Liposomes modified with superhydrophilic polymer linked to a nonphospholipid anchor exhibit reduced complement activation and enhanced circulation.
We report the synthesis of an acyl-anchored superhydrophilic polymer (SHP) for external surface modification of liposome surface. N¹-(2-aminoethyl)-N⁴-hexadecyl-2-tetradecylsuccinamide conjugated with SHP (HDAS-SHP) was synthesized and used for modifying the liposome surface. Unlike polyethylene glycol (PEG)-phospholipids, which are commonly used for manufacturing stealth liposomes, HDAS-SHP is devoid of both PEG and phosphoryl groups and possesses a zwitterionic polymeric chain. Circulation persistence of the ⁹⁹(m)Tc-labeled HDAS-SHP liposomes was documented by gamma camera imaging. After 24 h postinjection, approximately 30% of injected HDAS-SHP liposomes were present in blood as compared with only 4.5% of the plain liposomes. HDAS-SHP liposomes inhibited complement activation. They were found to be amenable to pH-gradient-based active loading of Adriamycin in a stable manner. At 37°C, HDAS-SHP liposomes provided better encapsulation efficiencies than the liposomes modified with DSPE-PEG₂₀₀₀. These results provide a strong basis for HDAS-SHP as a viable alternative to PEG-phospholipids for imparting stealth characteristics to drug delivery vehicles such as liposomes. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:114-123, 2015.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, 73117.
Okhil K
OK
Nag
Vivek R
VR
Yadav
Brandon
B
Croft
Andria
A
Hedrick
Vibhudutta
V
Awasthi
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D003167:Complement Activation / Q000187:drug effects; D004317:Doxorubicin; D004337:Drug Carriers / Q000008:administration & dosage* / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics; D004339:Drug Compounding; D004355:Drug Stability; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008081:Liposomes; D008297:Male; D011108:Polymers / Q000009:adverse effects* / Q000032:analysis / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000009:adverse effects* / Q000097:blood / Q000737:chemistry; D011877:Radionuclide Imaging; D017207:Rats, Sprague-Dawley; D013499:Surface Properties; D013667:Technetium; D014018:Tissue Distribution; D051598:Whole Body Imaging
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; C000601035:N1-(2-aminoethyl)-N4-hexadecyl-2-tetradecylsuccinamide-poly(N-(carboxymethyl)-2-(isobutyryloxy)-N,N-dimethylethanammonium); D011108:Polymers; D000644:Quaternary Ammonium Compounds; D013667:Technetium; D004317:Doxorubicin
Adriamycin; drug delivery systems; liposomes; persistence circulation; pharmacokinetics; polymers; stealth liposomes; superhydrophilic polymer; zwitterion