**3.1 Passive targeting**

112 Rheumatoid Arthritis – Treatment

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

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

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,

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

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).

arthritis patients who do not respond to other DMARDs.,

kidney damage (Schiffelers et al., 2006; Zachariae, 1999).

1994; Wolverton & Remlinger, 2007).

function.

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 passive and active targeting of inflamed joint tissue.

Fig. 1. Drug delivery strategies in the treatment of rheumatoid arthritis. Passive targeting of the pannus can be achieved by creating carriers that can only pass through leaky vasculature, while active targeting can be facilitated by a ligand that is specific for receptors of rheumatoid arthritis synovial fibroblasts (RASFs), rheumatoid arthritis synovial macrophages (RASMs), or activated vascular endothelial cells (VECs).

The Development of Targeted Drug Delivery Systems for Rheumatoid Arthritis Treatment 115

Fig. 3. Various polymer architectures investigated for use in drug delivery via polymer-drug

Nanoparticulate carrier systems permit entrapment/encapsulation of therapeutics without modification, as is requisite for polymer-drug conjugates. The colloidal particles can range in size from 10 nm to 1 m; however, sizes are more typically between 20 and 300 nm, thereby minimizing uptake by macrophages of the reticuloendothelial system, while permitting passive targeting of tissue with leaky vasculature. Liposomes, micelles, metallic nanoparticles, and polymeric nanoparticles constitute the most commonly used

conjugates. (A) Linear polymers, with PEG as an example, (B) star, polymers and (C)

Fig. 4. Various nanoparticulate carrier systems. (A) Micelles, (B) liposomes, and (C)

et al., 1993; Monkkonen & Heath, 1993; Monkkonen et al., 1994; Shaw et al., 1979) .

Liposomes are vesicles formed from phospholipid bilayers with aqueous centers. Consequently, liposomes are used to encapsulate both hydrophobic and hydrophilic drugs within the bilayer and the aqueous core, respectively. Liposomal properties are largely controlled through the choice of phospholipids, as well as the addition of sterols, particularly cholesterol, and glycolipids (Jain, 2008). Although conventional liposomes suffer from rapid uptake by the reticuloendothelial system, incorporation of PEG into the bilayer yields so called "stealth" liposomes with enhanced circulation times. Starting with the anticancer compound Doxil (Gabizon, 2001), several PEG-modified liposomes with encapsulated therapeutics have reached commercialization (Joralemon, et al., 2010). As a consequence, liposomal use has been widely studied as a potential carrier system for drug delivery for rheumatoid arthritis (Foong & Green, 1993; Konigsberg et al., 1999; Monkkonen

nanoparticulate carrier systems for drug delivery (Fig. 4) (Jain, 2008).

dendrimers.

polymeric nanoparticles.

**3.3.2 Nanoparticulate carrier systems** 
