title: Biodegradable polyglycerols with randomly distributed ketal groups as multi-functional drug delivery systems.
abstract: Biodegradable multi-functional polymeric nanostructures that undergo controlled degradation in response to physiological cues are important in numerous biomedical applications including drug delivery, bio-conjugation and tissue engineering. In this paper, we report the development of a new class of water soluble multi-functional branched biodegradable polymer with high molecular weight and biocompatibility which demonstrates good correlation of in vivo biodegradation and in vitro hydrolysis. Main chain degradable hyperbranched polyglycerols (HPG) (20-100 kDa) were synthesized by the introduction of acid labile groups within the polymer structure by an anionic ring opening copolymerization of glycidol with ketal-containing epoxide monomers with different ketal structures. The water soluble biodegradable HPGs with randomly distributed ketal groups (RBHPGs) showed controlled degradation profiles in vitro depending on the pH of solution, temperature and the structure of incorporated ketal groups, and resulted in non-toxic degradation products. NMR studies demonstrated the branched nature of RBHPGs which is correlating with their smaller hydrodynamic radii. The RBHPGs and their degradation products exhibited excellent blood compatibility and tissue compatibility based on various analyses methods, independent of their molecular weight and ketal group structure. When administered intravenously in mice, tritium labeled RBHPG of molecular weight 100 kDa with dimethyl ketal group showed a circulation half life of 2.7 ± 0.3 h, correlating well with the in vitro polymer degradation half life (4.3 h) and changes in the molecular weight profile during the degradation (as measured by gel permeation chromatography) in buffer conditions at 37 °C. The RBHPG degraded into low molecular weight fragments that were cleared from circulation rapidly. The biodistribution and excretion studies demonstrated that RBHPG exhibited significantly lower tissue accumulation and enhanced urinary and fecal excretion when compared to non-degradable HPG of similar molecular weight. Excellent biocompatibility together with in vivo degradability and clearance of RBHPGs make them attractive for the development of multi-functional drug delivery systems.
authors.affiliation: Centre for Blood Research, University of British Columbia, Vancouver BC V6T 1Z3, Canada.
authors.forename: Rajesh A
authors.initials: RA
authors.lastname: Shenoi
authors.forename: Benjamin F L
authors.initials: BF
authors.lastname: Lai
authors.forename: Muhammad
authors.initials: M
authors.lastname: Imran ul-haq
authors.forename: Donald E
authors.initials: DE
authors.lastname: Brooks
authors.forename: Jayachandran N
authors.initials: JN
authors.lastname: Kizhakkedathu
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005990:Glycerol / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011108:Polymers / Q000737:chemistry*
chemical_list: D001672:Biocompatible Materials; D011108:Polymers; C043941:polyglycerol; D005990:Glycerol