Engineering metal-phenolic capsules with tailored properties for controlled bio-nano interactions

© 2016 Dr. Yi JuCapsules have emerged as a useful platform for biomedical applications due to their tunable physicochemical and biological properties. Metal-phenolic networks (MPNs) have recently been developed as a facile and rapid capsule engineering technique based on the coordination between natural polyphenols and metal ions. By changing the incorporated metal ion, MPN capsules can be endowed with diverse functionalities, and applied for drug delivery, bio-imaging, and catalysis. However, natural polyphenols (e.g., tannic acid [TA]) exhibit significant nonspecific interactions with biological systems. For example, the incorporation of TA into MPN capsules can lead to nonspecific binding and association with healthy cells, and rapid clearance by phagocytes in blood before reaching the disease site. Therefore, controlling the interactions between biological systems and nanoengineered MPN materials (bio-nano interactions) is of significant importance for drug delivery and other biomedical applications. In this thesis, bio-nano interactions with MPN capsules were controlled using synthetic polyphenol derivatives (polymer-phenolic conjugates) with desired properties as building blocks to coordinate with metal ions, instead of using natural polyphenols. To reduce nonspecific bio-nano interactions, low-fouling material, poly(ethylene glycol) (PEG), was conjugated with multiple catechol groups to synthesize PEG-polyphenol. The conjugated catechol groups facilitated the coating of PEG-polyphenol on templates and also allowed for cross-linking with metal ions to form MPNs. PEG-MPN capsules exhibited 3-fold lower nonspecific protein adsorption and 34-fold lower nonspecific cellular association compared with TA-MPN capsules. Moreover, PEG-MPN capsules showed rapid disassembly at physiologically relevant acidic pH (e.g., 5), which allowed for the controlled release of cargo in intracellular compartments. After establishing a low-fouling and pH-degradable system, hyaluronic acid (HA)-polyphenol was synthesized and assembled into the MPN capsules to enhance specific cellular interactions for targeted drug delivery. Due to the high binding affinity of HA to CD44, the incorporation of HA significantly enhances the targeting ability of the MPN capsules to CD44 overexpressing (CD44+) cancer cells, compared with CD44 minimal-expressing (CD44–) cancer cells. Furthermore, the level of targeting and nonspecific binding can be controlled by varying the ratio of HA and PEG incorporated into the MPN capsules. Encapsulation of anticancer drugs into the capsules with an optimized HA/PEG ratio led to significantly higher cytotoxicity to CD44+ cells compared with CD44– cells, demonstrating a potential application for targeted drug delivery. Finally, the effect of protein coronas on targeting specificity of HA-based MPN capsules was investigated. Protein coronas derived from human serum improved the targeting specificity of HA capsules (more than 3-fold) by reducing nonspecific interactions and maintaining specific capsule-cell interactions. Moreover, the effects of protein coronas on the targeting ability of HA capsules varied depending on the molecular weight of HA. Overall, by using synthetic polyphenol derivatives as building blocks, MPN capsules with desired properties were engineered, and their interactions with biological systems were well controlled