Elsevier

Journal of Controlled Release

Volume 190, 28 September 2014, Pages 624-636
Journal of Controlled Release

Review
Liposomal corticosteroids for the treatment of inflammatory disorders and cancer

https://doi.org/10.1016/j.jconrel.2014.05.039Get rights and content

Abstract

Glucocorticoids (GC) are known for their potent immunosuppressive and anti-inflammatory properties. As a consequence, they have been extensively used for the treatment of many different diseases. Prolonged and/or high-dose GC therapy, however, generally comes with severe side effects, resulting not only from their very diverse mechanism(s) of action, but also from their relatively poor biodistribution. Drug delivery systems, and in particular liposomes, have been extensively used to enhance the biodistribution and the target site accumulation of GC, and to thereby improve the balance between their efficacy and their toxicity. Many different types of liposomes have been employed, and both local and systemic treatments have been evaluated. We here summarize the progress made in the use of liposomal GC formulations for the treatment of asthma, rheumatoid arthritis, multiple sclerosis and cancer, and we show that the targeted delivery of GC to pathological sites holds significant clinical potential.

Introduction

Ever since their first description by Alec Bangham more than half a century ago, liposomes have been extensively used for drug delivery applications [1], [2], [3]. Because of their relatively straightforward preparation, as well as their excellent biodegradability and biocompatibility, liposomal systems have progressed into one of the most extensively used and clinically most advanced drug delivery platforms [4].

Liposomes are composed of phospholipids, which, due to their amphiphilic nature, spontaneously self-assemble into vesicular structures when dispersed in aqueous media. In these lipid vesicles, the hydrophilic head groups line up and face the outer aqueous environment, while another layer of polar heads face the aqueous interior, segregating the hydrophobic tail groups of both layers from the aqueous environment (Fig. 1). The vesicular membrane [2], which in fact may consist of a number of bilayers, provides the liposome with structural stability, and enables the encapsulation of pharmacologically active agents, either in the layer itself for lipophilic compounds, or – more commonly – in the aqueous core for hydrophilic compounds [5]. When administered locally, the liposomal formulation allows for prolonged retention of the encapsulated drug at the injected site by limiting its diffusion and degradation (‘depot’ function). By limiting renal excretion and hepatic degradation, some liposome formulations, especially those with high transition-temperature saturated phospholipids and high cholesterol content, optionally containing a small percentage of PEGylated lipids (so-called ‘long circulating liposomes’) improve the pharmacokinetics of encapsulated drugs when administered systemically, allowing them to circulate for prolonged periods of time.

In addition, the ‘Enhanced Permeability and Retention’ (EPR) effect [7] promotes the accumulation of liposomes in tissues characterized by enhanced vascular leakiness, such as tumors and sites of inflammation, while at the same time attenuating their localization in healthy non-target tissues. In addition, liposomes can also be administered locally, such as through inhalation, and can increase the delivery and accumulation of drug molecules in the target tissue. As a consequence, liposomal drugs tend to be more effective and less toxic than standard (low-molecular-weight) drugs, they can be administered less frequently, and can improve both time- and cost-effectiveness.

Glucocorticoids (GC) are a class of steroid hormones that possess strong immunosuppressive and anti-inflammatory activity. Ever since their introduction in the 1950s, GC have therefore been extensively used in diseases caused by an excessively active immune system, such as allergies, asthma, autoimmune diseases and sepsis [8]. GC exert their effects by binding to the glucocorticoid receptor (GR) [9], which, once inside the nucleus, modulates several DNA transcription factors. This leads to the up-regulation of anti-inflammatory protein production and to a concomitant down-regulation of pro-inflammatory protein production (Fig. 2) [10].

In addition to such relatively slow genomic effects, GC also display more rapid non-genomic effects, including e.g. inhibition of arachidonic acid release and alterations in cation transport across the plasma membrane [12]. The genomic and non-genomic effects together, change the metabolism of lipids, carbohydrates, proteins and have been shown to affect bones, neurons, glial cells, and the electrolyte and water balance [7]. Although the glucocorticoid receptor (GR) is involved, the exact molecular mechanism driving the non-genomic activity of GC still remains unclear [7], [12], [13].

Because of their broad pharmacologic activity, GC are notorious for their side effects. These include immunosuppression (and the increased risk of infection), musculoskeletal complications (such as osteoporosis, osteonecrosis, myopathy), growth suppressive effects (in children), hypertension, rapid weight gain, diabetes, hypertriglyceridemia, hypercholesterolemia, dermatological effects (fat redistribution, thinning of the skin, allergic reactions), glaucoma, peptic ulcer disease, decelerated wound healing, and electrolyte imbalance [7], [14].

The encapsulation of GC in liposomes has been extensively evaluated over the past 2–3 decades. This is done to reduce the volume of distribution and the off-target accumulation of GC, thereby lowering their toxicity, as well as to increase and prolong drug levels at the pathological site, to improve their therapeutic efficacy. We here summarize several key advances in this area of research, and provide an overview of studies showing the potential usefulness of liposomal GC for improving the treatment of asthma, multiple sclerosis, rheumatoid arthritis and cancer.

Section snippets

Pathophysiology of asthma and therapeutic role of glucocorticoids

Asthma is a chronic respiratory disorder with a strong allergic component, which is characterized by an obstruction of the pulmonary airways, causing shortness of breath, wheezing, coughing and chest tightness or pain [15]. The disease initially develops with bronchial provocation and hyper-responsiveness, followed by bronchial inflammation and swelling of the inner walls of the airways (lamina reticularis). In addition, increased growth of mucus cells leads to mucus hypersecretion and a

Pathophysiology of cancer and therapeutic role of glucocorticoids

Cancer is a diverse class of diseases characterized by (epi-) genetic abnormalities causing uncontrolled cell growth. Cancer cells can invade adjacent tissues and spread to other body parts by metastasis, making cancer a progressive disease with a high mortality rate. Symptoms of cancer can be classified into 3 groups: i) local symptoms, such as unusual lumps/swelling (tumor), hemorrhage, pain and ulceration; ii) symptoms of metastasis (spreading), such as enlarged lymph nodes, cough and

Conclusions and perspectives

Although GC are highly potent drugs, and although they have been proven to be useful for the treatment of many different diseases, the severe side effects associated with their prolonged and/or high-dose use have somewhat limited their broad clinical applicability. Consequently, in order to improve drug efficacy and at the same time reduce toxicity, significant research efforts have focused on the development of drug delivery systems for GC.

Particularly liposomes have been used for targeted GC

Acknowledgments

The authors gratefully acknowledge financial support by the European Research Council (ERC-StG-309495: NeoNaNo), by the European Union (COST-Action TD1004), by NOW (HIFUCHEM 030-301; Rubicon 825.12.015) and by the DFG (LA 2937/1-2).

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