**3.3.1 Polymer-drug conjugates**

In 1975, Ringsdorf proposed a model for polymer-based drug delivery wherein discrete sections of a polymer backbone are used for attachment of therapeutics, solubilizers, and targeting moieties (Fig. 2) (Ringsdorf, 1975). Since this seminal manuscript, numerous macromolecular therapeutics have been synthesized and evaluated. Although initial research focused on the use of N-(2-hydroxypropyl) methacrylamide (HPMA) based upon similarity to Ringsdorf's Model, polymers with a variety of architectures and structural elements are currently being explored, including linear mono- and di-functional polymers, star polymers, and dendrimers (Fig. 3) (Kopecek et al., 2000; Peterson et al., 2003). Dendrimers can alternatively be classified as nanoparticulate carriers when drug molecules are entrapped within the interior rather than covalently linked to the surface functional groups (Gillies & Frechet, 2005; M. Liu & Frechet, 1999). Mono- and di-hydroxyl terminated poly(ethylene glycol) (PEG) have proven to be the most versatile polymers for increasing the stability, solubility, and pharmacokinetic properties of associated therapeutics, with several PEG-drug conjugates on the market for a number of indications (Joralemon et al., 2010). Only recently has this research translated to the development of macromolecular therapeutics for the treatment of rheumatoid arthritis, as discussed further in Section 4. Despite demonstrated success, polymer-drug conjugates suffer from the necessity to chemically modify the drug molecule and the potential to reduce therapeutic activity and efficacy by such modification (Haag & Kratz, 2006; Kim et al., 2009).

Fig. 2. (A) Ringsdorf's model of polymer-drug conjugates for drug delivery. (B) HPMA was investigated for use due to similarity to Ringsdorf's model.

Fig. 3. Various polymer architectures investigated for use in drug delivery via polymer-drug conjugates. (A) Linear polymers, with PEG as an example, (B) star, polymers and (C) dendrimers.
