Highlights
- •Oligonucleotides as alternative candidates for targeted therapies.
- •siRNAs open doors to hitting ‘undruggable’ targets.
- •Translation of siRNAs to clinics is dependent on delivery platform.
- •Nanoparticles have been widely studied for siRNA delivery.
- •siRNAs have great potential in drug-resistant HER2-positive breast cancer.
Abstract
This Review discusses the various types of non-coding oligonucleotides, which have
garnered extensive interest as new alternatives for targeted cancer therapies over
small molecule inhibitors and monoclonal antibodies. These oligonucleotides can target
any hallmark of cancer, no longer limited to so-called “druggable” targets. Thus,
any identified gene that plays a key role in cancer progression or drug resistance
can be exploited with oligonucleotides. Among them, small-interfering RNAs (siRNAs)
are frequently utilized for gene silencing due to the robust and well established
mechanism of RNA interference. Despite promising advantages, clinical translation
of siRNAs is hindered by the lack of effective delivery platforms. This Review provides
general criteria and consideration of nanoparticle development for systemic siRNA
delivery. Different classes of nanoparticle candidates for siRNA delivery are discussed,
and the progress in clinical trials for systemic cancer treatment is reviewed. Lastly,
this Review presents HER2 (human epidermal growth factor receptor type 2)-positive
breast cancer as one example that could benefit significantly from siRNA technology.
How siRNA-based therapeutics can overcome cancer resistance to such therapies is discussed.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
ESMO Member Login
Login with your ESMO username and password.
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Cancer Treatment ReviewsPurchase one-time access:
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Hallmarks of cancer: The next generation.Cell. 2011; 144: 646-674
- Comprehensive molecular portraits of human breast tumours.. 2012; 490: 61-70
- Illuminating the silence: understanding the structure and function of small RNAs.Nat Rev Mol Cell Biol. 2007; 8: 23-36
- RNA-based therapeutics – current progress and future prospects.Chem Biol. 2012; 19: 60-71
- Challenging the future of siRNA therapeutics against cancer: the crucial role of nanotechnology.Cell Mol Life Sci. 2014; 71: 1417-1438
- A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity.Nucleic Acids Res. 2009; 37: 2867-2881
- MicroRNA: function, detection, and bioanalysis.Chem Rev. 2013; 113: 6207-6233
- MicroRNAs as oncogenes and tumor suppressors.Develop Biol. 2007; 302: 1-12
- Systemic delivery of a miR34a mimic as a potential therapeutic for liver cancer.Mol Cancer Ther. 2014; 13: 2352-2360
- Phosphorothioate oligodeoxynucleotides: what is their origin and what is unique about them?.Antisense Nucleic Acid Drug Dev. 2000; 10: 117-121
- In vivo fate of phosphorothioate antisense oligodeoxynucleotides: predominant uptake by scavenger receptors on endothelial liver cells.Nucleic Acids Res. 1997; 25: 3290-3296
- RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform.Annu Rev Pharmacol Toxicol. 2010; 50: 259-293
- Oblimersen sodium (genasense bcl-2 antisense oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung cancer.Clin Cancer Res. 2004; 10: 4245s-4248s
- Lessons learnt from Genasense’s failure.Nat Rev Drug Discov. 2004; 3: 542
Inman S. Custirsen combination misses goal in phase III mCRPC trial. OncLive. Plainsboro, NJ; 2014.
- Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target.Nat Med. 2005; 11: 623-629
- Generation 2.5 antisense oligonucleotides targeting the androgen receptor and its splice variants suppress enzalutamide resistant prostate cancer cell growth.Clin Cancer Res. 2015;
- Abstract LB-227: preclinical pharmacology and clinical efficacy of AZD9150 (ISIS-STAT3Rx), a potent next-generation antisense oligonucleotide inhibitor of STAT3.Cancer Res. 2014; 74: LB-227
- A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors.Mol Cancer Ther. 2005; 4: 948-955
- An open-label, phase 2 trial of RPI.4610 (Angiozyme) in the treatment of metastatic breast cancer.Cancer. 2012; 118: 4098-4104
- Antisense, RNAi, and gene silencing strategies for therapy: mission possible or impossible?.Drug Discovery Today. 2008; 13: 513-521
- A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma.Invest New Drugs. 2014; 32: 178-187
- Stability study of unmodified siRNA and relevance to clinical use.Oligonucleotides. 2008; 18: 345-354
- A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity.Nucleic Acids Res. 2009;
- Silencing efficacy prediction: a retrospective study on target mRNA features.Biosci Rep. 2015; 35: e00185
- Gene therapy progress and prospects: development of improved lentiviral and retroviral vectors–design, biosafety, and production.Gene Ther. 2005; 12: 1089-1098
- Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment.ACS Nano. 2013; 7: 9571-9584
- Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors.Nat Biotechnol. 2005; 23: 709-717
- Understanding biophysicochemical interactions at the nano-bio interface.Nat Mater. 2009; 8: 543-557
- Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution.Mol Pharm. 2008; 5: 487-495
- PEGylated nanoparticles for biological and pharmaceutical applications.Adv Drug Deliv Rev. 2003; 55: 403-419
- Stealth properties to improve therapeutic efficacy of drug nanocarriers.J Drug Deliv. 2013; 2013: 19
- In vivo toxicity of cationic micelles and liposomes.Nanomed Nanotechnol Biol Med. 2015; 11: 467-477
- In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis.Biomaterials. 2003; 24: 1121-1131
- Cationic and PEGylated amphiphilic cyclodextrins: co-formulation opportunities for neuronal sirna delivery.PLoS ONE. 2013; 8: e66413
- Cationic polymer modified mesoporous silica nanoparticles for targeted siRNA delivery to HER2+ breast cancer.Adv Funct Mater. 2015; 25: 2646-2659
- A cell-penetrating helical polymer for siRNA delivery to mammalian cells.Mol Ther. 2012; 20: 1599-1609
- Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review.J Control Release. 2000; 65: 271-284
- Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology.Adv Drug Deliv Rev. 2014; 66: 2-25
- Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes.Clin Cancer Res. 2001; 7: 243-254
- Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.Nature. 2010; 464: 1067-1070
- First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement.Cancer Discov. 2013; 3: 406-417
- Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology.Cancer Res. 2013; 73: 2412-2417
- Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges.Int J Nanomed. 2015; 10: 1399-1414
- Tumor-targeted delivery of siRNA by self-assembled nanoparticles.Mol Ther. 2007; 16: 163-169
- Comparison of the endocytic properties of linear and branched PEIs, and cationic PAMAM dendrimers in B16f10 melanoma cells.J Control Release. 2007; 117: 291-300
- Targeting of drugs and nanoparticles to tumors.J Cell Biol. 2010; 188: 759-768
- Tissue-penetrating delivery of compounds and nanoparticles into tumors.Cancer Cell. 2009; 16: 510-520
- Breaking down the barriers: siRNA delivery and endosome escape.J Cell Sci. 2010; 123: 1183-1189
- Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection.Biochemistry. 1996; 35: 5616-5623
- Advances in lipid nanoparticles for siRNA delivery.Pharmaceutics. 2013; 5: 498-507
- Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics.J Control Release. 2015; 203: 1-15
- The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic.Mol Pharm. 2009; 6: 659-668
- Polymeric carrier systems for siRNA delivery.Curr Top Med Chem. 2012; 12: 108-119
- Superparamagnetic nanoparticle clusters for cancer theranostics combining magnetic resonance imaging and hyperthermia treatment.Theranostics. 2013; 3: 366-376
- Quantum dots versus organic dyes as fluorescent labels.Nat Methods. 2008; 5: 763-775
- The optical, photothermal, and facile surface chemical properties of gold and silver nanoparticles in biodiagnostics, therapy, and drug delivery.Arch Toxicol. 2014; 88: 1391-1417
- Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis.Biomaterials. 2015; 66: 41-52
- Gold nanoparticles: recent advances in the biomedical applications.Cell Biochem Biophys. 2015;
- Biodegradable and renal clearable inorganic nanoparticles.Adv Sci. 2016; 3
- Biodegradable calcium phosphate nanoparticle with lipid coating for systemic siRNA delivery.J Control Release. 2010; 142: 416-421
- Mesoporous silica nanoparticle nanocarriers: biofunctionality and biocompatibility.Acc Chem Res. 2013; 46: 792-801
- The effect of surface charge on the uptake and biological function of mesoporous silica nanoparticles in 3T3-L1 cells and human mesenchymal stem cells.Biomaterials. 2007; 28: 2959-2966
- Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe.Sci Transl Med. 2014; 6: 260ra149
- Cyclodextrin and polyethylenimine functionalized mesoporous silica nanoparticles for delivery of siRNA cancer therapeutics.Theranostics. 2014; 4: 487-497
- Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous silica nanoparticles for efficient siRNA delivery in vitro and in vivo.Nanoscale. 2013; 5: 4291-4301
- Codelivery of an optimal drug/siRNA combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo.ACS Nano. 2013; 7: 994-1005
- Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors.Biomaterials. 2008; 29: 487-496
- An RGD-modified MRI-visible polymeric vector for targeted siRNA delivery to hepatocellular carcinoma in nude mice.PLoS ONE. 2013; 8: e66416
- Nanoparticle delivery of pooled siRNA for effective treatment of non-small cell lung caner.Mol Pharm. 2012; 9: 2280-2289
- Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma.Sci Transl Med. 2013; 5
- Understanding the toxicity of carbon nanotubes.Acc Chem Res. 2013; 46: 702-713
- Antitumor activity and prolonged survival by carbon-nanotube-mediated therapeutic siRNA silencing in a human lung xenograft model.Small. 2009; 5 (Weinheim an der Bergstrasse, Germany): 1176-1185
- Mitochondrial toxicity of cadmium telluride quantum dot nanoparticles in mammalian hepatocytes.Toxicol Sci. 2015; 146: 31-42
- In vivo toxicity assessment of non-cadmium quantum dots in BALB/c mice.Nanomedicine. 2015; 11: 341-350
- SiRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury.J Am Soc Nephrol. 2009; 20: 1754-1764
- Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA.Proc Natl Acad Sci. 2014; 111: 11449-11454
- Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane.Proc Natl Acad Sci. 2012; 109: 3137-3142
- Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression.Cancer Res. 2008; 68: 9788-9798
- First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors.J Clin Oncol. 2014; 32: 4141-4148
- A phase I dose escalation study of TKM-080301, a RNAi therapeutic directed against PLK1, in patients with advanced solid tumors.in: AACR 104th annual meeting. 2013 (Washington, DC)
- Knockdown of [beta]-catenin with dicer-substrate siRNAs reduces liver tumor burden in vivo.Mol Ther. 2014; 22: 92-101
- Safety and activity of DCR-MYC, a first-in-class Dicer-substrate small interfering RNA (DsiRNA) targeting MYC, in a phase I study in patients with advanced solid tumors.in: ASCO annual meeting 2015. 2015
- Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery.Cancer Res. 2005; 65: 6910-6918
- Clinical experiences with systemically administered siRNA-based therapeutics in cancer.Nat Rev Drug Discov. 2015; 14: 843-856
- Cancer facts & figures 2015.American Cancer Society, Atlanta2015
- Correlation of HER2 overexpression with gene amplification and its relation to chromosome 17 aneuploidy: a 5-year experience with invasive ductal and lobular carcinomas.Int J Clin Exp Pathol. 2014; 7: 6254-6261
- Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer.J Natl Cancer Inst. 2014; 106
- Handbook of HER2-targeted agents in breast cancer.Springer Healthcare Communications, London, UK2013
- Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2–positive breast cancer.J Clin Oncol. 2009; 27: 5838-5847
Gu S, Hu Z, Ngamcherdtrakul W, Castro DJ, Morry J, Reda MM, et al. Therapeutic siRNA for drug-resistant HER2-positive breast cancer. Oncotarget, in press. http://dx.doi.org/10.18632/oncotarget.740. http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=7409.
- Polymalic acid-based nanobiopolymer provides efficient systemic breast cancer treatment by inhibiting both HER2/neu receptor synthesis and activity.Cancer Res. 2011; 71: 1454-1464
- Targeting polo-like kinase in cancer therapy.Clin Cancer Res. 2010; 16: 384-389
- Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis.Sci Transl Med. 2012; 4: 130ra48
- ScFv-decorated PEG-PLA-based nanoparticles for enhanced siRNA delivery to Her2(+) breast cancer.Adv Health Mater. 2014; 3: 1792-1803
- Influence of geometry, porosity, and surface characteristics of silica nanoparticles on acute toxicity: their vasculature effect and tolerance threshold.ACS Nano. 2012; 6: 2289-2301
- In vivo bio-safety evaluations and diagnostic/therapeutic applications of chemically designed mesoporous silica nanoparticles.Adv Mater. 2013; 25: 3144-3176
- Biocompatibility of mesoporous silica nanoparticles?.Comments Inorg Chem. 2016; 36: 61-80
- The effect of PEGylation of mesoporous silica nanoparticles on nonspecific binding of serum proteins and cellular responses.Biomaterials. 2010; 31: 1085-1092
- Engineered nonviral nanocarriers for intracellular gene delivery applications.Biomed Mater. 2012; 7 (054106)
Article Info
Publication History
Published online: February 21, 2016
Accepted:
February 15,
2016
Received in revised form:
February 13,
2016
Received:
December 10,
2015
Identification
Copyright
© 2016 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
