title: One-pot synthesis of pH-responsive hybrid nanogel particles for the intracellular delivery of small interfering RNA.
abstract: This report describes a novel, one-pot synthesis of hybrid nanoparticles formed by a nanostructured inorganic silica core and an organic pH-responsive hydrogel shell. This easy-to-perform, oil-in-water emulsion process synthesizes fluorescently-doped silica nanoparticles wrapped within a tunable coating of cationic poly(2-diethylaminoethyl methacrylate) hydrogel in one step. Transmission electron microscopy and dynamic light scattering analysis demonstrated that the hydrogel-coated nanoparticles are uniformly dispersed in the aqueous phase. The formation of covalent chemical bonds between the silica and the polymer increases the stability of the organic phase around the inorganic core as demonstrated by thermogravimetric analysis. The cationic nature of the hydrogel is responsible for the pH buffering properties of the nanostructured system and was evaluated by titration experiments. Zeta-potential analysis demonstrated that the charge of the system was reversed when transitioned from acidic to basic pH and vice versa. Consequently, small interfering RNA (siRNA) can be loaded and released in an acidic pH environment thereby enabling the hybrid particles and their payload to avoid endosomal sequestration and enzymatic degradation. These nanoparticles, loaded with specific siRNA molecules directed towards the transcript of the membrane receptor CXCR4, significantly decreased the expression of this protein in a human breast cancer cell line (i.e., MDA-MB-231). Moreover, intravenous administration of siRNA-loaded nanoparticles demonstrated a preferential accumulation at the tumor site that resulted in a reduction of CXCR4 expression.
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.
authors.forename: Sm Z
authors.initials: SZ
authors.lastname: Khaled
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.|Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, 80131 Italy.|CEINGE-Biotecnologie Avanzate, s.c.a r.l., Naples, 80145 Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Cevenini
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.|Department of Biomedical Engineering, University of Houston, Houston, Texas, 77204 United States.
authors.forename: Iman K
authors.initials: IK
authors.lastname: Yazdi
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.|Fondazione SDN IRCCS, Naples, 80143 Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Parodi
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Evangelopoulos
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.|Fondazione SDN IRCCS, Naples, 80143 Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Corbo
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Scaria
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.
authors.forename: Ye
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.
authors.forename: Seth G
authors.initials: SG
authors.lastname: Haddix
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.|Department of Life and Environmental Sciences, Università Politecnica delle Marche, Ancona, 60131 Italy.
authors.forename: Bruna
authors.initials: B
authors.lastname: Corradetti
authors.affiliation: CEINGE-Biotecnologie Avanzate, s.c.a r.l., Naples, 80145 Italy.|Fondazione SDN IRCCS, Naples, 80143 Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
authors.affiliation: Department of Regenerative Medicine: Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston, Texas, 77030 United States.
authors.forename: Ennio
authors.initials: E
authors.lastname: Tasciotti
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005260:Female; D006801:Humans; D008689:Methacrylates / Q000737:chemistry; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D000067492:RNAi Therapeutics; D019718:Receptors, CXCR4 / Q000235:genetics; D012822:Silicon Dioxide / Q000737:chemistry
chemical_list: C527276:CXCR4 protein, human; D002412:Cations; D003692:Delayed-Action Preparations; D008689:Methacrylates; D011108:Polymers; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D012822:Silicon Dioxide; C519537:diethylaminoethyl methacrylate
keywords: Cancer therapy; Lysosomal escape; Nanoparticles; pH-responsive polymer; siRNA delivery