Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Saltzman, W. Mark
Abstract
The clinical translation of nanomedicines has been closely tied to the development ofnovel drug delivery techniques. In particular, nanoparticle formulations promise to improve the pharmacokinetics, selective accumulation at the target site, and intracellular delivery of therapeutics. Extensive research efforts have identified structure-function relationships between nanoparticle physicochemical properties (e.g. size, charge, surface functionalization) and biological fate. However, studying the biological impact of nanoparticle surface topography still remains a challenge due to the limited spatial control of conventional nanoparticle surface coatings based on hydrophilic linear polymers including poly(ethylene glycol) (PEG). In this dissertation, we investigated a novel method to precisely control the surface topography of polymeric PEGylated nanoparticles. We synthesized shape-persistent amphiphilic poly(lactic acid) (PLA)-PEG bottlebrush block copolymers (BBCP) with different length PEG side chains. BBCPs self-assembly into spherical micellar nanoparticles was highly predictable based on the BBCP architecture. In addition, we demonstrated that modification of PEG side chain length and distribution enabled the precise hierarchical control over the nanoparticle shell and surface topography. More importantly, we found that the nanoparticle surface topography had a profound impact on the nanoparticle’s biological interactions in vitro and in vivo. Nanoparticles with rough surface adsorbed unique serum proteins onto their surface not abundant in the protein corona of conventional smooth-surfaced nanoparticles composed of linear PLA-PEG copolymers. In addition, rough-surfaced nanoparticles achieved prolonged systemic blood circulation (i.e., circulation half-lives up to 29 h compared to 13 h for linear PLA-PEG) with the extent dependent on the surface topography. Nanoparticles formed from BBCPs exhibited high accumulation in solid tumors over extended periods of up to a week. We also observed high internalization of nanoparticles into cancer cells in vivo (i.e., up to 70% nanoparticle positive cells) which is a common obstacle for conventional long-circulating PEGylated nanoparticles. Lastly, we developed novel PEG-norbornene macromonomers to modify the backbone chemistry of the PEG-bottlebrush shell and study the effect of the bottlebrush backbone on the nanoparticle’s biological fate. We revealed that hydrophobic and cationic modifications reduce the in vitro cellular uptake while all nanoparticles showed prolonged blood circulation and high tumor accumulation regardless of backbone chemistry. Overall, the findings in this dissertation highlight the importance of nanoparticle surface topography in improving the performance of nanocarriers for nanoparticle drug delivery. Furthermore, the effect of surface topography on nanoparticle interactions with biomolecules and the nanoparticle’s biological fate suggest the potential of this platform for other biomedical applications.
Recommended Citation
Grundler, Julian, "Modifying the Surface Topography of PEGylated Nanoparticles Based on Bottlebrush Block Copolymer for Drug Delivery Applications" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1115.
https://elischolar.library.yale.edu/gsas_dissertations/1115
