Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/116762
Title: pH-Controlled Liposomes for Enhanced Cell Penetration in Tumor Environment
Authors: Barattin, Michela 
Mattarei, Andrea 
Balasso, Anna
Paradisi, Cristina 
Cantù, Laura
Del Favero, Elena
Viitala, Tapani
Mastrotto, Francesca 
Caliceti, Paolo 
Salmaso, Stefano 
Keywords: cell penetration enhancers;controlled cell uptake;pH-responsive liposomes;sheddable liposome coating;site-selective drug delivery
Keywords Plus: PROTEIN TRANSDUCTION DOMAIN;IN-VITRO;CATIONIC LIPOSOMES;TAT PEPTIDE;GENE DELIVERY;DC-CHOL;NANOPARTICLES;MECHANISM;ARGININE;SYSTEM
Mesh headings: Liposomes
Secondary Mesh headings: Antineoplastic Agents;HeLa Cells;Humans;Hydrogen-Ion Concentration;Peptides
Issue Date: 30-May-2018
Publisher: AMER CHEMICAL SOC
Journal: ACS applied materials & interfaces 
Abstract: 
An innovative pH-switchable colloidal system that can be exploited for site-selective anticancer drug delivery has been generated by liposome decoration with a new novel synthetic non-peptidic oligo-arginine cell-penetration enhancer (CPE) and a quenching PEGylated counterpart that detaches from the vesicle surface under the acidic conditions of tumors. The CPE module ( Arg4- DAG) is formed by four arginine units conjugated to a first-generation (G1) 2,2-bis(hydroxymethyl)propionic acid (bis-MPA)/2,2-bis(aminomethyl)propionic acid (bis-AMPA) polyester dendron terminating with 1,2-distearoyl-3-azidopropane for liposome bilayer insertion. The zeta potential of the Arg4- DAG-decorated liposomes increased up to +32 mV as the Arg4- DAG/lipids molar ratio increased. The Arg4- DAG liposome shielding at pH 7.4 was provided by methoxy-PEG5 kDa-polymethacryloyl sulfadimethoxine (mPEG5 kDa-SDM8) with 7.1 apparent p Ka. Zeta potential, surface plasmon resonance and synchrotron small-angle X-ray scattering analyses showed that at pH 7.4 mPEG5 kDa-SDM8 associates with polycationic Arg4- DAG-decorated liposomes yielding liposomes with neutral zeta potential. At pH 6.5, which mimics the tumor environment, mPEG5 kDa-SDM8 detaches from the liposome surface yielding Arg4- DAG exposure. Flow cytometry and confocal microscopy showed a 30-fold higher HeLa cancer cell association of the Arg4- DAG-decorated liposomes compared to non-decorated liposomes. At pH 7.4, the mPEG5 kDa-SDM8-coated liposomes undergo low cell association while remarkable cell association occurred at pH 6.5, which allowed for the controlled intracellular delivery of model macromolecules and small molecules loaded in the liposome under tumor conditions.
URI: http://hdl.handle.net/20.500.12857/116762
ISSN: 19448244
DOI: 10.1021/acsami.8b03469
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