Programmable 3D printed conductive polymers for releasing neutrally-charged drugs

Abstract

Conductive polymers (CPs) are a class of functional polymers that can respond to a voltage stimulus. As a drug delivery system (DDS), the voltage applied to CPs can modulate drug release, offering unprecedented spatial and temporal control as we strive for precision and personalised medicines. However, this requires the drug to be charged in order to respond to a voltage stimulus, where unfortunately there are numerous drugs that are neutrally-charged. Herein, we propose an innovative solution that leverages charged polymeric particles as an intermediary vehicle. In this investigation, we electrospray paracetamol, a neutrally-charged drug, with poly(lactic-co-glycolic acid) (PLGA) to obtain drug-loaded microparticles with an overall negative charge of −53.01 ± 2.71 mV. The drug-loaded microparticles were then mixed with a CP and fabricated into films using a three dimensional (3D) printer. The films were subjected to voltages of 0, +1 and −1 V, where multivariate analysis of variance (MANOVA) revealed statistical significance in their drug release profiles. Applying −1 V (i.e., the same charge as the PLGA particle) resulted in a three-fold increase in drug release compared to 0 V (i.e., passive release), increasing from 9.82 ± 1.32 % to 29.03 ± 2.34 %. Furthermore, the platform was confirmed to respond and exhibit pulsatile release when switching the voltage “on-and-off”. Another benefit of leveraging PLGA discovered included sustained drug release, which is discussed. The findings suggest that charged polymeric particles can enable voltage-responsive release of neutrally-charged drugs from CPs, and signals a promising strategy for widening the clinical impact of CPs as DDSs.

Introduction

Medicines should be designed with the precision medicine framework in mind, ensuring the precision and customisability of the therapeutic to meet the patient’s needs [1,2]. A significant advancement is the development of smart drug delivery systems (DDS), which offer advanced control over the delivery of a therapeutic [3]. These smart DDS encompass various stimuli-responsive materials, where the external stimuli can be controlled. This includes conductive polymers (CPs), which are a class of functionalised materials that can change their properties in response to electrical stimuli [[4], [5], [6]]. By incorporating these polymers into a DDS, it is possible to create electro-responsive pharmaceuticals for additional control over drug release [[7], [8], [9]]. For example, recent work has demonstrated that CPs stimulated with voltage yielded a 20-fold change in drug release [10], controllable and responsive pulsatile release [11], real-time control using in vivo studies [[12], [13], [14]] and multifunctional properties in both drug release and biosensing [[15], [16], [17]]. Hence, there is potential to achieve an additional level of programmable and real-time control using CPs. This precise control over drug release will not only enhance therapeutic efficacy and minimise side effects but also garner the prospect of progressing towards digital pharmaceuticals [[17], [18], [19], [20]], and integrating therapeutics within the healthcare internet of things (IoT) infrastructure [17], Furthermore, the recent food and drug administration (FDA) approval of a medical device containing CPs demonstrates their clinical translation potential [21].

Despite the above potential, one limitation of CPs as smart DDSs is that while neutrally-charged drugs can be incorporated into CPs, they will not respond to the applied voltage polarity [22]. This means that many of the drugs that are neutrally-charged cannot be digitally programmed to release on-demand. Examples include common over-the-counter drugs like paracetamol [23], and widely prescribed drugs like atorvastatin [24] and carbamazepine [25]. Such drugs can benefit from programmable and on-demand release to avoid undesirable health consequences, or benefit from intelligent and automated release to combat unpredictable onset of symptoms (e.g., an unexpected seizure). Thus, there is a need to develop a mechanism that allows neutrally-charged drugs to be responsive to programmable release, thereby expanding the clinical potential of CPs.

A potential strategy to allow neutrally-charged drugs to respond to voltage-stimulated CPs is to use charged polymeric carriers. These are particulate systems with their surface containing charged moieties, which have been exploited as a standalone DDS to enhance cellular uptake or adhesion onto biological targets that exhibit the opposite charge [[26], [27], [28], [29], [30], [31]]. Furthermore, both experimental and theoretical studies have shown that polymeric particles that are charged respond to an electric field by undergoing electrophoretic motion, governed by their surface charge [32,33]. Their movement has been found to occur in liquid, viscoelastic media and, to some extent, migrating across the surface of skin tissue, thereby demonstrating their ability to migrate through a range of media [32,34,35]. A prominent polymer example is poly(lactic-co-glycolic acid) (PLGA), which is fabricated as either a nano- or microparticle to encapsulate drug, with multiple studies reporting that PLGA maintains its surface charge after being loaded with drugs [[36], [37], [38], [39]], whilst possessing excellent biocompatibility, improved drug stability, solubility and permeability [40,41]. Thus, it stands to reason that charged polymeric particles can facilitate the voltage responsive release of neutrally-charged drugs in CPs by migrating under an electric field and expelled from the CP matrix.

To that end, it was hypothesised that neutrally-charged drugs encapsulated with PLGA microparticles will respond to voltage stimuli in CPs. In this study, a drug-loaded PLGA microparticle was fabricated and then loaded onto a CP, which was subsequently 3D printed into films. Furthermore, the system’s drug release kinetic in response to both excitatory and inhibitory voltages was elucidated. Moreover, a thorough characterisation of both the microparticles and the composite film to facilitate our understanding of the release profile. Our primary aim was to determine whether charged polymeric particles containing neutrally-charged drugs can be released in response to a voltage stimulus.

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Materials

Poly(lactic-co-glycolic Acid) PLGA (50:50, PURASORB PDLG 5002) was purchased from Corbion (Amsterdam, Netherlands). Paracetamol (≥99.0 % purity), poly(3,4-ethylenedioxythiophene)-poly(stryrenesulfonate) (PEDOT:PSS) (768,618-1G), acetone, and dimethylformamide (DMF) were obtained from Sigma Aldrich (Gillingham, UK). Thermoplastic polyurethane (TPU) (ElastollanR) was received from BASF (Ludwigshafen, Germany). Deionized water was generated using ELGA water purification system (VWS Ltd., UK). Phosphate-buffered saline (PBS) (pH = 7.4) was prepared using 8.0 g/L NaCl, 0.2 g/L KCl, 1.42 g/L Na2HPO4 and 0.24 g/L KH2PO4, all of which were also purchased from Sigma Aldrich (Gillingham, UK).

Manal E. Alkahtani, Yiding Liu, Hanxiang Li, Haya Alfassam, Christopher A.R. Chapman, Rylie Green, Simon Gaisford, Abdul W. Basit, Mine Orlu, Moe Elbadawi, Programmable 3D printed conductive polymers for releasing neutrally-charged drugs, Materials Today Advances, Volume 29, 2026, 100702, ISSN 2590-0498, https://doi.org/10.1016/j.mtadv.2026.100702.

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