Synthesising delivery platforms for poorly soluble, cytotoxic chemotherapeutics remains a crucial challenge in modern medicine. Biomimetic polymer nanocarriers combine biocompatibility, biodegradability and structural tenability, making them ideal for stable transport and controlled release. This thesis investigates the synthesis and optimisation of functional poly(amino acid) and poly(hydroxy acid) systems for the encapsulation and conjugation of therapeutics, producing well-defined polymeric platforms capable of self-assembly and of controlled release of their respective payload.
Monomer synthesis was addressed through preparation of a library of N- and O-carboxyanhydrides (NCA, OCA) including Fmoc-, Z- and Boc-protected lysine NCAs and mandelic acid OCA. Traditional phosgene-activated synthetic strategies were evaluated against modern phosgene-free alternatives, revealing distinct differences in safety, purity and robustness to undesirable side reactions. From these monomers, via ring-opening polymerisation (ROP), were synthesised two complementary amphiphilic block copolymer platforms. In the first, mPEG-b-poly(mandelic acid) copolymers were synthesised under systematically varied reaction conditions. The products exhibited narrow molecular weight distributions and self-assembled into sub-200 nm nanoparticles with low polydispersity. These platforms were capable of encapsulating doxorubicin with high efficiency and demonstrated slow, pH-responsive release behaviour with no unwanted burst release and limited leakage at physiological pH. This highlighting the potential of the PMA backbone for pH-sensitive drug delivery.
The second system utilised mPEG-b-PLys block copolymers, synthesised under extensive kinetic and mechanistic investigation including in-situ FTIR monitoring. Challenges with the Fmoc- and Z-protected systems were addressed, with Boc-protected championed for its robust synthesis and rapid, simple deprotection. Subsequent post-polymerisation modification introduced oligo(ethylene glycol) grafts to relieve steric congestion around lysine pendant amines, enabling efficient carbamate conjugation to SN38. The resulting conjugates formed uniform nanoparticles that exhibited excellent stability and sustained release under physiologically relevant conditions.
