Size-Dependent in Vivo Transport and Interactions of Ultrasmall Nanoparticles
The past decade has witnessed the accelerating development of ultrasmall nanoparticles (NPs) in disease diagnosis and treatment. Fundamental understanding of the in vivo transport and nano-bio interactions of ultrasmall nanoparticles not only advances their biomedical applications but also is important for understanding physiology at nano scale. Among many factors, size of NPs is known to play a key role in determining their elimination and targeting. For elimination, NPs with size larger than 6 nm are easily accumulated in the liver, spleen etc. while NPs with size smaller than 6 nm are readily eliminated through the kidneys into urine. Subtle differences, even a several-atom difference in size can result in dramatically distinct renal clearance efficiency. For targeting, it has been conventionally deemed that only NPs within the size range of 10-100 nm can efficiently target tumors through the enhanced permeability and retention (EPR) effect, but in recent years, we have witnessed that ultrasmall nanoparticles (<6 nm) not only retain the EPR effect but also display deeper and more homogenous distribution in solid tumors than larger ones. Moreover, subtle differences of ultrasmall NPs in size also can result in their distinct accumulation and interactions in tumors. This dissertation aims to fundamentally understand the size-dependent elimination and targeting of ultrasmall nanoparticles in the body. In this dissertation, Chapter 1 reviews the current understanding of in vivo transport and interactions of nanoparticles in the kidneys and tumors in terms of nanoparticle size. Chapter 2 describes the size-dependent glomerular filtration of sub-nm gold nanoclusters and illustrates a unique size scaling law which shows that the glomerular barrier behaves as an atomically precise bandpass filter in a sub-nm regime. Chapter 3 focuses on the accumulation and interaction of subnm gold nanoclusters in solid tumor at the cellular level and illustrates that smaller nanoclusters display higher cellular uptake efficiency in solid tumors than larger counterparts. In addition to metal-based nanomaterials, Chapter 4 describes the in vivo transport and nano-bio interactions of ultrasmall organic materials. By utilizing PEGylated (<10,000 Da) organic dyes, we not only found a general molecular weight dependent scaling law in renal clearance but also observed the renal tubular secretion of indocyanine green after PEGylation, which in turn greatly enhanced its targeting to primary and metastatic tumors. Finally, Chapter 5 presents conclusion and outlook.