The interaction of cationic polymers and their bisphosphonate derivatives with hydroxyapatite.
Conjugating proteins with bisphosphonates (BPs), a class of molecules with exceptional affinity to hydroxyapatite (HA), is a feasible means to impart bone affinity to protein-based therapeutic agents. To increase the targeting effectiveness while minimizing protein modification, a polymeric linker containing multiple copies of BPs could be constructed for protein conjugation and targeting to bone. Towards this goal, poly(L-lysine) (PLL) and poly(ethylenimine) (PEI) were utilized as the polymeric backbones to incorporate a BP, namely 2-(3-mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (thiolBP), by using N-hydroxysuccinimidyl polyethylene glycol maleimide and succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, respectively. In vitro and in vivo mineral affinity of the polymer-BP conjugates were determined in comparison with the unmodified polymers. The in vitro results indicated strong binding of the cationic polymers to HA in their unmodified form. BP conjugation did not enhance the inherent mineral affinity of the polymers; in contrast, certain modifications negatively affected the polymers' binding to the HA. In vivo results from a subcutaneous implant model in rats also showed no significant difference in mineral affinity of the BP modified and unmodified PEI. We conclude that thiolBP conjugation to the cationic polymers PLL and PEI was not beneficial for increasing the mineral affinity of the polymeric molecules. The strong interaction between the cationic polymers and HA may make the polymers suitable for imparting mineral affinity to bone-acting therapeutics.
Zhang
Sufeng
S
Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, T6G 2G6, Canada.
Wright
Jennifer E I
JE
Ozber
Natali
N
Uludağ
Hasan
H
D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D001857:Bone Matrix / Q000737:chemistry; D004164:Diphosphonates / Q000737:chemistry*; D016503:Drug Delivery Systems; D017886:Durapatite / Q000737:chemistry*; D020007:Implants, Experimental; D011094:Polyethyleneimine / Q000737:chemistry*; D011107:Polylysine / Q000737:chemistry*; D051381:Rats; D023822:Tissue Engineering
D001672:Biocompatible Materials; D004164:Diphosphonates; D011107:Polylysine; D011094:Polyethyleneimine; D017886:Durapatite