Nanomedicine: An Emerging era of Theranostics and Therapeutics for Rheumatoid Arthritis

Naila Qamar; Ammara Arif; Attya Bhatti; Peter John

Disclosures

Rheumatology. 2019;58(10):1715-1721. 

In This Article

Abstract and Introduction

Abstract

RA is a multifactorial autoimmune inflammatory disease characterized by synovitis, bone destruction and joint dysfunction that leads to shortening of lifespan and increased mortality rates. Currently available treatments of RA, by controlling various symptoms, only delay disease progression and have their own side effects. Consequently, there is the need for a novel therapeutic strategy that offers a more sustainable and biocompatible solution. Nanomedicine is a modern branch of nanobiotechnology that provides targeted therapy to inflamed rheumatic joints and thus prevents unwanted off-target side effects. This review highlights various nanotheranostic and nanotherapeutic strategies that are currently being used for the treatment of RA.

Introduction

RA is a common polyarticular autoimmune inflammatory disease described by cartilage and bone destruction in the synovial joints leading to joint impairment and decrease in life expectancy.[1–3] Although the exact mechanism of RA is still unclear, environmental and genetic factors are known to contribute to disease susceptibility.[1] In the synovial tissues, the immune system releases certain enzymes and chemicals that lead to erosion of bones and cartilage, which is one of the major factors resulting in arthritis, a disease affecting numerous joints of the body including the small joints of the hands, wrists, elbows, shoulders, knees, hip, cervical spine, ankles and feet.[4,5,8] The global prevalence of RA is about 0.5–1%;[6–9] in the developing countries its prevalence varies and various studies indicate that the Western countries have a greater prevalence of RA than others.[7,10] It is three times more common among females as compared with males[6,11] and more prevalent in women above 65 years of age, which could be attributed to hormonal changes.[12]

The existing treatments of RA, such as NSAIDs, DMARDs, glucocorticoids and biologic drugs,[1,6] either produce symptomatic relief or alter the disease process. Although these are effective treatments, their use is restricted because of their damaging side effects, such as cardiac complications, gastrointestinal damage and ulcers, along with immunosuppression that leads to the development of opportunistic infections.[1] Etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira) are some of the biologics used to treat RA[6,13] and many other inflammatory conditions. Despite recent medical advances, there is still an unmet need to develop treatments for RA because of safety and efficacy concerns associated with the currently available drugs.[13]

Adverse consequences due to non-selective activity of the currently available RA therapeutics can be reduced by encapsulating these bioactive molecules in nanocarriers for a more targeted approach to delivering the drugs at the desired site of action (i.e. the joints) by avoiding frequent or high dosing, to achieve an effective drug concentration locally.[2,14] Furthermore, nanocarriers can be engineered to protect these bioactive molecules from degradation, thus increasing their bioavailability, while decreasing off-target side effects. There can be targeting of certain specific receptors or of macrophage uptake to invade diseased tissues such as inflamed joints;[13,15] and the uptake of nanocarriers by spleen and liver can be prevented by modifying their physiochemical properties, such as enhanced penetration through biological barriers and encapsulation.[16] Once the nanocarriers reach the target tissue or organ, the drug can be released in a controlled fashion depending on the pH, temperature, solubility, redox conditions, etc. Scientists have been successful in making nanomaterials that respond to these physical or biological stimuli, termed 'intelligent' or 'smart' delivery systems.[17] This allows investigators to examine or re-examine bioactive molecules that were previously thought to be too toxic to deliver through a systemic route.[14] Nanomedicine is the use of nanotechnology in medicine to ease the diagnosis, treatment and monitoring of treatment[18] by using nanoparticles, dendrimers, polymeric micelles, drug-loaded liposomes,[19] nanocapsules and nanogels. In addition polymer–protein conjugates, polymer–drug conjugates and antibodies also come under the umbrella of nanomedicine.[13]

The most important phenomenon for the treatment of RA and other chronic inflammatory disorders is enhanced permeability and retention because of the extensive systemic nature of inflammation. Synthesis of nanoparticles that are ideally sized (10–1000 nm) and modification of their surface with appropriate functional groups can help increase their circulation time and hence provide maximum benefit in performing their desired task.[20] The nanomedicine actively or passively accumulates in the inflamed joints through an enhanced permeation and retention effect. The permeation and accumulation of nanomaterials at the site of inflammation is facilitated by disturbed vasculature and decreased lymphatic drainage under inflammatory conditions and at solid tumours through passive targeting. An appropriate receptor-specific ligand is attached to a nanocarrier for precise binding in the case of active targeting, which aids in increased efficacy and reduced systemic side effects.[13,21]

In one approach, theranostics, nanomedicine may open up a new way to associate diagnosis and treatment.[22,23] Biodegradable, biocompatible and disease-modifying anti-rheumatic nanomedicines (DMARNs) represent a likely therapeutic approach for osteoarthritis and RA. The enhanced bioavailability and bioactivity of DMARNs at the site of inflammation is due to the combination of unique physiochemical properties of nanocarriers and the pathophysiological properties of inflamed joints, through selective targeting and minimization of off-target adverse effects. Therefore, nanomedicine not only reduces the drug dosage but also decreases the treatment duration.[24] The surface modifications of nanomaterials such as nanoparticles (metallic, polymeric, solid-lipid nanoparticles), nanocomposites, nanoconjugates, nanocarriers, nanowhiskers, micelles, specifically coated nanoparticles and receptor-targeted nanoparticles allow the selective targeting of inflamed joints through the linked drugs, ligands, and prognostic or diagnostic markers, as illustrated in Figure 1. Some of the nanotheranostic and nanotherapeutic approaches utilizing these nanomaterials that have been proved to be effective in RA are summarized in Figure 2.

Figure 1.

Role of nanomaterials in amelioration of joint damage

Figure 2.

Various theranostic and therapeutic applications of nanomaterials

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