'SMART' Drug Delivery Systems:Double-Targeted pH-Responsive Pharmaceutical Nanocarriers

摘要

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-phosphati-dylethanolamine (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 PEG2000-PE or PEG5000-PE) or by even longer pNP-PEG-PE moieties used to attach antibodies to the nanocarrier (non-pH-degradable PEG3400-PE or PEG5000-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.