Copper-64 doped gold nanoclusters (64CuAuNCs) have been reported to serve as sensitive nanoprobes for positron emission tomography (PET) imaging for cancers, allowing for improved radiolabel stability and diagnostic accuracy. However, improvement is still needed to obtain reduced mononuclear phagocytic system (MPS) uptake and prolonged blood circulation to enhance the accumulation in tumors via the EPR effect. In contrast to the standard coating material poly(ethylene glycol) (PEG), which is reported with accelerated blood clearance upon repeated dose injections due to anti-PEG antibodies generated by the immune system, antibiofouling zwitterionic materials have shown great potential with resistance to nonspecific protein adsorption, which will reduce the clearance of nanoparticles by MPS and increase the blood elimination half-life. In this study, biocompatible and degradable zwitterionic polyphosphoesters (zPPEs) have been developed as novel coating materials for CuAuNCs towards improved biodistribution. The PPEs were facilely synthesized by a ring-opening polymerization (ROP) of butynyl phospholane (BYP) with 3-azidopropanol as the initiator. High monomer conversion (&gt; 99%) was observed for BYP in ca. 15 min with narrow dispersity, suggested by nuclear magnetic resonance (NMR) spectroscopy and size exclusion chromatography (SEC). The azide and hydroxyl groups in the chain ends can be utilized for further modifications such as targeting ligand conjugation. The polymer side chains were subsequently functionalized with cysteines via thiol-yne “click” reaction to afford the zPPEs. Citrate-capped CuAuNCs were synthesized by reduction of HAuCl4 and Cu(NO3)2 with NaBH4 in the presence of trisodium citrate, characterized by ultraviolet-visible spectroscopy (UV/Vis) and transmission electron microscopy (TEM). The surface of CuAuNCs was replaced with zPPEs by directly adding the CuAuNC solution into the zPPE solution while stirring, after which a red shift of the plasmon absorption band was observed in the UV/Vis spectrum. The radioactive synthesis showed quantitative incorporation of 64Cu into the nanostructure. Preliminary biodistribution studies showed improved blood circulation time of the zPPE-coated 64CuAuNCs compared to the traditional PEGylated counterparts.

Design and synthesis of zwitterionic polyphosphoester-based coating materials for 64Cu doped Au nanoclusters towards advanced in vivo pharmacokinetics

253rd National Meeting (2017)

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