Rheumatoid arthritis (RA) is the most common inflammatory arthritis, affecting about 1 percent of the general population worldwide. In United States, about 4.5% of people over the age of 55 people have been affected (1, 2).
As a symmetric disease, RA usually involves the same joints on both sides of the body. Angiogenesis and microvascular lesions are common features of RA inflammation, which leads to abnormal serum protein infiltration into the synovia (3-5). Damaged or depleted lymphatics have been observed in the synovium of RA patients as well (6, 7).
Although the exact cause of rheumatoid arthritis is unknown, many medications have been developed to relieve its symptoms and slow or halt its progression. Most commonly used medications rest on three principal approaches: symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroid and disease-modifying antirheumatic drugs (DMARDs) (3).
Considerable effort has been made to identify and develop new therapeutic strategies for the treatment of RA. RA medications, such as cycloxygenase-2 (COX-2) specific inhibitor (a NSAID) (8), tumor necrosis factor (TNF) blockers and interleukin-1 receptor antagonists (IL-1Ra) (DMARDs) have been used for clinical applications (3). Although the new generation of antirheumatic drugs have higher specificity to their molecular target, most of them do not have specificity to the diseased tissue, which lead to various side effects that limit their clinical application. Well-known side effects of NSAIDs include indigestion, stomach bleeding, liver and kidney damage, ringing in ears (tinnitus), fluid retention, and high blood pressure (9). Well known side effects of corticosteroids include bruising, thinning of bones, cataracts, weight gain, redistribution of fat, diabetes and high blood pressure (10). Some DMARDs are immunosuppressants and usually lead to serious side effects, such as increased susceptibility to infection (3). The recent withdrawal of Vioxx® (COX-2 inhibitor, Merck) is a good example of the tremendous impact that side effects can have on an otherwise effective drug.
The ubiquitous in vivo distribution of receptors utilized by most of the antirheumatic drugs is a leading cause of their side effects. Therapeutic delivery systems, which could specifically deliver anti-arthritis drugs to the diseased tissue of RA patients, may avoid many of the side effects that are manifested in other tissues while achieving much greater clinical therapeutic efficacy.
The application of water-soluble polymers as a drug carrier for effective delivery of the drug to the desired sites (macromolecular therapy) has been extensively studied for the past two decades in the treatment of solid tumors (11). Because of the “leaky” vasculature and poorly developed lymphatic system, extravasated macromolecules can be efficiently accumulated in the solid tumor. This phenomenon is termed tumor-selective “enhanced permeability and retention” (EPR) and has been used successfully to target anti-cancer drugs to solid tumors (12).
Studies using micro-particular carriers, such as liposomes for the delivery of anti-arthritic agents to a RA joint indicate some promising results in an animal model of arthritis (13). But the hepatotropism of the liposome may be problematic due to secondary livery toxicity. Therefore, there exists a need in the art for an effective drug delivery system that targets the appropriate tissues.
USPTO Backgrounds
USPTO Backgrounds