Citation: Vagenas, D.; Pispas, S. Triple Hydrophilic Statistical Terpolymers via RAFT Polymerization: Synthesis and Properties in Aqueous Solutions. Polymers 2023, 15, 2492. https://doi.org/10.3390/ polym15112492 Academic Editor: Shin-Ichi Yusa Received: 28 April 2023 Revised: 23 May 2023 Accepted: 26 May 2023 Published: 29 May 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). polymers Article Triple Hydrophilic Statistical Terpolymers via RAFT Polymerization: Synthesis and Properties in Aqueous Solutions Dimitrios Vagenas and Stergios Pispas * Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 11635 Athens, Greece; dimitrisv98@gmail.com * Correspondence: pispas@eie.gr Abstract: In this work, we report the synthesis of novel triple hydrophilic statistical terpolymers consisting of three different methacrylate monomers with varying degrees of responsivity to solu- tion conditions. Terpolymers of the type poly(di(ethylene glycol) methyl ether methacrylate-co-2- (dimethylamino)ethylmethacrylate-co-oligoethylene glycol methyl ether methacrylate), P(DEGMA- co-DMAEMA-co-OEGMA), and of different compositions, were prepared by using the RAFT method- ology. Their molecular characterization was carried out using size exclusion chromatography (SEC) and spectroscopic techniques, including 1 H-NMR and ATR-FTIR. Studies in dilute aqueous media by dynamic and electrophoretic light scattering (DLS and ELS) show their potential responsiveness regarding changes in temperature, pH, and kosmotropic salt concentration. Finally, the change in hydrophilic/hydrophobic balance of the formed terpolymer nanoparticles during heating and cool- ing was studied using fluorescence spectroscopy (FS) in conjunction with pyrene giving additional information on the responsiveness and internal structure of the self-assembled nanoaggregates. Keywords: triple hydrophilic copolymers; responsive copolymers; RAFT polymerization; self-assembly; nanoaggregates 1. Introduction Over the last few years, the fabrication of polymers, which demonstrate fascinat- ing properties in solutions and can be applied in numerous studies, most of the time concerning the biomedical field, has been accelerated due to the tremendous evolution of polymerization techniques. Reversible addition fragmentation chain transfer (RAFT) is such a polymerization technique, providing versatility, control, and “livingness” to the synthesis process despite its radical attributes. Via this technique, it is possible to synthesize copolymers of different architectures and molecular weights, with a signifi- cantly low-molecular-mass dispersity and high end-group functionality [1]. Their induced self-assembly in aqueous solutions, regardless of their architecture, makes them ideal candidates for biomedical applications, such as drug delivery, gene delivery, or even tissue engineering [2,3]. In most cases, block copolymers are the epicenter of research, mainly because of their unique self-assembly in aqueous solutions, ending up in micelle forma- tion, a well-defined morphology where nanoscale particles are concerned. However, the synthesis of block copolymers can be difficult and time-consuming due to the sequential addition of monomers for each block and sometimes the postpolymerization treatment that may be necessary. On the other hand, statistical (or random) copolymers can be prepared via a one-step reaction, applying the RAFT technique, given the potential to copolymerize two or more monomers simultaneously [4]. It is well known that the self-assembly of statistical copolymers provides less-well-defined nanostructures, as monomers/segments are randomly distributed along the polymer chains. However, supramolecular interactions occur in such systems, resulting in a variety of morphologies, which are worthy of further study. In fact, their nanostructures could be proven essential concerning the efficiency either of drug encapsulation or of its release. Polymers 2023, 15, 2492. https://doi.org/10.3390/polym15112492 https://www.mdpi.com/journal/polymers