Unprotonatable and ROS‐Sensitive Nanocarrier for NIR Spatially Activated siRNA Therapy with Synergistic Drug Effect

Abstract

Although small interfering RNA (siRNA) therapy has achieved great progress, unwanted gene inhibition in normal tissues severely limits its extensive clinical applications due to uncontrolled siRNA biodistribution. Herein, a spatially controlled siRNA activation strategy is developed to achieve tumor‐specific siRNA therapy without gene inhibition in the normal tissues. The quaternary ammonium moieties are conjugated to amphiphilic copolymers via reactive oxygen species (ROS)‐sensitive thioketal (TK) linkers for co‐delivery of siRNA and photosensitizer chlorin e6 (Ce6), showing excellent siRNA complexation capacity and near infrared (NIR)‐controlled siRNA release. In the normal tissue, siRNAs are trapped and degraded in the endo‐lysosomes due to the unprotonatable property of quaternary ammonium moiety, showing the siRNA activity “off” state. When NIR irradiation is spatially applied to the tumor tissue, the NIR irradiation/Ce6‐induced ROS trigger siRNA endo‐lysosomal escape and cytosolic release through the photochemical internalization effect and cleavage of TK bonds, respectively, showing the siRNA activity “on” state. The siRNA‐mediated glutathione peroxidase 4 gene inhibition enhances ROS accumulation. The synergistic antitumor activity of Ce6 photodynamic therapy and gene inhibition is confirmed in vivo. Spatially controlled tumor‐specific siRNA activation and co‐delivery with Ce6 using unprotonatable and ROS‐sensitive cationic nanocarriers provide a feasible strategy for tumor‐specific siRNA therapy with synergistic drug effects.

Combinational Gene Therapy toward Cancer with Nanoplatform: Strategies and Principles

“…As shown in Figure C, a pronounced decrease of VEGF and fewer tumor foci were seen in the Au-siRNA-PAA-AS1411 group, which was treated with a combination of tumor-responsive genetic therapy, chemotherapy, and photothermal treatment. By designing the ROS-responsive materials, NIR spatially activated siRNA therapy can be achieved to treat tumor sites with PDT therapy . In normal tissue, siRNA molecules cannot function due to being trapped and broken down in endolysosomes.…”

Nanoarchitectures to Deliver Nucleic Acid Drugs to Disease Sites

“…By encapsulaing appropriate photo-sensitizer (e. g., Ce6) in nanocomposites, highly toxic singlet oxygen ( 1 O 2 ) is produced by NIR irradiation, and cooperates with siRNA for still more efficient therapy. [120,121] Alternatively, prodrugs encapsulated in nanocomposites can be converted to pharmacologically active species by the longer wavelength light from upconversion nanoparticles (e. g., reduction of Pt IV to Pt II for cancer therapy), and cooperate with siRNA for therapy. [122] In another example, [123] NIR light was directly employed for simultaneous release of both siRNA and antisense oligonucleotide analog (peptide nucleic acid which has a polypeptide backbone [124] ) in target cell.…”

“…Use of upconversion nanoparticles for photo‐induced release of siRNA provides other advantages. By encapsulaing appropriate photo‐sensitizer (e. g., Ce6) in nanocomposites, highly toxic singlet oxygen ( 1 O 2 ) is produced by NIR irradiation, and cooperates with siRNA for still more efficient therapy [120,121] . Alternatively, prodrugs encapsulated in nanocomposites can be converted to pharmacologically active species by the longer wavelength light from upconversion nanoparticles (e. g., reduction of Pt IV to Pt II for cancer therapy), and cooperate with siRNA for therapy [122] …”

Recent Advances in Nanoparticle-Mediated Co-Delivery System: A Promising Strategy in Medical and Agricultural Field

“…Multiple nanoparticles (NPs) have been designed and evaluated as carriers to deliver small molecule drugs for medical or agriculture field, including polymeric NPs, lipid NPs and other inorganic NPs [ 18 , 19 ]. In addition, NPs can deliver various nucleic acid molecules, proteins or photosensitizers, which have been extensively investigated [ 20 , 21 , 22 ].…”