PhD Oral Exam - Kadambari Kadambari, Chemistry

When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.

Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.

Abstract

Stimuli-responsive degradable amphiphilic block copolymers (SRD-ABPs) have been extensively explored as promising building blocks in the construction of smart nanoassemblies exhibiting controlled/enhanced release of encapsulated molecules including therapeutics. A recent advance involves the development of dual SRD-ABPs designed with cleavable linkages responsive to two stimuli, typically acidic pH and light. Herein, we report a new approach to achieve dual acidic pH/light responses with a single labile linkage employing conjugated benzoic imine chemistry. As a proof-of-concept, a well-defined poly(ethylene glycol)-based SRD-ABP containing conjugated benzoic imine pendants in the hydrophobic block was synthesized by reversible deactivation radical polymerization and post-polymerization modification. The synthesized copolymer self-assembled in aqueous solution to form colloidally stable nanoassemblies, consisting of acid/light-degradable hydrophobic cores surrounded with hydrophilic coronas. Upon exposure to acidic pH and UV/visible light, the nanoassemblies degraded through change in hydrophobic/hydrophilic balance of micelle cores.

Extending this strategy, conjugated aromatic imine bonds are unique in their ability to respond to both acidic pH through acid-catalyzed hydrolysis and to visible light through photo-induced E/Z isomerization, thus enabling dual responsiveness with a single chemical group. We report a robust strategy to fabricate core-crosslinked nanogels bearing extended conjugate aromatic imine linkages, exhibiting controlled degradation in response to dual acidic pH and visible light. The strategy involves pre-crosslinking a poly(ethylene glycol)-based block copolymer bearing reactive imidazole pendants with a diol crosslinker bearing extended conjugate aromatic imine, followed by dispersion of the crosslinked polymer in aqueous solution. The fabricated nanogels are non-cytotoxic, colloidally stable, and capable of encapsulating curcumin. They exhibit controlled/enhanced release of curcumin in acidic pH and under visible light irradiation, with synergistic release under dual stimuli. Furthermore, curcumin-loaded nanogels reduce cell viability in a controlled manner, unlike the free drug.

We further report aqueous nanocolloids based on step-growth conjugated poly(benzoic imine)s (M-PCs) bearing aromatic imine bonds on the backbones with absorption in the visible range (λ = 420 nm). These nanocolloids, fabricated with polymeric stabilizers, display excellent colloidal stability in physiological environments. They undergo disintegration upon degradation of the M-PC backbone under acidic pH and visible light irradiation. These results demonstrate the potential of extended aromatic imine-based nanoplatforms for dual acid/visible light-responsive therapeutic delivery with controlled/enhanced release of encapsulated drugs.