Drug delivery systems based on intrinsically conducting polymers

Abstract

This work provides an overview of the up to date research related to intrinsically conducting polymers (ICPs) and their function as novel drug delivery systems (DDSs). Drugs administrated to patients do not always reach the targeted organ, which may affect other tissues leading to undesired side-effects. To overcome these problems, DDSs are under development. Nowadays, it is possible to target the administration and, most importantly, to achieve a controlled drug dosage upon external stimuli. Particularly, the attention of this work focuses on the drug release upon electrical stimuli employing ICPs. These are well-known organic polymers with outstanding electrical properties similar to metals but also retaining some advantageous characteristics normally related to polymers, like mechanical stability and easiness of processing. Depending on the redox state, ICPs can incorporate or release anionic or cationic molecules on-demand. Besides, the releasing rate can be finely tuned by the type of electrical stimulation applied. Another interesting feature is that ICPs are capable to sense redox molecules such as dopamine, serotonin or ascorbic acid among others. Therefore, future prospects go towards the design of materials where the releasing rate could be self-adjusted in response to changes in the surrounding environment. This recompilation of ideas and projects provides a critic outline of ICPs synthesis progress related to their use as DDSs. Definitely, ICPs are a very promising branch of DDSs where the dose can be finely tuned by the exertion of an external stimulus, hence optimizing the repercussions of the drug and diminishing its side effects.

Introduction

The understanding of human and animal diseases increases year by year, which results in a greater capacity to design and synthetize new drugs for curing them. However, the efficacy of such drugs becomes less relevant if they are not delivered efficiently with the appropriate dosage for the disease stage, if they not directed to the correct target, and/or if they are left to interact with unwanted targets for a long time, leading to serious side effects.

Rapid developments are also under way in the biomaterials field, which have a great impact on patient care [1]. Although the release and efficacy of a broad variety of drugs, antibodies, enzymes and vaccines have been improved for decades [2,3], the need of drug delivery systems (DDSs) with controlled, localized and efficient drug dosage remains. The principal problems of conventional drug administration methods are the poor solubility and rapid degradation of the drugs, the possible normal tissue damage, the unfavourable pharmacokinetics, the low biodistribution, and the lack of selectivity. DDSs can be used to improve the drugs solubility by incorporating amphiphilic components (e.g. lipids or specially designed polymers). Furthermore, DDSs provide a carrier for the drug, making difficult the accidental extravasation and increasing the protection from early stage degradation. Besides, they can slow down the renal clearance, reduce side effects and increase drug concentrations in the diseased tissue by the enhanced permeability and retention effect or by ligand-mediated targeting.

The first steps aimed at the production of DDSs were done in 1950, when drugs were incorporated into solid polymers to obtain sustained drug release for agricultural purposes. In next decades, those approaches were extended to biomedicine [4] and, since then, this field have not stopped burgeoning. The first patent for controlled drug release, which consisted on the utilization of coatings onto edible tablets, was deposited by Wurster [5]. In 1968 Zaffaroni founded ALZA, the first company dedicated to the commercialization of DDSs, which started releasing low molecular weight drugs, like pilocarpine, using ethylene vinyl acetate copolymer and poly(hydroxyethyl-methacrylate). Later on, many other polymers were used to retain both low and high molecular weight molecules, which were released in a slow fashion manner when exposed to aqueous conditions [6].

In the 1960s, Bangham and Horne studied lipids as units for bilayered structures [7], promoting the research of liposomes as potential drug carriers [8]. Nowadays, some systems based on lipids are commercially used for cancer therapy, as for example DaunoXome (liposomal Daunorubicin), Doxil (liposomal Doxorubicin) and Ara-C liposomal (liposomal Citarabine). Later on, DDSs extended towards many other inorganic materials (e.g. iron oxide [9,10], gold [11,12], and silicon [13,14]) and organic materials [15]. Among the latter, polymers outstand from the rest since they can be modelled and processed into a wide range of forms, such as membranes, fibers, foams, micelles, dendrimers, nanoparticles (NPs) and hydrogels. This adjustable feature, combined with their ease of handling, results in materials that can be accommodated for the treatment of a huge number of medical conditions. Some of these materials are used clinically for a wide range of therapies. For example, Lupron Depot, which consists of poly(lactic-co-glycolic) acid (PLGA) microspheres that encapsulate the hormone leuprolide, is used to treat advanced prostate cancer.

Biodegradable polymers, as for example poly(lactic acid) (PLA) and PLGA, are suitable materials for sustained long term release in vivo. However, there is no control when the drug wants to be delivered as a response to a change or on demand. New-born systems are those called stimuli responsive or smart biomaterials. When there is an environment change some materials are designed to exert a response (e.g. pressure, pH, enzymes, level of glucose or temperature) or, alternatively, the responses can be remotely trigged by an external stimuli (e.g. near infrared light, ultrasounds, magnetic fields or electric currents). The former materials respond to localized changes on the ambient of pathological abnormalities and promote the drug release, while the latter ones are stimulated on demand for pulsatile drug delivery. Overall, it has been claimed that the global advanced market for DDSs is expected to grow from roughly $178.8 billion in 2015 to nearly $227.3 billion by 2020 [16].