Current development of targeted oligonucleotide-based cancer therapies: Perspective on HER2-positive breast cancer treatment

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.

Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles

“…Nanoparticles are also widely studied as delivery platforms for genes, oligonucleotides, drugs, and imaging agents, providing numerous opportunities in developing theranostic agents or co-delivering synergistic therapeutic agents within the same nanoparticle. For instance, we have recently reviewed different classes of nanoparticle candidates for siRNA delivery and the progress in clinical trials for systemic cancer treatment [179]. Nanoparticles are typically viewed as merely passive delivery carriers.…”

Targeted Treatment of Metastatic Breast Cancer by PLK1 siRNA Delivered by an Antioxidant Nanoparticle Platform

“…There is no effective treatment for metastatic cancer so far, current treatment focuses on slowing disease progression and maintaining the quality of life. Targeted delivery of siRNAs by nanoparticles holds great promise for cancer treatment since siRNA can target any gene deemed important to cancer progression, metastasis, and drug resistance with high specificity (3). To that end, we have recently developed and optimized a polymer-coated mesoporous silica nanoparticles (NP) for siRNA delivery to treat trastuzumab-resistant HER2+ breast tumors (4).…”

Follicle-stimulating hormone peptide-conjugated nanoparticles for targeted shRNA delivery lead to effective gro-α silencing and antitumor activity against ovarian cancer

“…Nanoparticles, such as polymer- and lipid-based carriers, have been widely used to deliver RNAi drugs to improve the stability, circulation time, and cell uptake (Debus et al., 2010 ; Ngamcherdtrakul et al., 2016 ; Young et al., 2016 ; Shi et al., 2017 ). Cationic polymers, such as PEI, are able to strongly condense negatively charged DNA plasmids through electrostatic interactions, leading to high transfection efficiency levels, as well as high toxicity (de Wolf et al., 2007 ; Sun & Zhang, 2010 ; Ngamcherdtrakul et al., 2016 ; Kaczmarek et al., 2017 ). Thus, PEI as an RNAi drug carrier is often combined with PEG-based polymers because as a neutral and biocompatible polymer, PEG can shield the positive charge on the surface of PEI and improve colloidal stability and blood compatibility (Smith et al., 2015 ; Ngamcherdtrakul et al., 2016 ).…”

“…Cationic polymers, such as PEI, are able to strongly condense negatively charged DNA plasmids through electrostatic interactions, leading to high transfection efficiency levels, as well as high toxicity (de Wolf et al., 2007 ; Sun & Zhang, 2010 ; Ngamcherdtrakul et al., 2016 ; Kaczmarek et al., 2017 ). Thus, PEI as an RNAi drug carrier is often combined with PEG-based polymers because as a neutral and biocompatible polymer, PEG can shield the positive charge on the surface of PEI and improve colloidal stability and blood compatibility (Smith et al., 2015 ; Ngamcherdtrakul et al., 2016 ). The amount of PEG grafting and the PEG chain length are related to the ability of PEG to reduce the toxicity of PEI (Park et al., 2005 ; Zhang et al., 2008 ; Smith et al., 2015 ).…”