Development of transition metal-coordinated bilirubin nanoparticles for theranostics applications

Abstract

Prompted by multidisciplinary approaches and cutting-edge nanotechnology in the field of bio-medicine at 21st century, a newly minted term, ‘theranostics’ was born in the context of nano-medicine and gained numerous attentions. It comes from the fusion of two independent terms, ‘diagnosis’ and ‘therapy’ for diseases, and facilitates diagnosing, treating and monitoring therapeutic response at the same time in a one shot with smart nano-material systems. However, before their smooth landing for clinical translation, there are several hurdles to overcome. Those are safety issues regarding toxicity and biodegradability of materials, conflicting aims between ‘diagnosis’ and ‘therapy’ and irrelevant clinical settings or targets under current clinical practice. That’s why majority of ‘theranostics’ nanoparticles are not melted into clinics yet, even though they have shown very decent systems in preclinical area. Therefore, harmonizing above issues should be pivotal when designing and engineering the theranostics nanoparticles in light of potential clinical translation. Bilirubin (BR), an endogenous material accounts for jaundice, is recently garnered attention having a more beneficial role in human body. It has revealed that it is in charge of defying against oxidative stress by scavenging the reactive oxygen species (ROS), indispensable molecules produced in daily activities. In the past, by conjugating water-insoluble BR with water-soluble Polyethylene Glycol (PEG) moiety, my team developed and applied amphiphilic PEGylated BR-based nanoparticle system (BRNP) which facilitates anti-oxidative activity in inflammatory environments yet preventing them from being accumulated in body. In this context, BR is a very attractive, raw material in terms of safety and intrinsic antioxidant nature compared to other pre-existing artificial or inorganic ingredients often used for nanomaterial recipe. Herein, differing from previous approaches which focused on anti-oxidative abilities of BR to treat the diseases, I pursued the different physicochemical properties of BR for my upcoming theranostic studies by bio-inspired approach using transition metals. It is mainly stemmed from BR’s intrinsic metal-chelating ability manifested in the formation of poly-bilirubinate black pigment gallstones in bile duct in some pathological situations. In these gallstones, BR forms direct coordination bonds with a couple of metal ions, including $Cu^{2+}$ and $Ca^{2+}$. Thus, I hypothesized that PEGylated BR could also operate through dative bonding to serve as a carrier of various medicinal-related metal ions for potential biomedical applications. In chapter 1, introduction of nanoparticle-based ‘theranostics’ and BR-based nanoparticle systems are described, followed by description of main inspiration of this thesis, poly-bilirubinate black pigment gallstone for the schematic guidance. In chapter 2, I developed platinum (Pt)-based anticancer drug (cisplatin)-chelated BRNP (cisPt@BRNP) with unique near infrared light (NIR)-absorption properties for use as a new photonic nanomaterial for combined photoacoustic imaging (PAI) and photothermal therapy (PTT) of cancers. In chapter 3, I engineered PEGylated BR coated superparamagnetic iron oxide nanoparticles (SPIONs) for working as a ROS stimuli-responsive smart nanomaterial with generally applicable platforms in the fields of in vitro, in vivo and sensor. In conclusion, these two metal-coordinated, hybrid nanoparticle systems successfully prove bio-inspired, robust engineering strategy in BR-based nanoparticles and given the endogenous origin of BR, these systems will guarantee superior bio-compatibility and clear away the safety issues arisen in the era of nano-medicine. Moreover, versatile theranostics usage of metal-incorporated BR-based nanoparticles in line with expanded utility of nano-medicine will hold far-reaching promise for clinical translation down the road.