Synthesis And Polymerization Of DOPA-NTA Towards Novel MRI Contrast Agent

Poly(amino acid)s are widely applied in biomedical fields including drug delivery and tissue engineering due to their excellent biocompatibility and biodegradability.Amino acid N-carboxyanhydride(NCA)and N-thiocarboxy-anhydrides(NTA)are two common cyclic monomers to synthesize poly(amino acid)s by ring-opening polymerization(ROP).NCA polymerization cannot tolerate nucleophilic hydroxyl groups which have the ability of initiation,hence NCA monomers with hydroxyl groups need to be protected before polymerization and deprotection is required after polymerization.In contrast,our group find out that NTAs are much more stable to tolerate nucleophilic groups such as hydroxyl groups.In this work,we report two novel NTA monomers with unprotected phenolic hydroxyl groups,i.e.tyrosine NTA(Tyr-NTA)and dopa NTA(DOPA-NTA),which were synthesized and well characterized for the first time.Primary amines can initiate controlled ring-opening homo-and copolymerization of Tyr-NTA and DOPA-NTA and the chain lengths of poly(amino acid)s can be controlled by the feed ratio of monomer and initiator.We also clearly demonstrated that the phenolic hydroxyl groups do not initiate the NTA polymerization.This work provides a new method for the direct synthesis of poly(amino acid)s with phenolic hydroxyl pendant groups without protection.Moreover,we synthesized amphiphilic copoly(amino acid)s polydopa-b-polysarcosines(PDOPA-b-PSars)and the repeating pendant catechol segments have the high affinity of Fe3+,which subsequently self-assembled into nanoparticles with Fe3+in the water.The ratio of the hydrophilic PSar segment and the hydrophobic PDOPA fraction can be adjusted for the stability and chelation quantity of Fe3+ during micellization.The sizes of Fe3+-chelated nanoparticles are in the range of 10 and 50 nm in the water.The longitudinal relaxivity value(r1 =5.6 mM-1 s-1)of nanoparticles labeled as NPDS1 is higher than commercial DTPA-and DOTA-Gd3+agents and the micelles behave effective vessel MRI contrast enhancement in vivo after injection into the vena caudalis of nude mice with a moderate duration(150 min).We also achieved magnetic resonance angiography in rabbit by using Volume Rendering(VR)and Maximum Intensity Projection(MIP)techniques,which clearly displayed 3D images of vein and arteries.Biocompatibility studies evidenced the non-toxic and safe use of such Fe3+-chelated nanoparticles in cell studies.In short,our Fe3+-DOPA MRI contrast agent formed from amphiphilic poly(amino acid)s has the potential to replace traditional commercial Gd3+ agents for applications in diagnostic radiology and imaging as a novel efficient Gd-free MRI contrast agent.