Colloidal drug delivery vehicles, relevant for targeted therapy, often benefit from design attributes such as hydrophilic polymer coatings, which optimize their therapeutic index [1], [2]. Besides attempts to further upgrade the gold-standard poly(ethylene glycol) [3], [4], recent research explored zwitterionic macromolecules for such purpose [5], [6]. Polymers based on 2-(methacryloyloxy)ethyl phosphorylcholine (MPC) have attracted special attention due to their favorable properties (e.g., ability to evade the immune system incl. the accelerated blood clearance phenomenon, and to prolong circulation half-life) [7], [8], [9] and proven biocompatibility (tested up to trials in humans) [10]. Furthermore, MPC-based polymers are an excellent example of “bioinspiration”, in which novel, improved materials are developed from the remarkable solutions found in living organisms (i.e., hydrophilicity and biocompatibility of the head-group of phospholipids) with the aim to “imitate” their chemistry and/or functionality [11].

Zwitterionic macromolecules reveal pronounced hydrophilicity while maintaining an overall neutral net charge. In aqueous environments, said polymers are well-solvated and “intrapolymer” interactions make the attached grafts expand away from a surface, thus, generating protecting layers [12]. Polymer characteristics (e.g., type of monomer(s), molecular weight) and environmental factors (e.g., type of solvent(s), ionic strength) determine the quality of the layer architecture [13], [14]. Furthermore, the method utilized to “anchor” a given polymer on a surface often influenced layer features like thickness and density of surface coverage [15], [16], [17]. For targeted drug therapy, the application of amphiphilic triblock copolymers is of particular interest, because the coating can be “attached” to the surface easily during or post particle manufacturing and, furthermore, the formed layer architecture can be precisely engineered [15], Beck-Broichsitter, 2023, [19].

In this context, the author has synthesized and tested a library of PMPC-based triblock copolymers and identified general design principles and structure-function relationships, which affected the in vitro performance of PMPC-coated nanoparticles [18]. Triblock copolymers with one central hydrophobic poly(propylene) (PPG) of ≥2 kDa flanked by two hydrophilic PMPC blocks each of ≥5 kDa were shown to be the most promising. In the current study, the author expanded on this approach by pre-selecting one PMPC-PPG-PMPC polymer and challenging the respective colloidal formulation on two distinct routes of administration.