Abstract:
The overarching objective of this research was to develop polypeptides and use
them as intelligent multifunctional coatings for the delivery of nucleic acid-based
therapeutics, specifically, messenger RNA (mRNA). I successfully synthesized
poly(ethylene glycol)-poly(β-benzyl-L-aspartate) (PEG-PBLA) and poly(γ-benzyl-L-
glutamate) (PBLG). I conducted extensive research on the synthesis of poly(β-benzyl-
L-aspartate) (PBLA) and further functionalized it using different types of amines,
including diethylenetriamine (DET), ethylenediamine (EDA), triethylenetetramine
(TET), and tetraethylenepentamine (TEP) to obtain polyaspartamides with varying
amine functionalities. These functionalized polymers were used to coat lipid
nanoparticles (LNPs) for enhanced mRNA delivery.
This work was inspired by the growing need for effective, non-viral vectors for
gene therapy, particularly in delivering nucleic acid-based therapeutics, including
mRNA. LNPs have shown significant promise as non-viral vectors for the delivery of
nucleic acid-based therapeutics owing to their biocompatibility as well as their
unprecedented efficacy to encapsulate and protect sensitive payloads (e.g., mRNA).
However, enhancing the performance of LNPs, particularly in terms of stability and
cellular uptake, remains a perpetuating challenge, which necessitate alternative
strategies to address this problem. To achieve this, I first focused on the synthesis of
poly(aspartic acid) (PAsp) derivatives functionalized with different types of amines. I
synthesized PAsp(DET), PAsp(EDA), PAsp(TET), and PAsp(TEP) using a two-step
process. The first step involves the ring-opening polymerization (ROP) of β-benzyl-L-
aspartate N-carboxyanhydride (BLA-NCA) to synthesize PBLA, followed by the
x
aminolysis of the pendant benzyl ester groups using different types of amines,
including EDA, DET, TET, and TEP. The resulting polymers exhibited diverse
cationic charge densities, which I hypothesized would influence their interactions
with LNPs and improve mRNA encapsulation as well as release
