Abstract
Polymeric micelles that can respond to changes in pH have emerged as appealing systems to achieve localised drug release. These micelles can be prepared from homopeptide block copolymers, which are attractive alternatives to traditional synthetic polymers due to their unique ability to form secondary structures. However, naturally occurring amino acids have a limited variety of side chain functional groups, requiring additional modifications to tune pH-responsivity. In addition, further work is required to better understand how these structural changes to the peptide side chains can influence their pH-responsive behaviour and self-assembly. Herein, we investigate the pH responsive behaviour of a series of poly[(ethylene glycol)-b-(pyridinylmethyl glutamate)] (PEG-b-P#PG) copolymers modified with different pyridine regioisomers (para (# = 4), meta (# = 3), or ortho (# = 2) relative to the polymer chain). Potentiometric and nuclear magnetic resonance (NMR) spectroscopic titrations, coupled with zeta (ζ)-potential measurements, provided information on the ionisation behaviour of the copolymers and their acid dissociation constant (pK
) values. At neutral pH, the copolymers assembled into micelles with unique structures and exhibited characteristic pK
values resulting from the different pyridine regioisomers, which influenced the pH-responsive behaviour of the micelles. Changes in the morphology and secondary structure of the micelles as a function of pH were interrogated using dynamic light scattering (DLS), synchrotron small-angle X-ray scattering (SAXS) and circular dichroism (CD) spectroscopy. Disassembly of the PEG-b-P#PG micelles was observed when the solution pH was below the pK
, indicating that a high degree of ionisation (> 85 %) is necessary to disrupt the secondary structures of the peptide blocks. These results provide important insights into the design of pH-responsive polymer-homopeptide block copolymers and the influence of side chain regioisomers on their ionisation and assembly behaviour.