Synthesis of a Double-Hydrophilic Block Copolymer with a Multifunctional Block: Spontaneous Formation of Polyion Complex Micelles from a Single Cationic–Anionic Copolymer

A double-hydrophilic block copolymer (DHBC) exhibiting a multifunctional block was obtained via a multistep synthesis. First, the parent copolymer, Par. Pol., P(OEGMEA)-b-PAA, composed of a neutral block of poly(oligo(ethylene glycol))-methyl ether acrylate (P(OEGMEA)) and a weak polyacid block of poly(acrylic acid) (PAA), was synthesized by RAFT polymerization. Then, the PAA block was modified via the activation/amidation route, using N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS) to activate the DHBC, yielding the activated copolymer Act. Pol., before reaction with N-Boc ethylenediamine. The resulting amidated copolymer, named Ami. Pol., composed of P(OEGMEA)-b-P(AA-s-(Acyl urea)-s-(N-Boc)), exhibits several functional groups on the second block: acrylates from the PAA backbone, pending N-Acyl urea, and finally pending N-Boc ethylenediamine. N-Acyl urea exhibits tertiary amines, while N-boc ethylenediamine adds primary amines protected by a tert-butyl group, which can later be removed by a deprotection step using trichloroacetic acid (TCA), yielding the final P(OEGMEA)-b-P(AA-s-(Acyl urea)-s-(AA/NH₂)) copolymer, labeled De. Pol. We characterized the DHBC at every stage of the modification (i.e., parent copolymer, activated copolymer, amidated copolymer, and deprotected copolymer) using a combination of NMR and elemental analysis to assess the number of units of each group in the second block. After activation/amidation, N-Acyl urea groups represent ca. 13–32% of the second block, depending on the activation conditions, while the amount of N-Boc ethylenediamine groups is ca. 8–34%, depending on the amidation conditions. We demonstrated the efficient removal of the tert-butyl protection groups after deprotection without any damage to the DHBC. Due to the presence of acrylates and amine functions, the activated, amidated, and deprotected copolymers exhibit pH-tunable self-assembling properties. Samples were studied at pH values ranging from 2 to 9, using dynamic light scattering (DLS), ζ-potential measurements, and ATR-FTIR, and well-defined micelles were observed at pH values ranging from 4–9. The combination of measurements, coupled with DLS studies as a function of salt, provided evidence that micelles were formed by electrostatic complexation between the positively charged N-Acyl urea pending groups and the unmodified negatively charged acrylate species. Micelles were then characterized using a combination of light and small-angle neutron scattering (SANS). Notably, an optimum pH range for micellization of 5–7 with a single population was obtained by dynamic light scattering (DLS). SANS data were successfully fitted using a model of polymer micelles, which provided information about the core radius of the micelles R (6.3 ± 0.1 nm for amidated copolymer at pH = 5), the gyration radius of the P(OEGMEA) chains in the micelle shell R_g (3.3 ± 0.1 nm), and the polydispersity in size σ (13 ± 1%). SANS patterns of amidated copolymers as a function of concentration were also studied, and data were successfully fitted by adding a hard-sphere structure factor, providing evidence of intermicellar interactions. Finally, SANS patterns of the deprotected copolymer showed a decrease in the core radius (R = 5.3 ± 0.1 nm at pH = 5), consistent with the removal of the bulky tert-butyl groups. The method developed here allows the formation of DHBCs that not only exhibit self-assembling properties in water due to the addition of N-Acyl urea groups but also present extra functional groups (in our case, primary amines).