title: Triblock Copolymer Nanovesicles for pH-Responsive Targeted Delivery and Controlled Release of siRNA to Cancer Cells.
abstract: New pH-responsive polymersomes for active anticancer oligonucleotide delivery were prepared from triblock copolymers. The delivery systems were formed by two terminal hydrophilic blocks, PEG and polyglycerolmethacrylate (poly-GMA), and a central weakly basic block, polyimidazole-hexyl methacrylate (poly-ImHeMA), which can complex with oligonucleotides and control vesicle formation/disassembly via pH variations. Targeted polymersomes were prepared by mixing folate-derivatized and underivatized copolymers. At pH 5, ds-DNA was found to complex with the pH-responsive copolymers at a N/P molar ratio above ∼2:1, which assisted the encapsulation of ds-DNA in the polymersomes, while low association was observed at pH 7.4. Cytotoxicity studies performed on folate receptor overexpressing KB and B16-F10 cells and low folate receptor expressing MCF-7 cells showed high tolerance of the polymersomes at up to 3 mg/mL concentration. Studies performed with red blood cells showed that at pH 5.0 the polymersomes have endosomolytic properties. Cytofluorimetric studies showed a 5.5-fold higher uptake of ds-DNA loaded folate-functional polymersomes in KB cells compared to nontargeted polymersomes. In addition, ds-DNA was found to be localized both in the nucleus and in the cytosol. The incubation of luciferase transfected B16-F10 cells with targeted polymersomes loaded with luciferase and Hsp90 expression silencing siRNAs yielded 31 and 23% knockdown in target protein expression, respectively.
authors.affiliation: †Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131, Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gallon
authors.affiliation: ‡School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Matini
authors.affiliation: ‡School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.
authors.forename: Luana
authors.initials: L
authors.lastname: Sasso
authors.affiliation: ‡School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mantovani
authors.affiliation: §Centro de Investigation Principe Felipe (CIPF), Polymer Therapeutics Laboratory, Av. Eduardo Primo Yúfera 3, E-46012, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Armiñan de Benito
authors.affiliation: §Centro de Investigation Principe Felipe (CIPF), Polymer Therapeutics Laboratory, Av. Eduardo Primo Yúfera 3, E-46012, Valencia, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Sanchis
authors.affiliation: †Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131, Padova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Caliceti
authors.affiliation: ‡School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.
authors.forename: Cameron
authors.initials: C
authors.lastname: Alexander
authors.affiliation: §Centro de Investigation Principe Felipe (CIPF), Polymer Therapeutics Laboratory, Av. Eduardo Primo Yúfera 3, E-46012, Valencia, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Vicent
authors.affiliation: †Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131, Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Salmaso
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000235:genetics*; D003600:Cytosol / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007624:KB Cells; D061986:MCF-7 Cells; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D058973:Folate Receptors, GPI-Anchored; D008689:Methacrylates; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols