononuclear phagocyte system (MPS), poor cellular uptake and endosomal release are examples of physiological barriers that siRNAs need to overcome [17,18]. Several viral and nonviral delivery vectors, such as adenovirus, polyplexes, liposomes, and micelles, amongst others, have been developed to overcome these obstacles and improve RNAi therapeutic efficacy in vivo [19][20][21][22][23][24][25].…”

mentioning

confidence: 99%

Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

Nascimento

Gattacceca

Singh

et al. 2016

Nanomedicine (Lond.)

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Background: The present study focuses on biodistribution profile and pharmacokinetic parameters of EGFR-targeted chitosan nanoparticles (TG CS nanoparticles) for siRNA/cisplatin combination therapy of lung cancer. Material & methods: Mad2 siRNA was encapsulated in EGFR targeted and nontargeted (NTG) CS nanoparticles by electrostatic interaction. The biodistribution of the nanoparticles was assessed qualitatively and quantitatively in cisplatin (DDP) sensitive and resistant lung cancer xenograft model. Results: TG nanoparticles showed a consistent and preferential tumor targeting ability with rapid clearance from the plasma to infiltrate and sustain within the tumor up to 96 h. They exhibit a sixfold higher tumor targeting efficiency compared with the NTG nanoparticles. Conclusion: TG nanoparticles present as an attractive drug delivery platform for RNAi therapeutics against NSCLC.

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mentioning

confidence: 99%

Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

Nascimento

Gattacceca

Singh

et al. 2016

Nanomedicine (Lond.)

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“…However, LNP-formulated siRNAs still have limitations in the clinic 9 . LNP-formulated siRNAs are more efficient at escaping endosomal compartments, but they are prone to immune activation 9 and their immunogenicity and cytotoxicity has been 9 . In comparison, the preparation of Toc-HDO is significantly less complex, and they were not found to be immunostimulatory in our evaluations (Table 1).…”

Section: Resultsmentioning

confidence: 99%

DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing

Yokota

2016

Clinical & Exp Neuroim

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Antisense oligonucleotides (ASOs) are recognized therapeutic agents for the modulation of specific genes at the post-transcriptional level. Similar to any medical drugs, there are opportunities to improve their efficacy and safety. Here we develop a short DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from double-stranded RNA used for short interfering RNA and single-stranded DNA used for ASO. A DNA/locked nucleotide acid gapmer duplex with an a-tocopherol-conjugated complementary RNA (Toc-HDO) is significantly more potent at reducing the expression of the targeted mRNA in liver compared with the parent single-stranded gapmer ASO. Toc-HDO also improves the phenotype in disease models more effectively. In addition, the high potency of Toc-HDO results in a reduction of liver dysfunction observed in the parent ASO at a similar silencing effect. HDO technology offers a novel concept of therapeutic oligonucleotides, and the development of this molecular design opens a new therapeutic field.

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“…To realize the potential of RNAi based therapeutics, efficient delivery of an RNAi trigger (siRNA) has been a major obstacle (25), particularly to target tissues other than liver (26,27). Previously, we described an efficient and selective liver targeting siRNA delivery system termed dynamic polyconjugates (DPC; refs.…”

Section: Introductionmentioning

confidence: 99%

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Wong

Cheng

Hamilton

et al. 2018

Molecular Cancer Therapeutics

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Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2a (HIF2a) and that an overabundance of HIF2a functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2a that utilizes a targeting ligand that selectively binds to integrins avb3 and avb5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2a-specific RNAi trigger resulted in HIF2a gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.

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Current issues of RNAi therapeutics delivery and development

Cited by 184 publications

References 42 publications

Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

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