pH-Induced Amphiphilicity-Reversing Schizophrenic Aggregation by Alternating Copolymers

A series of copolymers with controlled monomer sequences are prepared via the reversible addition–fragmentation chain transfer polymerization of tert -butyl carbamate (Boc)- l -alanine (VBA) and Boc- l -alanyl- l -leucine-conjugated styrenic (VBD) monomers with l -alanine-appended maleimide (NMA). Monomer distribution in the copolymer is examined by both 1 H and 13 C NMR spectroscopy which eventually confirms an alternate placement of the different monomers throughout the polymer main chain in both the copolymerization systems: VBA–NMA and VBD–NMA. After the successful expulsion of the pendant Boc groups, the deprotected copolymers with free −NH 3 + and −COOH functionalities in the side chain show pH-induced solubility transition in the pH range 3–8. As signified from 1 H NMR analysis, this solubility transition is mainly associated with a pH-dependent schizophrenic core–shell alteration of the aggregated polymer structure in aqueous solution which is also supported by the dynamic light scattering measurements showing a variation of the hydrodynamic diameters of the aggregates at different solution pH values. Scanning electron microscopy and transmission electron microscopy further evidenced the schizophrenic nature of deprotected copolymers where significant morphological variations (from spherical micelles to vesicles or nearly wormlike aggregates) are obtained as a result of varying the solution pH value. The observed morphologies at different solution pH values are explained via computer simulations of a model chain with varying hydrophobicity of alternating side groups. Such schizophrenic morphological transitions of the deprotected copolymers enable us to investigate their drug encapsulation and sustained release behaviors depending on the pH of the aqueous solution. To the best of our knowledge, this is the first report where an alternating copolymer shows pH-induced schizophrenic morphological transition behavior.