The Synthesis of Fucose and Drug Conjugated Polymer Nanoparticles Capable of Metal Ion Encapsulation

This research presents a dual approach to advancing cancer therapy and sustainable
polymer synthesis. To overcome the limitations of chemotherapeutic drugs like
camptothecin (CPT), such as poor solubility and off-target effects, a series of polymer-drug
Conjugates were developed. These conjugates, utilising biodegradable polymers including
polysarcosine (PSar) and polyglutamic acid (PGA), were engineered to self-assemble into
nanoparticles (NPs), improving CPT’s water solubility and enabling targeted delivery to
pancreatic cancer cells via fucose modificatton. The synthesis of camptothecin glycinate
Inittiated polysarcosine (CPT-Gly-PSar) conjugates achieved a high drug content but exhibited instability in NPs formation. This was overcome by PGA conjugation, forming PGA-(PSar-Gly-CPT), which produced stable NPs in PBS solution for four weeks across different concentrattons. Also, PSar modificatton further refined NP uniformity, with PGA-[(CPT-Gly)-co-(PSar)] outperforming PGA-(CPT-Gly) in size consistency and stability. The fucose-incorporated conjugate, PGA-[(CPT-Gly)-co-(F-PSar)], achieved a high drug content and formed stable NPs. Drug release studies showed a slow, sustained release in pH 7.4 PBS solution, but its extremely slow CPT release in pH 5.0 acetate buffer solution shows it may be a potential candidate for adjuvant therapy for targeting S-phase cancer cells.
Additionally, Cu²⁺ ion complexation using PGA-[(CPT-Gly)-co-(F-PSar)] was explored to
integrate chemotherapeutic and chemodynamic therapies (CDT) for enhanced efficacy. Cu²⁺ complexation was analysed via thermogravimetric analysis (TGA), which revealed an incomplete metal complexation, possibly due to acid produced during sample preparation. Energy dispersive X-ray (EDX) analysis identtfied the residue as copper oxide, and dialysis at acidic solution confirmed the Cu²⁺ release in acidic conditions. Concurrently, to eliminate the use of toxic phosgene derivatives in polymer production, amino acid diketopiperazines (DKPs) and morpholines (DKMs) were synthesised as alternatives to NCAs and assessed for ring-opening polymerisation (ROP) to produce biocompatible and biodegradable poly(amino acids) and polydepsipeptides. This work advances cancer therapy through innovative, targeted drug delivery systems and promotes sustainable polymer chemistry by developing safer synthesis alternatives, laying a foundation for future clinical and environmental applications.