Fully degradable hydrophilic polyals for protein modification.
Modification of proteins with hydrophilic polymers is an effective strategy for regulation of protein pharmacokinetics. However, conjugates of slowly or non-biodegradable materials, such as poly(ethylene glycol), are known to cause long-lasting cell vacuolization, in particular in renal epithelium. Conjugates of more degradable polymers, e.g., polysaccharides, have a significant risk of immunotoxicity. Polymers that combine complete degradability, long circulation in vivo, and low immuno and chemical toxicity would be most beneficial as protein conjugate components. This study explores new fully biodegradable hydrophilic polymers, hydrophilic polyals. They are nontoxic, stable at physiological conditions, and undergo proton-catalyzed hydrolysis at lysosomal pH. The model enzyme-polyal conjugates were prepared with 61-98% yield using conventional and novel conjugation techniques and retained 90-95% of specific activity. The model conjugates showed a significant prolongation of protein circulation in rodents, with a 5-fold reduction in the renal accumulation. The data suggests that hydrophilic polyals may be useful in designing protein conjugates with improved properties.
Yurkovetskiy
Alexander
A
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2696, USA.
Choi
Sungwoon
S
Hiller
Alexander
A
Yin
Mao
M
McCusker
Catherine
C
Syed
Sakina
S
Fischman
Alan J
AJ
Papisov
Mikhail I
MI
D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D001704:Biopolymers / Q000737:chemistry; D001709:Biotechnology / Q000379:methods; D001835:Body Weight; D002241:Carbohydrates / Q000737:chemistry; D002384:Catalysis; D002412:Cations; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016503:Drug Delivery Systems; D005029:Ethylenediamines / Q000737:chemistry; D005782:Gels; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D010100:Oxygen / Q000378:metabolism; D004369:Pentetic Acid / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011134:Polysaccharides / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution; D023822:Tissue Engineering
D001672:Biocompatible Materials; D001704:Biopolymers; D002241:Carbohydrates; D002412:Cations; D003432:Cross-Linking Reagents; D005029:Ethylenediamines; D005782:Gels; D011108:Polymers; D011134:Polysaccharides; D011506:Proteins; D011522:Protons; C506479:poly(1-hydroxymethylethylene hydroxymethylformal); D011107:Polylysine; D011092:Polyethylene Glycols; C031234:ethylenediamine; D004369:Pentetic Acid; D010100:Oxygen