New detachable poly(ethylene glycol) conjugates: cysteine-cleavable lipopolymers regenerating natural phospholipid, diacyl phosphatidylethanolamine.
A new strategy for the reversible attachment of methoxypoly(ethylene glycol) (mPEG) to an amino-containing substrate is described. The strategy is based on formation of a benzyl carbamate linkage substituted with a disulfide in the para or ortho position. While being stable under nonreducing conditions, the dithiobenzyl (DTB) urethane linkage is susceptible to cleavage by mild thiolysis with cysteine resulting in release of the parent amino component of the conjugate in its original form. The method is exemplified by preparation of mPEG-DTB-alcohol, its activation and attachment to distearoylphosphatidylethanolamine (DSPE). The resulting lipopolymer incorporates into liposomes, which are capable of losing their polymer coating under conditions approximating those existing in vivo. Implications for drug delivery are briefly discussed.
Zalipsky
S
S
Alza Corporation, 1050 Hamilton Court, Menlo Park, California 94025, USA. samuelz@sequus.com
Qazen
M
M
Walker
J A
JA
Mullah
N
N
Quinn
Y P
YP
Huang
S K
SK
D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry*; D016503:Drug Delivery Systems; D008081:Liposomes; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D010743:Phospholipids / Q000138:chemical synthesis / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D014520:Urethane / Q000031:analogs & derivatives / Q000737:chemistry*
D002219:Carbamates; D008081:Liposomes; D010714:Phosphatidylethanolamines; D010743:Phospholipids; C038089:1,2-distearoylphosphatidylethanolamine; D014520:Urethane; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D003545:Cysteine