A novel family of L-amino acid-based biodegradable polymer-lipid conjugates for the development of long-circulating liposomes with effective drug-targeting capacity.
The objective of this study was to develop biodegradable polypeptide-lipid conjugates for the design of polymer-coated long-circulating liposomes (LCL). Lipid conjugates of poly(hydroxyalkyl L-asparagine/L-glutamine) were synthesized and incorporated into 0.15 microm dipalmitoyl phosphatidylcholine (DPPC)-cholesterol liposomes. Circulation times and biodistribution were assessed in rats using a radioactive lipid marker. Evaluation of the therapeutic activity of prednisolone phosphate loaded in 0.1 microm PHEA-DPPC-cholesterol liposomes in a rat experimental arthritis model was performed to demonstrate the drug-targeting potential of the polymer-coated liposomes. Coating of liposomes with poly(hydroxyethyl L-asparagine) (PHEA) and poly(hydroxyethyl L-glutamine) (PHEG) extended the circulation half-life to a similar extent as poly(ethylene glycol) (PEG), which is normally used for the preparation of LCL. Glutamine polymers with a hydroxypropyl or a hydroxybutyl group instead of hydroxyethyl group also yield prolonged circulation, however, not to the same extent as PHEA/G. The pharmacokinetic properties of PHEA-liposomes were independent of the lipid dose even at very low lipid doses of around 50 nmol per rat. PLP was successfully entrapped in PHEA-liposomes. These liposomes were shown to be stable in the circulation and equally effective in rat experimental arthritis as PLP encapsulated in PEG-liposomes. PHEA and PHEG are attractive alternative polymers for the design of LCL: their performance is similar to that of PEG-liposomes but they have the advantage of being biodegradable.
Metselaar
Josbert M
JM
Department of Pharmaceutics, Utrecht University, The Netherlands.
Bruin
Peter
P
de Boer
Leo W T
LW
de Vringer
Tom
T
Snel
Cor
C
Oussoren
Christien
C
Wauben
Marca H M
MH
Crommelin
Daan J A
DJ
Storm
Gert
G
Hennink
Wim E
WE
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry / Q000493:pharmacokinetics; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics; D001169:Arthritis, Experimental / Q000188:drug therapy; D001673:Biodegradation, Environmental; D016503:Drug Delivery Systems; D006207:Half-Life; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D014018:Tissue Distribution
D000596:Amino Acids; D000893:Anti-Inflammatory Agents; D008055:Lipids; D008081:Liposomes; D011108:Polymers; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols