title: Receptor-Mediated Surface Charge Inversion Platform Based on Porous Silicon Nanoparticles for Efficient Cancer Cell Recognition and Combination Therapy.
abstract: Negatively charged surface-modified drug delivery systems are promising for in vivo applications as they have more tendency to accumulate in tumor tissues. However, the inefficient cell uptake of these systems restricts their final therapeutic performance. Here, we have fabricated a receptor-mediated surface charge inversion nanoparticle made of undecylenic acid modified, thermally hydrocarbonized porous silicon (UnTHCPSi) nanoparticles core and sequentially modified with polyethylenimine (PEI), methotrexate (MTX), and DNA aptamer AS1411 (herein termed as UnTHCPSi-PEI-MTX@AS1411) for enhancing the cell uptake of nucleolin-positive cells. The efficient interaction of AS1411 and the relevant receptor nucleolin caused the disintegration of the negative-charged AS1411 surface. The subsequent surface charge inversion and exposure of the active targeting ligand, MTX, enhanced the cell uptake of the nanoparticles. On the basis of this synergistic effect, the UnTHCPSi-PEI-MTX@AS1411 (hydrodynamic diameter is 242 nm) were efficiently internalized by nucleolin-positive MDA-MB-231 breast cancer cells, with an efficiency around 5.8 times higher than that of nucleolin-negative cells (NIH 3T3 fibroblasts). The receptor competition assay demonstrated that the major mechanism (more than one-half) of the internalized nanoparticles in MDA-MB-231 cells was due to the receptor-mediated surface charge inversion process. Finally, after loading of sorafenib, the nanosystem showed efficient performance for combination therapy with an inhibition ratio of 35.6%.
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki , Helsinki FI-00014, Finland.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki , Helsinki FI-00014, Finland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Correia
authors.affiliation: Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku , Turku FI-20014, Finland.
authors.forename: Ermei
authors.identifier: http://orcid.org/0000-0002-8300-6533
authors.initials: E
authors.lastname: Mäkilä
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki , Helsinki FI-00014, Finland.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Laboratory of Industrial Physics, Department of Physics and Astronomy, University of Turku , Turku FI-20014, Finland.
authors.forename: Jarno
authors.identifier: http://orcid.org/0000-0002-5245-742X
authors.initials: J
authors.lastname: Salonen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki , Helsinki FI-00014, Finland.
authors.forename: Jouni J
authors.initials: JJ
authors.lastname: Hirvonen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki , Helsinki FI-00014, Finland.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Faculty of Pharmacy, University of Helsinki , Helsinki FI-00014, Finland.
authors.forename: Hélder A
authors.identifier: http://orcid.org/0000-0001-7850-6309
authors.initials: HA
authors.lastname: Santos
mesh_terms: D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D053758:Nanoparticles; D016062:Porosity; D012825:Silicon
chemical_list: D012825:Silicon
keywords: combination therapy; drug delivery; selective cell recognition; surface charge inversion; targeting