The Synthesis of a Multiblock Osteotropic Polyrotaxane by Copper(I)-Catalyzed Huisgen 1,3-Dipolar Cycloaddition

The design and synthesis of a novel bone-targeting polyrotaxane delivery system that utilizes alendronate (ALN) as targeting moiety is presented in this manuscript. For the introduction of ALN, it is first conjugated to α-cyclodextrin (α-CD) and subsequently threaded onto a short poly(ethylene glycol) (PEG) chain, forming a pseudopolyrotaxane. Using click chemistry, this assembly is copolymerized with bulky monomers that bear imaging and/or therapeutic agent(s) to prevent ALN-functionalized α-CD from dethreading. Overall bone affinity of this novel polymer conjugate can be easily controlled by changing the number of ALN-α-CD incorporated. The osteotropicity of the delivery system was also confirmed in vivo.A novel bone-targeting delivery system is described that uses a multiblock α-cyclodextrin/poly(ethylene glycol) polyrotaxane scaffold. The system is assembled by conjugating the bone-targeting moiety, alendronate (ALN), to α-cyclodextrin (α-CD), threading these conjugates onto an acetylene-terminated PEG backbone, and copolymerizing the entire assembly with a sterically bulky diazide monomer. The overall bone-binding affinity can be freely adjusted.