Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis

doi:10.1016/j.addr.2004.01.012

Advanced Drug Delivery Reviews

Volume 56, Issue 8, 29 April 2004, Pages 1205-1217

https://doi.org/10.1016/j.addr.2004.01.012 Get rights and content

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by inflammation of the joints and destruction of cartilage and bone, often compromising both the quality and duration of life. The disease pathology is complex, involving the infiltration and activation of various populations of immune cells along with the release of destructive inflammatory mediators into the synovium of affected joints. Although it is still debatable whether activated macrophages are the primary promoters of RA, emerging data clearly show that the biological activity of this subset of inflammatory cells greatly contributes to both the acute and chronic stages of the disease. The further discovery of folate receptor expression on these activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring RA has opened the possibility of exploiting folic acid to target attached drugs to this population of pathologic cells. Indeed, recent studies have shown that folate-linked imaging and therapeutic agents can be selectively delivered to arthritic joints, allowing both visualization and treatment of RA, with little or no collateral toxicity to normal tissues. This review will first summarize data documenting specific expression of the folate receptor on activated macrophages and then focus on the development of folate-targeted diagnostic and therapeutic agents for guided intervention into rheumatoid arthritis.

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by destructive inflammation of both internal organs and joints, the latter typically manifested as damage to cartilage, bone, tendons, and ligaments. Statistics show that RA and related musculoskeletal disorders affect greater than 0.5–1% of the population worldwide, and it is predicted that one out of every five Americans will suffer from one of these disorders by 2020 [1]. Females are affected by RA three times more often than males, and the disease can start at any age, with a peak incidence at 50–60 years of age [2]. Tragically, ∼80% of the affected population becomes disabled within 20 years of symptom onset, making RA the most common cause of disability in the workforce [3], [4]. Not surprisingly, the total social and medical costs attributed to RA are predicted to exceed US$100 billion by 2020 [5], [6]. While several anti-arthritic drugs are now available, many of these are very costly and have limited efficacy and/or undesirable side effects [7], [8]. Therefore, researchers throughout the world are attempting to develop safer and more effective treatments that can selectively target the cellular and molecular mediators of the inflammatory disease.

Section snippets

Pathogenesis and treatment of RA

A large number of recent studies demonstrate that activated macrophages constitute the key effector cells in RA [9], [10], [11], [12]. Although these reports do not exclude important roles for other immune cells, they clearly define a direct correlation between the level of macrophage activity and the observed joint inflammation, articular pain, and bone erosion. Molecularly, this correlation is explained by the fact that activated macrophages secrete multiple potent mediators of inflammation

Folate receptor expression on leukocytes

The folate receptor (FR) is a 38 kDa glycosylphosphatidylinositol-anchored protein that binds to the vitamin folic acid with high affinity (K_D<1 nM) [41], [42]. Following binding, rapid endocytosis delivers a fraction of the receptors into a low pH compartment where dissociation of the vitamin from its receptor is promoted [43]. Interestingly, covalent conjugation of small molecules, proteins, and even liposomes to the γ-carboxyl moiety of folic acid does not alter its ability to bind the

Diagnostic imaging of rheumatoid arthritis using folate-targeted radiopharmaceuticals

As inferred above, we have recently shown that FR expression on activated macrophages can be exploited to selectively target imaging agents to sites of inflammation in rats with adjuvant-induced arthritis [40]. Thus, EC20, a folate-conjugated radiopharmaceutical complexed with ^99mTc [55], was administered to diseased rats intraperitoneally, and its biodistribution was assessed 4 h later by nuclear scintigraphy. Resulting images revealed accumulation of EC20 in the arthritic extremities, as well

Folate-targeted therapies for rheumatoid arthritis

It has recently been demonstrated that the surfaces of folate receptor positive cancer cells can be decorated with highly immunogenic hapten molecules by targeting the cells with folate-hapten conjugates ([60], see also chapter by Lu et al.). Under conditions where the animal has recently been immunized against the hapten, the hapten-decorated cells are then rapidly bound by anti-hapten antibodies, leading to immune cell-mediated killing of the cancer cells by a process termed

Advantages of folate-targeted drug delivery in the treatment of rheumatoid arthritis

The primary objective of drug targeting is to deliver therapeutic or imaging agents specifically to pathologic, but not healthy cells, thereby avoiding the collateral toxicity that often plagues otherwise highly effective drugs. Based on many emerging observations, it can now be concluded that the activated macrophage is a principle contributor to the induction and maintenance of rheumatoid arthritis, and consequently, would constitute a primary target for therapeutic intervention into RA.

Perspectives and future directions

As summarized briefly above, there is now strong evidence to indicate that activated, but not resting macrophages, express a functionally active folate receptor, and that this receptor can be exploited to deliver folate-linked imaging and therapeutic agents specifically to the arthritic appendages of mice, rats, dogs and humans (unpublished data, and [40], [54]). However, because this discovery was made only recently, folate targeting has been applied to date only to the delivery of imaging

Acknowledgments

Supported in part by a grant from Endocyte.

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Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis

Abstract

Introduction

Section snippets

Pathogenesis and treatment of RA

Folate receptor expression on leukocytes

Diagnostic imaging of rheumatoid arthritis using folate-targeted radiopharmaceuticals

Folate-targeted therapies for rheumatoid arthritis

Advantages of folate-targeted drug delivery in the treatment of rheumatoid arthritis

Perspectives and future directions

Acknowledgments

Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States

Arthritis Rheum.

Epidemiology of the Rheumatic Diseases

The clinical management of rheumatoid arthritis and osteoarthritis strategies for improving clinical effectiveness

Br. J. Rheumatol.

The longterm outcomes of rheumatoid arthritis: work disability: a prospective 18 year study of 823 patients

J. Rheumatol.

The economic costs and social physiological impact on musculoskeletal conditions

Arthritis Rheumatol.

The costs of rheumatoid arthritis: absolute, incremental, and marginal estimates

J. Rheumatol., Suppl.

Direct medical costs of disease and gastrointestinal side effects during treatment for arthritis

Am. J. Med.

Cost-conscious prescribing of nonsteroidal anti-inflammatory drugs for adults with arthritis. A review and suggestions

Arch. Intern. Med.

Macrophages in rheumatoid arthritis

Arthritis Res.

Synovial tissue macrophages and joint erosion in rheumatoid arthritis

Ann. Rheum. Dis.

Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity

Arthritis Rheum.

Synovial tissue macrophage populations and articular damage in rheumatoid arthritis

Arthritis Rheum.

Pathogenesis of joint damage in rheumatoid arthritis

J. Rheumatol.

Mononuclear phagocytes and rheumatoid synovitis. Mastermind or workhorse in arthritis?

Arthritis Rheum.

Therapeutic strategies for rheumatoid arthritis

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Celebrex, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis

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