Design and functions of phospholipid polymer cell shuttles for modern pharmaceutical formulations

Abstract

The development of polymeric biomaterials for modern pharmaceutical formulations has attracted considerable attention, given the recent trend of advanced pharmaceutical modalities that have increased molecular weight and hydrophobicity. Phospholipid polymers, such as poly[2-methacryloyloxyethyl phosphorylcholine (MPC)-co–n-butyl methacrylate (BMA)] (PMB) is a promising candidate for use as cytocompatible drug carrier materials. PMB is a bioinspired polymer that mimics the plasma membrane and offers superior biomaterial properties, such as bioinert and antibiofouling characteristics. By adjusting the copolymer composition and molecular weight, water-soluble PMB can be synthesized, resulting in the formation of polymeric lipid nanoaggregates. Water-soluble PMB can stably solubilize poorly water-soluble drugs. Moreover, PMB exhibits bidirectional permeation across the plasma membrane. This polymer lipid nanoaggregate, which diffuses and penetrates through intra- and extracellular spaces, was designed as a “cell shuttle”. This focus review discusses studies of cell shuttles in the context of multipharmaceutical modalities, including the effects of polymer architecture on intracellular internalization, the intracellular delivery of hydrophobic compounds, and the cytosolic delivery of proteins. Finally, the utilities of the phospholipid polymer-based cell shuttle are outlined from the perspective of pharmaceutical sciences.

Introduction

The development of synthetic chemistry, biotechnology, and advanced analytical technology has enabled the design and production of compounds and proteins as active pharmaceutical ingredients (APIs) [1,2,3,4]. Chemical APIs are becoming increasingly complex and possess high molecular weights. Drugs targeting protein‒protein interactions (PPIs) have emerged in the global market. In addition, the use of recombinant proteins as APIs has led to a paradigm shift in the treatment of intractable disease [5]. Some PPI modulators and proteins are classified as medium- or high-molecular-weight drugs, which have difficulty crossing the plasma membrane [6].

Materials for pharmaceutical formulations are required to assist these APIs by improving their stability, intracellular availability, pharmacokinetics, and pharmacodynamics [7, 8]. Polymer-based nanomaterials are suitable for achieving these objectives [8, 9]. In particular, poly(ethylene glycol) (PEG) conjugation and PEGylation have been studied for decades and have demonstrated superior performance in preclinical and clinical research [9]. In recent years, anti-PEG antibodies have been reported in individuals who received mRNA vaccines [10]. The immunogenicity of PEG can lead to undesired immune responses, including the accelerated blood clearance (ABC) phenomenon observed with PEGylated nanomaterials [11,12,13]. The ABC phenomenon is an obstacle to medicines that require multiple administrations and is a cause of unanticipated reactions. Hence, alternative materials to PEG have attracted much attention in biomaterial science [12, 13].

Phospholipid polymers are promising candidates for pharmaceutical formulation materials [14,15,16]. A series of copolymers composed of 2-methacryloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate (BMA), known as poly(MPC-co-BMA) (PMB), are bioinspired polymers [17, 18]. Water-insoluble PMB-coated biointerfaces possess excellent antibiofouling properties and completely suppress foreign body reactions [19,20,21,22]. Water-soluble phospholipid polymers can disperse poorly water-soluble compounds in aqueous media by simply mixing them with the polymer. Moreover, amphiphilic phospholipid polymers can permeate across the plasma membrane. The copolymer of MPC and ferrocene, poly(MPC-co-vinyl ferrocene) (pMFc), permeated the plasma membrane and mediated extracellular electron transfer by utilizing the redox activity of the ferrocene unit. This resulted in the alteration of the intracellular redox state to an oxidative state, which induced apoptosis [23,24,25]. This polymer is internalized into the cell and subsequently exits outside the cell. A nanomaterial that exhibits this bidirectional cellular permeation is defined as a “cell shuttle”. We aim to improve and extend the functionalities of the cell shuttle for use as pharmaceutical formulation materials. This focus review summarizes our efforts concerning a phospholipid polymer-based cell shuttle (Fig. 1). We discuss the relationship between bidirectional cellular permeation and the polymer architecture of cell shuttles, the cellular distribution of poorly water-soluble compounds, and the intracellular delivery of proteins.

Effects of phospholipid polymer architecture on cellular internalization and exiting

Polymer architecture influences the behavior of polymer assemblies in water and their interactions with the plasma membrane. Amphiphilic linear polymers have been studied for many years. Compared with nonlinear polymers, linear polymers tend to adopt a more expanded conformation in solution. Branched polymers exhibit a wide variety of branching shapes. Star polymers, which have polymer chains extending from one branching point, are the simplest branched polymers and have been studied from the perspective of polymer physics for decades [26,27,28]. Star polymers have lower solution viscosity than linear polymers [29, 30]. Near the branching point of star polymers, an excluded volume effect occurs because their polymer chains crowd the surrounding polymer proximity [31].

We studied the cellular internalization and exiting behavior of 4-armed star-shaped phospholipid polymers (Fig. 2(a)). Four-armed poly(MPC-co-BMA) (4armPMB) was synthesized by atom-transfer radical polymerization (ATRP), with polymer chains extended from a four-functional initiator, pentaerythritol tetrakis (2-bromoisobutyrate), using a copper catalyst. These star phospholipid polymers self-assembled in phosphate-buffered saline (PBS(−)), and their critical aggregation concentration (CAC) did not significantly differ from that of linear polymers [32]. The MPC homopolymer did not aggregate in aqueous solution. In contrast, the monomer composition and sequence significantly affect the CAC of polymers, as previously reported [33, 34] and as shown in our unpublished data. In our study [32], the monomer composition was fixed to 30 mol%/70 mol% MPC/BMA, and the basic solution properties were investigated, with a focus on the polymer architecture (star and linear polymers). Compared with linear PMB nanoaggregates (15 nm), 4armPMB nanoaggregates had a larger hydrodynamic diameter (25 nm) [32]. Moreover, 4armPMB nanoaggregates tended to take a broader conformation than that of linear PMB. 4armPMB has a branching point, and the polymer chains near the branching point expand because of the excluded volume. Temperature-variable 1H-NMR measurements revealed that the α-methyl groups of the polymer backbone in 4armPMB nanoaggregates had lower mobility than that of linear PMB at body temperature [32]. Therefore, 4armPMB covers the surface of the nanoaggregate with more MPC units than linear PMB does.

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Yoshizaki, Y., Konno, T. Design and functions of phospholipid polymer cell shuttles for modern pharmaceutical formulations. Polym J (2026). https://doi.org/10.1038/s41428-026-01174-5

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