Tumor-targeted pH/redox dual-sensitive unimolecular nanoparticles for efficient siRNA delivery.
A unique pH/redox dual-sensitive cationic unimolecular nanoparticle (NP) enabling excellent endosomal/lysosomal escape and efficient siRNA decomplexation inside the target cells was developed for tumor-targeted delivery of siRNA. siRNA was complexed into the cationic core of the unimolecular NP through electrostatic interactions. The cationic core used for complexing siRNA contained reducible disulfide bonds that underwent intracellular reduction owing to the presence of high concentrations of reduced glutathione (GSH) inside the cells, thereby facilitating the decomplexation of siRNA from the unimolecular NPs. The cationic polymers were conjugated onto the hyperbranched core (H40) via a pH-sensitive bond, which further facilitated the decomplexation of siRNA from the NPs. In vitro studies on the siRNA release behaviors showed that dual stimuli (pH=5.3, 10mM GSH) induced the quickest release of siRNA from the NPs. In addition, the imidazole groups attached to the cationic polymer segments enhanced the endosomal/lysosomal escape of NPs via the proton sponge effect. Intracellular tracking studies revealed that siRNA delivered by unimolecular NPs was efficiently released to the cytosol. Moreover, the GE11 peptide, an anti-EGFR peptide, enhanced the cellular uptake of NPs in MDA-MB-468, an EFGR-overexpressing triple negative breast cancer (TNBC) cell line. The GE11-conjugated, GFP-siRNA-complexed NPs exhibited excellent GFP gene silencing efficiency in GFP-MDA-MB-468 TNBC cells without any significant cytotoxicity. Therefore, these studies suggest that this smart unimolecular NP could be a promising nanoplatform for targeted siRNA delivery to EFGR-overexpressing cancer cells.
Department of Materials Science and Engineering, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Guojun
G
Chen
Department of Materials Science and Engineering, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Yuyuan
Y
Wang
Department of Materials Science and Engineering, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Ruosen
R
Xie
Department of Materials Science and Engineering, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Electronic address: shaoqingong@wisc.edu.
Shaoqin
S
Gong
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010084:Oxidation-Reduction; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism
C572557:GE11 peptide; D010455:Peptides; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors
Endosomal/lysosomal escape; Tumor-targeted; Unimolecular NP; pH/redox dual-sensitive; siRNA delivery