Impact of Dendritic Polymer Architecture on Self-assembly, Cellular Interactions, and Protein Adsorption
thesisposted on 03.03.2017, 00:00 authored by Ryan M. Pearson
Nanocarriers have demonstrated their great potential to revolutionize the diagnosis, treatment, and prevention of a variety of diseases, especially cancer. In this dissertation research, we systematically explored the role of dendritic polymer architecture on the self-assembly and cellular interactions of nanocarriers. A set of novel PEGylated dendron-based copolymers (PDC) were synthesized and characterized along with self-assembled dendron micelles (DM) with various surface functional groups and hydrophilic-lipophilic balances (HLB). The critical micelle concentration (CMC) of PDCs varied from 6.50 × 10-8 to 9.3 × 10-7 M and compared to synthesized linear-block copolymer (LBC) counterparts, the CMCs of PDCs were up to 100-times lower at similar HLBs, demonstrating their superior thermodynamic stability. Molecular dynamics (MD) simulations revealed that the hydrophobic core of the DM was more completely covered by dense poly(ethylene glycol) (PEG) compared to the linear micelle (LM). In vitro analyses of the DMs revealed that both the formation of non-specific and specific cellular interactions were controllable through modulation of the PEG corona length. Using folic acid (FA) as the model targeting agent, variation of the PEG corona length and PDC-FA content resulted in targeted DMs that achieved modular cellular interactions, ranging from minimal to 27-fold enhancements, compared to non-targeted DMs. The targeting efficiency of FA-targeted DMs was then compared to FA-targeted LMs at physiologically relevant (high serum) culture conditions. DMs and LMs exhibited similar targeting efficiencies in non-serum containing media; however, the use of serum containing media substantially reduced the targeting ability of LM, while DMs remained unaffected. Further studies provided evidence for the positive role of dendritic polymer architectures for overcoming the negative effect of protein corona formation on targeted cellular interactions. The controlled, high stability self-assembled structures produced by PDCs as well as the ability to engineer the cellular interactions of DMs through simple manipulation of physicochemical properties such as PEG corona length provide compelling evidence for the future development of DMs as targeted drug delivery platforms.