Nanoparticle systems that exploit host biology for diagnosis and treatment of disease

Abstract

Over the past 30 years, advances in nanotechnology have generated a multitude of nanostructures exhibiting a breadth of physical, chemical, and biological properties that have tremendous potential to improve the detection and treatment of disease. Despite this progress, biomedical nanotechnologies have yet to approach the same level of complexity as biological systems, which produce higher-order functions through coordinated interactions between multiple nanoscale components. This thesis aims to explore the potential of nanoparticles to interface with the host biology to perform systems-level applications that benefit disease sensing and treatment. First, we engineered nanoparticles to sense dysregulated protease activity associated with thrombosis and generate reporters that can be noninvasively quantified in the urine. These nanoparticles exploit the vascular transport of the circulatory system and the size filtration function of the renal system to emit reporters into the urine following proteolytic cleavage events. The reporter levels in the urine differentiate between healthy and thrombotic states and correlate with clot burden in a mouse model of pulmonary embolism. Next, we developed nanoparticles that homeostatically regulate the biological cascade responsible for haemostasis to prevent the aberrant formation of clots. These nanoparticles form a negative feedback loop with thrombin, a key enzyme in the coagulation cascade, to regulate their release of the anticoagulant heparin. In mice, they inhibited the formation of pulmonary embolisms without an associated increase in bleeding, the primary side-effect of antithrombotic therapy in the clinic. Finally, we investigated a two-component system whereby the first therapeutic entity induces the upregulation a molecular signal within a malignant environment to amplify the local recruitment of a secondary population of targeted nanoparticles. Here, the interaction between the initial therapeutic and the targeted nanoparticles occurred indirectly through a biological stress pathway. This cooperative targeting system delivered up to five-fold higher nanoparticle doses to tumors than non-cooperative controls, leading to delayed tumor growth and improved survival in mice. Together, these systems highlight the potential for interactive nanoparticle systems to perform highly complex functions in vivo by leveraging and modulating the host biology. In contrast to the current strategy of injecting large populations of nanoparticles that carry out identical, pre-defined tasks with little to no feedback from the in vivo environment, this work supports the construction of nanoparticle systems that leverage both synthetic and endogenous components to produce emergent behaviors for enhancing diagnostics and therapeutics.