In vitro and in vivo protein delivery from in situ forming poly(ethylene glycol)-poly(lactide) hydrogels.
Previous studies have shown that stereocomplexed hydrogels are rapidly formed in situ by mixing aqueous solutions of eight-arm poly(ethylene glycol)-poly(L-lactide) and poly(ethylene glycol)-poly(D-lactide) star block copolymers (denoted as PEG-(PLLA)(8) and PEG-(PDLA)(8), respectively). In this study, in vitro and in vivo protein release from stereocomplexed hydrogels was investigated. These hydrogels were fully degradable under physiological conditions. Proteins could be easily loaded into the stereocomplexed hydrogels by mixing protein containing aqueous solutions of PEG-(PLLA)(8) and PEG-(PDLA)(8) copolymers. The release of the relatively small protein lysozyme (d(h)=4.1 nm) followed first order kinetics and approximately 90% was released in 10 days. Bacteria lysis experiments showed that the released lysozyme had retained its activity. The relatively large protein IgG (d(h)=10.7 nm) could be released from stereocomplexed hydrogels with nearly zero order kinetics, wherein up to 50% was released in 16 days. The in vitro release of the therapeutic protein rhIL-2 from stereocomplexed hydrogels also showed nearly zero order kinetics, wherein up to 45% was released in 7 days. The therapeutic efficacy of stereocomplexed hydrogels loaded with 1x10(6) IU of rhIL-2 was studied using SL2-lymphoma bearing DBA/2 mice. The PEG-(PLLA)(8)/PEG-(PDLA)(8)/rhIL-2 mixture could be easily injected intratumorally. The released rhIL-2 was therapeutically effective as the tumor size was reduced and the cure rate was 30%, whereas no therapeutic effect was achieved when no rhIL-2 was given. However, the cure rate of rhIL-2 loaded stereocomplexed hydrogels was lower, though not statistically significant, compared to that of a single injection with 1x10(6) IU of free rhIL-2 at the start of the therapy (cure rate=70%). The therapeutic effect of rhIL-2 loaded stereocomplexed hydrogels was retarded for approximately 1-2 weeks compared to free rhIL-2, most likely due to a slow, constant release of rhIL-2 from the hydrogels.
Hiemstra
Christine
C
Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, Institute for Biomedical Technology, University of Twente, Enschede, The Netherlands.
Zhong
Zhiyuan
Z
Van Tomme
Sophie R
SR
van Steenbergen
Mies J
MJ
Jacobs
John J L
JJ
Otter
Willem Den
WD
Hennink
Wim E
WE
Feijen
Jan
J
D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D020100:Hydrogels / Q000737:chemistry*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use; D007700:Kinetics; D051379:Mice; D008811:Mice, Inbred DBA; D008837:Micrococcus / Q000187:drug effects; D008956:Models, Chemical; D009113:Muramidase / Q000008:administration & dosage / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011506:Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
D004337:Drug Carriers; D020100:Hydrogels; D007376:Interleukin-2; D011091:Polyesters; D011506:Proteins; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C083464:poly(ethyleneglycol-lactide); D009113:Muramidase