Biodegradable Polymer Nanodiscs as Novel Lipoprotein-Mimicking Nanocarriers for Anticancer Drug Delivery with High Stability and Long Circulation Time

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Non-technical descriptionA disc-shaped flying saucer that presumably navigates to Earth from a far away galaxy is awe-inspiring. Navigating through the human blood stream is no small feat either. To efficiently deliver drugs through blood circulation to reach deep-seated disease sites is one of the most critical challenges in treating cancer, the second largest cause of fatality in US and globally. Although significant strides have been made on developing various nanocarriers to help with that, efficacious patient responses remain modest compared to conventional drug formulations. The somewhat less stellar performance of nanocarriers is attributed to their poor transport inside the body. To address the deficiency, this project aims to develop a new family of nanocarrier called polymer nanodiscs that mimic the high-density lipoprotein nanoparticles (HDL) in human blood. The nascent form of HDL is well-known lipid nanodisc that mediates highly efficient cholesterol transport from peripheral cells back to the liver. Intriguingly, disc-shaped particles have been shown to outperform spherical ones with prolonged blood circulation half-lives and higher cellular internalization rates. Most nanocarriers under development are spherical in shape because it is technically challenging to prepare disc-shaped nanoparticles through chemical synthesis. This project will elucidate the design principles of biocompatible block copolymers that self-assemble with membrane-scaffold proteins (or membrane-scaffold polymers) into well-defined polymer nanodiscs to carry tumor-specific targeting and drug release moieties. If successful, it may bring forth another advance in harnessing nanotechnology for cancer diagnostics and treatment. The design concepts may have broad impact in other related fields, such as nanodisc-based immunotherapy, nanodisc-based structural and functional studies of membrane proteins, and the development of biomimetic 2-dimensional materials for applications in human health, clean energy, and environment. Through the integrated education and outreach activities, this project will help motivate graduate, undergraduate, and K-12 students to pursue career paths in the interdisciplinary area of materials science, nanoengineering, and biomedical science.Technical descriptionNanotechnology has been widely anticipated to benefit the diagnostic and treatment of cancers. Despite the significant strides in nanocarrier development, efficacious patient responses remain modest compared to conventional drug formulations. Clearly, a gap of knowledge exists on nanocarrier design beyond simply controlling their sizes. The lipoprotein-mimicking nanodiscs represent a novel family of 2-dimensional materials with great potential for drug delivery, as mounting evidence has suggested that disc-shaped particles outperform spherical ones with prolonged blood circulation half-lives and higher cellular uptake. Adapting lipid nanodiscs (LNDs) for anticancer drug delivery has attracted lots of attention, but as drug carriers LNDs suffer from low stability, short shelf life, limited drug loading capacity, and difficulty for chemical modifications. The objective of this project is to elucidate the self-assembly principle between amphiphilic block and random copolymers toward the formation of novel lipoprotein-mimicking polymer nanodiscs (PNDs) with excellent biocompatibility and biodegradability, long-term stability, high drug loading capacity, and facile modification chemistry for anticancer drug delivery. Synthetic strategies to prepare well-defined amphiphilic block copolymers that carry tumor-specific targeting and drug release moieties will be developed, and the self-assembly behavior between model block copolymers and membrane-scaffold proteins (MSPs) into PNDs will be elucidated. De novo designed synthetic membrane-scaffold polymers (MSPols) that potentially overcome the limitations of biologically-derived MSPs will also be explored to develop fully synthetic PNDs for anticancer drug delivery. PNDs are expected to break the limitations of LNDs without compromising their highly sought-after size and shape that favor prolonged circulation half-lives and enhanced cellular uptake, hence potentially bringing forth another advance in harnessing nanotechnology for cancer treatment. Besides anticancer drug delivery, this study will also fill a critical gap of knowledge on the rational design of synthetic biodegradable MSPols that rival MSPs in encasing nanodiscs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.