Surface design and controlled assembly of gold nanoparticles into biodegradable nanoclusters for biomedical imaging applications
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Gold nanoparticles have received significant interest recently due to their utility in biomedical imaging and therapy. Nanoparticles which exhibit intense extinction in the near infrared (NIR) region, where blood and tissue absorb light weakly, are of great interest as contrast agents for biomedical imaging applications. While strong NIR extinction often requires sizes greater than ~20-30 nm, effective clearance from the body to avoid toxic accumulation necessitates sizes below ~6 nm. Moreover, effective clearance depends upon lack of adsorption of serum proteins in the bloodstream onto the particles. Herein, this conflict is addressed by assembling sub-5 nm gold nanoparticles into clusters with controlled size and morphology, in order to provide intense NIR extinction. Furthermore, the surfaces of the primary gold nanoparticles are designed such that the particles avoid the adsorption of any serum proteins. Binary ligand monolayers of anionic citrate and appropriate amounts of either cationic lysine or zwitterionic cysteine are synthesized to completely prevent serum protein adsorption from undiluted fetal bovine serum. A mechanism is proposed whereby the zwitterionic tips which are present on both the lysine and cysteine ligands limit the interactions between serum proteins and the "buried" charges on the nanoparticle surfaces. These primary nanoparticles are subsequently assembled into biodegradable nanoclusters via "quenched assembly", wherein nanoclusters are assembled and subsequently quenched by the adsorption of a biodegradable polymer on the cluster surface. The sizes of completely reversible "quenched equilibrium" nanoclusters formed from gold nanoparticles coated with a mixture of lysine and citrate are tuned from 20 nm to 40 nm, and nanocluster size is semi-quantitatively predicted by a free-energy model. Additional control over nanocluster size and extinction is demonstrated by adding NaCl, which is shown to decrease the polymer adsorption on the clusters and thus decrease polymer bridging interactions. This nanocluster formation platform is extended to nanospheres capped with citrate and the thiolated, zwitterionic cysteine ligand. A general paradigm is presented whereby the sizes and optical properties of biodegradable gold nanoclusters formed from nanospheres which do not adsorb any serum proteins are tuned via control over van der Waals, electrostatic, depletion, and polymer bridging colloidal interactions.