Association of hydrophobically and electrostatically modified poly(ethylene glycol) with liposomes.

摘要

Liposomes are spheres made of lipid bilayers, enclosing aqueous volumes. The advantage of liposomal delivery is that it separates the functions required for drug delivery and allows more flexibility than alternate strategies. The adsorption of two types of polymers is demonstrated: comb-graft copolymers, where a PEG chain and anchor is repeated, and single-tailed polymers, where multiple binding sites occur in series followed by a PEG chain. HMPEGs are comb-graft copolymers with strictly alternating monodisperse PEG blocks (6, 12, or 35 kDa) bonded to C18 stearylamide hydrophobes. Cooperativity of HMPEGs is varied by (1) changing the degree of oligomerization at a constant overall ratio of PEG to anchor and (2) increasing the molecular weight of PEG at a constant degree of oligomerization. EMPEGs are single-tailed polymers, with PEG covalently bound to either polylysine or poly[2-(dimethylamino)ethyl methacrylate]. The architecture of these polymers is varied by increasing (1) the molecular weight of PEG and (2) the number of cationic charges. In addition, an electrostatic analog to the HMPEG, a strictly alternating PEG-amine copolymer with 15 repeating units of a 2 kDa PEG block bonded to a tertiary amine, is investigated.; The research focuses on the architecture-dependent adsorption of HMPEG polymers and their ability to protect against complement protein binding. Complement protein binding correlates with in vivo immune response. The surface rheology is measured, where the loss modulus vs. frequency data describes increasing viscous forces with HMPEGs anchored to a DPPC monolayer at the air/water interface. We also observe changes in the electrophoretic mobility of negatively-charged liposomes with increasing salt concentration and increasing polymer mass adsorbed.; Polymer protection evades the immune system but hinders delivery to the cell's cytoplasm. We demonstrate the triggered release of PEG-b-polycation copolymers by using the pH change from the bloodstream (pH 7.4) to the endosome (pH 5--6). Evidence of a pH sensitive PC:DAP (9:1, mol:mol) liposome shows that it is neutral at pH 7.4 and becomes positively charged at pH 5.5, repelling the polycation anchor. This delivery system enables gene delivery to cells.