**2. History and challenges of rheumatoid arthritis treatment**

Historically, rheumatoid arthritis has been treated with a combination of anti-inflammatory drugs and immunosuppressants. Although treatment has evolved from non-steroidal anti-

The Development of Targeted Drug Delivery Systems for Rheumatoid Arthritis Treatment 113

The pharmacokinetic profiles of most DMARDs are unfavorable (Tarner & Muller-Ladner, 2008). For example, the bioavailability, peak serum concentration, and half life of orally administered methotrexate varies considerably between patients. The large variability in pharmacokinetic parameters likely contributes to the toxicity observed in some patients (Weinblatt & Kremer, 1988). Given the high incidence of adverse side effects, in addition to variability in drug effectiveness, the application of drug delivery srategies would be a

In cancer treatment, drug carrier systems with a large hydrodynamic radius to prevent renal filtration and increase circulation time can passively target diseased tissue as a result of leaky vasculature and inadequate lymphatic drainage, an effect known as "enhanced permeation and retention" (EPR) (Gillies & Frechet, 2005; Lee et al., 2006; Padilla De Jesus et al., 2002). Although inflammatory tissue, as found with rheumatoid arthritis, does not display abnormal lymphatic drainage (Xu et al., 2003), long-circulating delivery systems have been shown to selectively accumulate within the inflamed synovial tissue, i.e. the pannus (Fiehn et al., 2004; Metselaar et al., 2002; Schiffelers et al., 2006; Vanniasinghe et al., 2008; Wunder et al., 2003). The pannus possesses an increased vascular permeability similar to that of solid tumors and, consequently, the vasculature can be exploited for passive targeting in an analogous manner (Walsh, 1999). Fig. 1 illustrates the principles behind

Fig. 1. Drug delivery strategies in the treatment of rheumatoid arthritis. Passive targeting of

vasculature, while active targeting can be facilitated by a ligand that is specific for receptors

the pannus can be achieved by creating carriers that can only pass through leaky

of rheumatoid arthritis synovial fibroblasts (RASFs), rheumatoid arthritis synovial

macrophages (RASMs), or activated vascular endothelial cells (VECs).

significant advancement in rheumatoid arthritis treatment.

passive and active targeting of inflamed joint tissue.

**3. Principles of drug delivery** 

**3.1 Passive targeting** 

inflammatory drugs (NSAIDs) to disease modifying anti-rheumatic drugs (DMARDs), including modern biologics, all of the drugs in use have severe, potentially life threatening, consequences due to non-specific targeting, often in combination with impaired immune function.

Rheumatoid arthritis treatment originated wtih NSAIDs, such as aspirin and other salicylates, which act as anti-inflammatory agents by interfering with the activity of cyclooxygenase (COX) enzymes and, consequently, the production of prostaglandins (PGs), which are key mediators of the inflammatory response. Despite a lack of efficacy relative to conventional DMARDs or biologics, NSAID use in combination therapy has continued (Mottram, 2003). The long term side effects of NSAIDs include gastrointestinal and cardiovascular complications, as well as impaired renal function (Dijkmans et al., 1995).

Similar to NSAIDs, glucocorticoids (GCs), including cortisone, dexamethasone, prednisolone, and prednisone, primarily act through inhibition of PG production and are still used in current rheumatoid arthritis treatment strategies. Additionally, GCs reduce the expression of several proinflammatory proteins, including interleukin-1, -2, and -6, granulocyte macrophage-colony stimulating factor (GM-CSF), and tumor necrosis factor- (TNF-) (Moreland & O'Dell, 2002). Although high doses can be immunosuppressive, as well as anti-inflammatory, doses are typically kept low in rheumatoid arthritis treatment to minimize the adverse consequences that include gastrointestinal complications, an increased risk of osteoporosis, visual problems, and negative skin effects (Strand & Simon, 2003).

In the 1920s, gold salts were used to treat rheumatoid arthritis based upon the belief that the disease was triggered by an infection (Mottram, 2003). Although the link to a bacterial origin has been dispelled, gold has been classified as the earliest form of DMARD. The side effects of gold include reduced liver and renal function, as well as pulmonary complications. Consequently, the use of gold as a treatment is now limited to only severe rheumatoid arthritis patients who do not respond to other DMARDs.,

Several cytotoxic, anti-cancer agents have been adapted as DMARDs. For example, methotrexate has been in use as an oncology drug since 1950 and as a DMARD since 1970. Although the mechanism of action in rheumatoid arthritis remains largely unclear, methotrexate is speculated to either reduce proliferation of infiltrating inflammatory cells or suppress the release of pro-inflammatory cytokines (Mottram, 2003). Despite periodic liver function tests and biopsies for patients undergoing methotrexate treatment, cirrhosis and fibrosis are known side effects, and fatalities have been reported (Goodman & Polisson, 1994; Wolverton & Remlinger, 2007).

Other common DMARDs include immunosuppressants originally developed to prevent organ transplant rejection, such as cyclosporine, tacrolimus, and sirolium. The immunosuppressive properties of the latter drugs appear to be primarily due to inhibition of T-cell activation (Mottram, 2003). All of these therapeutics are nephrotoxic; consequently, creatinine levels must be monitored during treatment to assess renal dysfunction and kidney damage (Schiffelers et al., 2006; Zachariae, 1999).

A better understanding of disease progression, particularly as pertains the imbalance in proand anti-inflammatory cytokines, has led to the recent development of a number of biologic therapies as DMARDs, for example anti-TNF−α monoclonal antibodies such as infliximab and adalimumab. Although the latter agents are intended to be more specific, systemic inhibition of key inflammatory molecules can also have negative consequences. In particular, patients receiving treatment with biologics have an increased incidence of serious infections. Furthermore, the efficacy in individual patients is often unpredictable (Strand et al., 2007).

The pharmacokinetic profiles of most DMARDs are unfavorable (Tarner & Muller-Ladner, 2008). For example, the bioavailability, peak serum concentration, and half life of orally administered methotrexate varies considerably between patients. The large variability in pharmacokinetic parameters likely contributes to the toxicity observed in some patients (Weinblatt & Kremer, 1988). Given the high incidence of adverse side effects, in addition to variability in drug effectiveness, the application of drug delivery srategies would be a significant advancement in rheumatoid arthritis treatment.
