**4.1 Polymer-drug conjugates for rheumatoid arthritis treatment**

116 Rheumatoid Arthritis – Treatment

Above a certain concentration, referred to as the critical micelle concentration (CMC), molecules that possess both hydrophobic and hydrophilic segments, such as amphipathic block-co-polymers, will self assemble to form colloidal particles with hydrophobic interiors and hydrophilic exteriors. Micelles are typically smaller than liposomes (20-50 nm) and the hydrophobic cores are used to entrap drugs that possess low aqueous solubility (Haag & Kratz, 2006). The CMC provides an indicator of stability, where systems with low CMCs are not easily disrupted or disintegrated (Oerlemans et al., 2010). Only a handful of investigators have used micelle-based drug delivery systems to improve the efficacy of DMARDs that have historically suffered from unpredictable pharmacokinetics resultant

Both metallic and polymeric nanoparticles are used to encapsulate drugs within the solid core. Although nanoparticles are defined as any system with a submicron ( 1 m) size (van Vlerken & Amiji, 2006), most typically have sizes below 200 nm (Jain, 2008). Metallic nanoparticles include iron-oxide nanoparticles, silica-gold nanoshells, gold nanoparticles, and Quantum dots (cadmium, selenium, and zinc) (Riehemann et al., 2009; van Vlerken & Amiji, 2006). Although originally developed for cancer treatment, these technologies are currently being translated to rheumatoid arthritis treatment applications (Corthey et al., 2010). The use of metals can yield multifunctional nanoparticles whereby both therapeutic delivery and imaging are facilitated (Riehemann et al., 2009). Polymer-based nanoparticles, are advantageous in that modification permits the ready addition of the following elements: targeting ligands, environment-sensitive drug release, and biologically functional polymers. The carrier systems discussed above can be further modified to optimize disease treatment. For example, co-administration of multiple therapeutics from one convenient platform is feasible. Additional modification with ligands specific for receptors found on diseased cells can facilitate active targeting. Furthermore, surface coating with PEG can be used to tailor circulation time (Riehemann et al., 2009; van Vlerken & Amiji, 2006). As detailed in Section 4, these technologies have only recently been applied in the realm of drug delivery for

Most drugs are inactive when bound to/encapsulated within the carrier system; therefore, a method that permits drug release at the diseased site is often requisite. Cellular uptake of therapeutic-loaded carrier systems typically proceeds by fluid-phase endocytosis, adsorptive endocytosis, or receptor-mediated endocytosis (Fig. 5). During each of these endocytotic processes, the pH drops from that within the extracellular space (pH ≈ 7.4 for healthy tissue and pH < 7.4 for diseased tissue) to pHs of ~6.0 and ~4.0 in the endosomes and lysosomes, respectively (Haag & Kratz, 2006; Petrak, 2005). Thus, the conjugate and particulate carriers can be formulated such that release is only permitted at a specified pH. Alternatively, drugs may be released after enzymes cause non-specific hydrolysis (Haag & Kratz, 2006; Kim et al., 2009). An ideal carrier system will only respond to environmental features unique to the diseased tissue, such as elevated levels of a specific enzyme. Stimuliresponsive drug delivery systems that are currently in development for the treatment of

**4. Current drug delivery systems and strategies for rheumatoid arthritis** 

A number of carrier systems have been designed to to improve rheumatoid arthritis treatment based upon the principles described in Section 3. These carrier systems provide an

from poor solubility (Bader et al., 2011; Koo et al., 2011; Zhang et al., 2007).

rheumatoid arthritis treatment.

**3.3.3 Therapeutic release from carrier systems** 

rheumatoid arthritis will be discussed in Section 5.

Several polymer-drug conjugates have been developed to improve the therapeutic efficacy of both conventional DMARDs and biologics. A number of these compounds were only recently applied to rheumatoid arthritis after originally being developed for cancer. For example, methotrexate conjugated to human serum albumin (MTX-HSA) was shown to passively accumulate within the inflamed paws of arthritic mice. Further study revealed a reduction in cellular invasion, a downregulation of proinflammatory cytokine levels, and a decrease in cartilage damage for arthritic mice treated with MTX-HSA relative to untreated, arthritic mice. The conjugates were also useful in preventing the onset of arthritis in mice when administered prior to induction (Fiehn et al., 2004; Wunder et al., 2003). Due to the limitations of exogenous albumin, a methotrexate pro-drug has recently been developed that will react with endogenous albumin upon administration (Fiehn et al., 2008).

Fig. 5. Cellular uptake of carrier systems occurs by an endocytotic process. Systems can be designed to release their therapeutic payload within the extracellular space, the endosome, or the lysosome.

As mentioned in Section 3, PEG has been used extensively in all areas of drug delivery. PEG-dexamethasone conjugates were recently synthesized that reduced joint inflammation when administered intravenously to arthritis rats (Liu et al., 2010). PEGylation has been applied to biologics, in addition to conventional, small molecule therapeutics. To the authors' knowledge, the only polymer-drug conjugate to reach clinical trials for rheumatoid arthritis treatment thus far is certolizumab pegol (CDP870), a PEG conjugated TNF antibody fragment originally developed for treatment of Chron's disease (Barnes & Moots, 2007). Administration to a number of patients who did not respond well to conventional DMARDs, particularly methotrexate, led to a reduction in disease activity and joint damage. Unfortunately, an increase in adverse side effects was also observed (Ruiz Garcia et al.,

The Development of Targeted Drug Delivery Systems for Rheumatoid Arthritis Treatment 119

**Nanoparticle** PLGA ― Betamethasone (Higaki et al., 2005)

E-Selectin

Peptide

Hyaluronic Acid

Cyclodextrin ― Methyl-

PLGA-PEG ― Betamethasone (Ishihara et al., 2009) PAMAM Dendrimer Folate Indomethacin (Chandrasekar et al.,

prendisolone

Chitosan Folate IL-1R Agonist (Fernandes et al., 2008)

2011), suggesting that PEGylation may not be the ideal method to improve the efficacy of

Other polymer-drug conjugates have shown some promise *in vitro*, such as PEG and HPMA conjugated cathepsin-K inhibitor (Wang et al., 2004). Furthermore, as will be desribed in more detail in Section 5, systems such as PEG and HPMA dexamethasone conjugates are now being developed that, not only target the pannus tissue, but also selectively release the

Several liposome systems have been tried for improved efficacy of rheumatoid arthritis treatments. This work was pioneered by Williams, et. al., who demonstrated that

― Cyclosporine A (Aliabadi et al., 2005)

― Cyclosporine A (Francis et al., 2005)

― Cyclosporine A (Francis et al., 2005)

― Cyclosporine A (Bader et al., 2011)

2007b)

(Hwang et al., 2008)

― (Banquy et al., 2008).

― (Zhang et al., 2008)

TRAIL (Kim et al., 2010),

― Gold (Corthey, et al., 2010)

Folate NF-B Decoy (Hattori et al., 2006),

**Micelle** PEG-

Poly(caprolactone)

Hydroxypropylcellulose-(POE-C16)

Polysialic Acid-Decylamine

PEG-TRAIL Hyaluronic Acid

Lipid PEG

rheumatoid arthritis therapeutics.

Gold Core-Gold(I)- Thiomalate

Polyoxyethylene Cetyl Ether (POE-C16)

Polyester Ligand for

PLGA-PEG cLABL

Table 1. Current drug delivery strategies for rheumatoid arthritis

therapeutic in the targeted region (Liu, et al., 2010; Quan et al., 2010).

**4.2 Liposomal carrier systems for rheumatoid arthritis treatment** 

Dextran-


Albumin ― Methotrexate (Wunder et al., 2003)

Inhibitor

Inhibitor

Antibody Fragment

― Clondronate (Camilleri et al., 1995;

― Prendisolone (Metselaar et al., 2002;

Camptothecin (Koo et al., 2011)

― Methotrexate (A. S. Williams, Camilleri,

PEG ― Dexamethasone (Liu, et al., 2010) HPMA ― Dexamethasone (Quan et al., 2010) PAMAM Dendrimer Folate Methotrexate (Thomas et al., 2011)

― Superoxide

Phosphogliv ― Methotrexate (Zykova et al., 2007)

― anti-TNF-IL-

siRNA

1 IL-6/ IL-18

Sialyl Lewis X

Intenstinal Peptide

PEG-Phospholipids Vasoactive

Dismutase

**Therapeutic Reference(s)** 

(Wang et al., 2004)

(Wang et al., 2004)

Love et al., 1992)

& Williams, 1994)

Corvo et al., 1999)

Metselaar et al., 2003)

(Hirai et al., 2007)

(Khoury et al., 2008; Khoury et al., 2006)

(Barnes & Moots, 2007)

**Group** 

PEG ― Cathepsin-K

HPMA ― Cathepsin-K

PEG ― TNF-

**Material(s) Targeting** 

**Type of Carrier** 

**Polymer-Drug Conjugate** 

**Liposome** Phospholipids

Cholesterol

and without covalently linked methotrexate) Cholesterol

Phospholipids Cholesterol PEG

Phospholipids Cholesterol PEG

Phospholipids Cholesterol

Cationic Phospholipids

Phospholipids (with


Table 1. Current drug delivery strategies for rheumatoid arthritis

2011), suggesting that PEGylation may not be the ideal method to improve the efficacy of rheumatoid arthritis therapeutics.

Other polymer-drug conjugates have shown some promise *in vitro*, such as PEG and HPMA conjugated cathepsin-K inhibitor (Wang et al., 2004). Furthermore, as will be desribed in more detail in Section 5, systems such as PEG and HPMA dexamethasone conjugates are now being developed that, not only target the pannus tissue, but also selectively release the therapeutic in the targeted region (Liu, et al., 2010; Quan et al., 2010).
