Liposomes with detachable polymer coating: destabilization and fusion of dioleoylphosphatidylethanolamine vesicles triggered by cleavage of surface‐grafted poly(ethylene glycol)

Abstract

Plasma-stable liposomes (100 nm) were prepared from dioleoylphosphatidylethanolamine (DOPE) and 3--6 tool% of a new disulfide-linked poly(ethylene glycol)-phospbolipid conjugate (mPEG-DTP-DSPE). In contrast to similar preparations containing non-cleavable PEG-phospholipid conjugate, thiolytic cleavage of the grafted polymer chains facilitated rapid and complete release of the liposome contents. Furthermore, the detachment of PEG from DOPE liposomes resulted in liposomal fusion. Finally, while formulation of pH-sensitive DOPE/ cholesterol hemisuccinate liposomes with mPEG-DTP-DSPE abolished the pH sensitivity, cleavage of the PEG chains completely restored this property. These are the first examples of new useful properties of liposomes grafted with cleavable polymer.

Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid

“…To improve the stability in the systemic circulation and the tumor accumulation, various groups have devised non-viral gene carriers with PEG. [13][14][15][16][17][18][19][30][31][32] Recently, cleavable PEG systems were developed, which are cleaved in response to an intracellular environment (e.g. low pH in endosome/ lysosomes, thiolytically small molecules, etc.…”

“…Most of the current cleavable PEG devices have been designed to be cleaved in response to the intracellular microenvironment, such as low pH or a specific enzyme in the endosome/lysosome and the reductive conditions in the cytoplasm. [14][15][16][17][18][19] Here, we report the development of a novel gene delivery system for cancer gene therapy, using a MEND modified with an enzymatically cleavable PEG-lipid. The cleavable PEG-lipid is composed of a PEG/matrix metalloproteinase (MMP)-substrate peptide 20 /1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) ternary conjugate (PPD), which is specifically cleaved by MMP in the extracellular space in tumor tissues.…”

Optimized cationic lipid‐based gene delivery reagents for use in developing vertebrate embryos

“…In addition, the multicomponent liposome structure of the reagent creates an excellent physical foundation on to which cell-specific targeting molecules can be bound in future experiments. The reagent has the advantage over current transfection techniques in that it does not require a potentially damaging electrical pulse to be applied to the embryo as with electroporation ( Sato et al, 2002), and it does not have the laborious preparation and associated toxicity that viral particles have (Kirpotin et al, 1996). The results of experiments using this new reagent will offer further insight into the mechanisms by which development can go awry, causing serious birth defects.…”

“…Polyethylene glycol was conjugated to dioleoyl phosphatidylethanolamine (DOPE) (Avanti Polar Lipids, Alabaster, AL) with the bifunctional crosslinker dithiobis(succinimidyl propionate) (DSP; Pierce, Rockford, IL), as previously described (Kirpotin et al, 1996;Longmuir et al, 2001). Briefly, methoxypolyethylene glycol amine, mPEG-NH 2 (Nektar Therapeutics, Huntsville, AL), dissolved in dimeth-ylformamide (DMF) was slowly added dropwise to a fivefold molar excess of DSP dissolved in DMF, while stirring vigorously.…”

On the formulation of pH-sensitive liposomes with long circulation times

“…In another approach, DOPE-containing liposomes were stabilized in the bilayer form through the addition of a cleavable lipid derivative of PEG in which the polymer was attached to a lipid anchor via a disulfide linkage (PEGUSUSUDSPE) [56,57]. Liposomes stabilized with either a non-cleavable PEG (PEGUDSPE) or PEGUSUSUDSPE retained an encapsulated dye at pH 5.5.…”