Block co-polymer metal-organic cage micelles : towards unimolecular, atomically precise and highly addressable composite nanoparticles

Abstract

Nanoparticles find applications in a variety of fields, including nanomedicine, electronics, and renewable energies, etc., and their performance relies critically on the ability to synthesize nanoparticles with well-defined size, structure, and function. However, most nanoparticles do not have a set molecular mass or composition and are intrinsically polydisperse. It is therefore challenging to control their properties with precision and fidelity. This dissertation demonstrates the design and progressive construction of atomically precise composite nanoparticles (APCNs), which have defined molecular mass, size, and nanostructure. The work is based on the hypothesis that well-defined polymers can be synergistically integrated with metal-organic cages/ polyhedrons (MOCs/ MOPs) to facilitate the formation of APCNs. To demonstrate the application of these new particles, we primarily use them for nanomedicine. In the first part of the dissertation, I describe my initial study that utilizes conventional polydispersed polymers to verify the hypothesis, which results in the self-assembly of star polymers that can undergo phase separation to form unimolecular micelles. The interplay between the MOP and BCPs and its impact on the composite nanoparticles are investigated in detail. The MOP grasps individual polymers in place and directs the resulting nanoparticles to form micelles that are insensitive to dilution and presents moderate stability against completing nucleophiles. The composite nanoparticles show a relatively more sustained release and enhanced therapeutic performance in a tumor bearing mouse model when encapsulating anticancer doxorubicin molecules. This is caused by the suppressed kinetics and extended blood circulation of micelles. The composite nanoparticles are unimolecular but not atomically precise since the polymer used is intrinsically polydisperse. In addition, the BCPs cannot effectively safeguard the MOP from completing nucleophiles because of their inherent impurity. In the next part of the dissertation, nanoparticles with atomic precision are approached by replacing the polydisperse polymers with a type of sequence defined polymers—polypeptoids, or poly-N-substituted glycines, synthesized following solid phase iterative protocols. The resulting star peptoids show atom-precision composition, which is confirmed by mass spectrometry, and the self-assembly of the star peptoids into unimolecular and atomically precise composite nanoparticles is validated by various methods including native mass spectroscopy and Förster resonance energy transfer. They possess structural synergy, uniform morphology, precise composition, and tunable functions. APCNs carrying an exact quantity of anticancer drugs have been formulated on a large scale and with fidelity and consistency. They show sustained release of the carried drugs and enhanced therapeutic index with reduced systemic toxicity. Given the versatility in designing MOPs and peptoids, we anticipate that the highly addressable composite nanoparticles will allow us to tailor assemblies and properties of nanoparticles precisely and tackle other important medical challenges.