1. Basics and Principles of Polymer Therapeutics

1.1 Pharmacological Effects

Small drug molecules and also large biomolecules like proteins or antibodies suffer rapid clearance from human body. The concentration of the drug compound drops rapidly as it is removed from the body. Treatment has to be repeated in order to keep the concentration over the therapeutic threshold. Otherwise immunogenic reactions start. There are two major reasons why polymer therapeutics improves drug delivery and pharmacokinetics: Polymerdrug conjugates show suppressed renal clearance and reduced immunogenic reactions. The concentration is being reduced very slowly over the time of treatment. In the ideal case, only a single application is required over the time of treatment. This is due to the following two mechanisms:

1. Preventing Degradation and Reducing Immunogenicity

   Polymer chains are covering the surface of a biopharmaceutical and thus effectively shield it against attacks by the immune system. The polymeric shield has characteristics rather like a solvent than a protein. This prevents uptake by cells of the retinal endothelial system (macrophage system). Recognition by the immune system (antibodies, proteases and other degradation enzymes etc.) is significantly reduced. The drug stays intact and is not destroyed (degraded or metabolized) during its presence in the body and journey through the physiological system.

2. Preventing Excretion

   Poly(amino acids), PEG and PAS are naturally very hygroscopic and surrounded by a large solvating sphere of water. Thus the overall so-called “hydrodynamic radius” is increased to an order of magnitude which is larger than the diameter of the glomerular capillaries (6 to 12 nm). Therefore, the drug is not excreted through the kidneys and simply stays longer in the body. Retarded renal filtration prolongs plasma half-life of the biological drug by means of a purely biophysical size effect, without any receptor interactions that may influence pharmacodynamics or lead to side effects.

These two main effects, i.e. preventing degradation and excretion, lead to a set of advantageous properties of polymer therapeutic drugs. The polymer forms a random conformation which is stable under native buffer conditions and body temperature and generates a large hydrodynamic volume, thus increasing the apparent size. Through the choice of different chain lengths and polymer design the hydrodynamic volume can be adjusted within broad limits.

Additional references, books and review articles:

• The dawning era of polymer therapeutics; R. Duncan; Nat Rev Drug Discov 2003; 2: 347-360. 
• PEGylation, successful approach to drug delivery; F. M. Veronese and G. Pasut; Drug Discovery Today 2005; 10: 1451-1458. doi:10.1016/ S1359-6446(05)03575-0 
• Poly(ethylene glycol)-Prodrug Conjugates: Concept, Design, and Applications; S. S. Banerjee, N. Aher, R. Patil and J. Khandare; J Drug Deliv. 2012; 2012: 17. doi:10.1155/2012/103973 
• Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives; K. Knop, R. Hoogenboom, D. Fischer and U. S. Schubert; Angew Chem. Int. Ed. 2010; 49: 6288-6308. doi:10.1002/ anie.200902672 ff 
• PEGylation - The Magic Wand. Turning Proteins and other Biopharmaceuticals into Super Performing Block Busters; T. Bruckdorfer; PharManufacturing 2007; 1: 34-41. 
• Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle; R. M. Schiffelers, A. Ansari, J. Xu, Q. Zhou, Q. Tang, G. Storm, G. Molema, P. Y. Lu, P. V. Scaria and M. C. Woodle; Nucleic Acids Res 2004; 32: e149. doi:10.1093/nar/gnh140 
• Tumor-targeted gene therapy: strategies for the preparation of ligand– polyethylene glycol–polyethylenimine/DNA complexes; M. Ogris, G. Walker, T. Blessing, R. Kircheis, M. Wolschek and E. Wagner; J Control Release 2003; 91: 173-181. doi:10.1016/S0168-3659(03)00230-X 
• Novel polymeric micelles for hydrophobic drug delivery based on biodegradable poly(hexyl-substituted lactides); T. Trimaille, K. Mondon, R. Gurny and M. Möller; Int J Pharm 2006; 319: 147-154. doi:10.1016/j.ijpharm.2006.03.036 
• PEGylated antibodies and antibody fragments for improved therapy: a review; A. P. Chapman; Adv Drug Deliv Rev 2002; 54: 531-545. doi:10.1016/S0169-409X(02)00026-1 
• Chemistry for peptide and protein PEGylation; M. J. Roberts, M. D. Bentley and J. M. Harris; Adv Drug Deliv Rev 2002; 54: 459-476. doi:10.1016/S0169-409X(02)00022-4 
• Peptide and protein PEGylation: a review of problems and solutions; F. M. Veronese; Biomaterials 2001; 22: 405-417. doi:10.1016/S0142- 9612(00)00193-9. 
• Functionalization of poly(ethylene glycol) and monomethoxypoly( ethylene glycol); A. F. Bückmann, M. Morr and G. Johansson; Makromol Chem 1981; 182: 1379-1384. doi:10.1002/ macp.1981.021820509
• New, easily removable poly(ethylene glycol) supports for the liquidphase method of peptide synthesis; V. N. R. Pillai, M. Mutter, E. Bayer and I. Gatfield; J Org Chem 1980; 45: 5364-5370. doi:10.1021/ jo01314a032
• Synthesis and characterization of poly(ethylene glycol) derivatives; J. M. Harris, E. C. Struck, M. G. Case, M. S. Paley, M. Yalpani, J. M. Van Alstine and D. E. Brooks; J Polym Sci Polym Chem Edn 1984; 22: 341- 352. doi:10.1002/pol.1984.170220207 
• Attachment of drugs to polyethylene glycols; S. Zalipsky, C. Gilon and A. Zilkha; Eur Polym J 1983; 19: 1177-1183. doi:10.1016/0014- 3057(83)90016-2 
• Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol; A. Abuchowski, T. van Es, N. C. Palczuk and F. F. Davis; J Biol Chem 1977; 252: 3578-81. 
• Process design for large-scale purification of formate dehydrogenase fromcandida boidinii by affinity partition; A. Cordes and M.-R. Kula; J Chromat 1986; 376: 375-384. doi:10.1016/S0378-4347(00)80853-1 
• Chemical modification of horseradish peroxidase with ethanalmethoxypolyethylene glycol: Solubility in organic solvents, activity, and properties; P. Wirth, J. Souppe, D. Tritsch and J.-F. Biellmann; Bioorg Chem 1991; 19: 133-142. doi:10.1016/0045-2068(91)90029-O 
• The Synthesis of Substituted Methoxy-Poly(Ethyleneglycol) Derivatives Suitable for Selective Protein Modification; T. P. Kogan; Synthetic Comm 1992; 22: 2417-2424. doi:10.1080/00397919208019100