title: "SMART" drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriers.
abstract: To develop targeted pharmaceutical carriers additionally capable of responding to certain local stimuli, such as decreased pH values in tumors or infarcts, targeted long-circulating PEGylated liposomes and PEG-phosphatidylethanolamine (PEG-PE)-based micelles have been prepared with several functions. First, they are capable of targeting a specific cell or organ by attaching the monoclonal antimyosin antibody 2G4 to their surface via pNP-PEG-PE moieties. Second, these liposomes and micelles were additionally modified with biotin or TAT peptide (TATp) moieties attached to the surface of the nanocarrier by using biotin-PE or TATp-PE or TATp-short PEG-PE derivatives. PEG-PE used for liposome surface modification or for micelle preparation was made degradable by inserting the pH-sensitive hydrazone bond between PEG and PE (PEG-Hz-PE). Under normal pH values, biotin and TATp functions on the surface of nanocarriers were "shielded" by long protecting PEG chains (pH-degradable PEG(2000)-PE or PEG(5000)-PE) or by even longer pNP-PEG-PE moieties used to attach antibodies to the nanocarrier (non-pH-degradable PEG(3400)-PE or PEG(5000)-PE). At pH 7.4-8.0, both liposomes and micelles demonstrated high specific binding with 2G4 antibody substrate, myosin, but very limited binding on an avidin column (biotin-containing nanocarriers) or internalization by NIH/3T3 or U-87 cells (TATp-containing nanocarriers). However, upon brief incubation (15-30 min) at lower pH values (pH 5.0-6.0), nanocarriers lost their protective PEG shell because of acidic hydrolysis of PEG-Hz-PE and acquired the ability to become strongly retained on an avidin column (biotin-containing nanocarriers) or effectively internalized by cells via TATp moieties (TATp-containing nanocarriers). We consider this result as the first step in the development of multifunctional stimuli-sensitive pharmaceutical nanocarriers.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Sawant
authors.forename: J P
authors.initials: JP
authors.lastname: Hurley
authors.forename: S
authors.initials: S
authors.lastname: Salmaso
authors.forename: A
authors.initials: A
authors.lastname: Kale
authors.forename: E
authors.initials: E
authors.lastname: Tolcheva
authors.forename: T S
authors.initials: TS
authors.lastname: Levchenko
authors.forename: V P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D004337:Drug Carriers; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D053758:Nanoparticles; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D008823:Micelles; D010714:Phosphatidylethanolamines; C483858:phosphatidylethanolamine; D011092:Polyethylene Glycols