Bioengineered siRNA-Based Nanoplatforms Targeting Molecular Signaling Pathways for the Treatment of Triple Negative Breast Cancer: Preclinical and Clinical Advancements

Abstract

Triple negative breast cancer (TNBC) is one of the most aggressive types of breast cancer. Owing to the absenteeism of hormonal receptors expressed at the cancerous breast cells, hormonal therapies and other medications targeting human epidermal growth factor receptor 2 (HER2) are ineffective in TNBC patients, making traditional chemotherapeutic agents the only current appropriate regimen. Patients’ predisposition to relapse and metastasis, chemotherapeutics’ cytotoxicity and resistance and poor prognosis of TNBC necessitates researchers to investigate different novel-targeted therapeutics. The role of small interfering RNA (siRNA) in silencing the genes/proteins that are aberrantly overexpressed in carcinoma cells showed great potential as part of TNBC therapeutic regimen. However, targeting specificity, siRNA stability, and delivery efficiency cause challenges in the progression of this application clinically. Nanotechnology was highlighted as a promising approach for encapsulating and transporting siRNA with high efficiency-low toxicity profile. Advances in preclinical and clinical studies utilizing engineered siRNA-loaded nanotherapeutics for treatment of TNBC were discussed. Specific and selective targeting of diverse signaling molecules/pathways at the level of tumor proliferation and cell cycle, tumor invasion and metastasis, angiogenesis and tumor microenvironment, and chemotherapeutics’ resistance demonstrated greater activity via integration of siRNA-complexed nanoparticles.

Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs

“…As stromal components, extracellular matrices (ECMs) such as collagen fibers, and high interstitial pressure would restrict the diffusion of nanoparticles in tumor tissues; then, the use of digestive enzymes such as collagenase and hyaluronidase has been investigated to improve nanoparticle delivery and gene transfer efficiency [ 268 , 269 , 270 , 271 ]. For active targeting to tumor, several ligands such as arginine-glycine-aspartate (RGD) peptide [ 272 ], HER-2-targeting peptide [ 273 ] and hyaluronic acid [ 274 ] have been used for nanoparticle delivery, and are promising for delivery of nucleic acid and gene medicines [ 275 , 276 ]. Targeting tumor-associated macrophages (TAMs) in the tumor microenvironment is also a useful strategy to combat tumors [ 277 ].…”

Clinical Advances of siRNA-Based Nanotherapeutics for Cancer Treatment

“…Clinical application of siRNA-based nanotherapies in treating a wide variety of tumors poses numerous advantages; (1) siRNA nanotherapeutics can selectively and preferentially target any gene within the cancerous cells, especially the undruggable targets [17,18]; (2) they are readily fabricated and modified, in addition to having good safety and efficacy profiles with minimal off-target effects and immunogenicity [19,20]; (3) various siRNA therapeutics exhibited a promising antiproliferative and tumor growth suppression effect in vitro through the stat6 pathway and PLK1 [21,22], suppression of angiogenesis through inhibition of receptors including VEGFs and VEGFR-1 [23,24], or inhibition of tumor invasion and metastasis via chemokines CXCL8 and CXCL11 [25].…”

“…RNA interference (RNAi) is an innovative approach based on the delivery of noncoding double-stranded RNA (dsRNA) into cancer cells to trigger a homology-dependent degradation of the targeted messenger RNA (mRNA), leading to a selective and specific gene silencing [ 1 , 2 ]. The RNAi mechanism was first described by Fire and colleagues [ 3 ].…”

In Vitro Cellular Uptake and Transfection of Oligoarginine-Conjugated Glycol Chitosan/siRNA Nanoparticles

“…RNA interference (RNAi) is an innovative approach for selective and specific gene silencing and has demonstrated potential for the treatment of various diseases [ 1 , 2 , 3 , 4 , 5 ]. In this pathway, RNA-induced silencing complex (RISC), formed from double-stranded small interfering RNA (siRNA), degrades target mRNA and inhibits protein synthesis [ 6 , 7 ].…”