High Capacity Nanoporous Silicon Carrier for Systemic Delivery of Gene Silencing Therapeutics

Abstract

Gene silencing agents such as small interfering RNA (siRNA) and microRNA offer the promise to modulate expression of almost every gene for the treatment of human diseases including cancer. However, lack of vehicles for effective systemic delivery to the disease organs has greatly limited their in vivo applications. In this study, we developed a high capacity polycation-functionalized nanoporous silicon (PCPS) platform comprised of nanoporous silicon microparticles functionalized with arginine-polyethyleneimine inside the nanopores for effective delivery of gene silencing agents. Incubation of MDA-MB-231 human breast cancer cells with PCPS loaded with STAT3 siRNA (PCPS/STAT3) or GRP78 siRNA (PCPS/GRP78) resulted in 91% and 83% reduction of STAT3 and GRP78 gene expression in vitro. Treatment of cells with a microRNA-18a mimic in PCPS (PCPS/miR-18) knocked down 90% expression of the microRNA-18a target gene ATM. Systemic delivery of PCPS/STAT3 siRNA in murine model of MDA-MB-231 breast cancer enriched particles in tumor tissues and reduced STAT3 expression in cancer cells, causing significant reduction of cancer stem cells in the residual tumor tissue. At the therapeutic dosage, PCPS/STAT3 siRNA did not trigger acute immune response in FVB mice, including changes in serum cytokines, chemokines and colony-stimulating factors. In addition, weekly dosing of PCPS/STAT3 siRNA for four weeks did not cause signs of sub-acute toxicity based on changes in body weight, hematology, blood chemistry, and major organ histology. Collectively, the results suggest that we have developed a safe vehicle for effective delivery of gene silencing agents.

Polyethylene glycol (PEG)-dendron phospholipids as innovative constructs for the preparation of super stealth liposomes for anticancer therapy

“…Indeed, nano-sized carriers have the potential to improve biopharmaceutical features, pharmacokinetic properties and the therapeutic efficacy of entrapped drugs [3]. A broad range of materials have been used for the fabrication of nanocarriers, including silicon and silica [4,5], lipids [6][7][8], polymers [9], surfactants [10,11], and metal [12]. Currently, there are several nanotherapeutics that are in clinical trials or have received approval, many of which are liposomal drugs [13,14].…”

Chitosan layered gold nanorods as synergistic therapeutics for photothermal ablation and gene silencing in triple-negative breast cancer

“…After a 6 and 8 h incubation period, some of the siRNA was present in the cytoplasm, suggesting that siRNA molecules had escaped from acidic organelles. The most probable mechanism for the observed lysosomal escape of siRNA is the proton sponge effect that can be triggered by polyamine moiety [11,12], which are present in the delivery vehicle.…”

“…In particular, it is important that nanodelivery systems can reduce uptake by the reticuloendothelial system (RES), enhance tumor accumulation through e.g. the enhanced permeability and retention (EPR) effect, and enhance endosomal/ lysosomal escape [9][10][11][12].…”

Nanobiotechnology for the Therapeutic Targeting of Cancer Cells in Blood

“…Moreover, by combining high capture efficiency of 3D nanotopographic features such as silicon nanowires with enhanced drug encapsulation for nanoporous materials, novel nanomedicines can possibly target a subpopulation of CTCs with CSC properties or multi-drug resistance. 67,113,128 In addition, since mouse models and clinical observations have provided evidence that CTC count correlates with disease progression in cancer patients, 28,65,154,160 it is intriguing that an implanted shunt system with similar nanostructure and surface functionalization could be utilized to filter out rare CTCs from the blood circulation. As a proof-of-concept, our group invented a biomimetic approach to capture and kill CTCs in vitro.…”