Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 97

4.4 Polymer-ProteinConjugates
Among the diff erent types of polymer therapeutics, polymer-protein
conjugates are the most abundant one in clinics (Table 4.5). More
than that, the first polymer therapeutic products were the polymer-
protein conjugates Zinostatin Stimaler ® and Adagen ® approved in
1990 for routine clinical use. Proteins as therapeutic agents, like
antibodies, cytokines, growth factors and enzymes, are limited
in their clinical application. They suff er from instability toward
degrading enzymes, short plasma half-life, and immunogenicity.
Thus, the coupling of proteins or peptides to polymer carriers could
overcome these limitations.
In the field of polymer-protein conjugates, PEG is the most
popular option since the clinical value of PEGylation is well
established. Besides PEG, only one more polymer conjugate has
entered the market. Maeda and co-workers synthesized SMANCS
(Zinostatin Stimaler ® ) by coupling two styrene maleic anhydride
(SMA) polymer chains with the anti-tumor protein neocarzinostatin
(NCS). During the preclinical trials they noticed that SMANCS was
passively accumulating at the tumor site. This phenomenon was
defined as the well-known now EPR eff ect [124]. SMANCS was
approved in Japan in 1990 for hepatocellular carcinoma.
PEG has been widely used for conjugation due to its good safety
profile, its hydrophilicity and the relative ease of conjugation to
proteins. PEGylation as delivery technology diff ers from the traditional
formulations, in which the drug is not released from the formulation
and in fact is classed as a new active pharmaceutical ingredient.
The market entry of PEG-protein conjugates was a landmark
achievement that advanced the whole field of polymer therapeutics.
PEGylation proved to be eff ective in shielding sensitive sites at the
protein surface, as well as prolonging the drug's half-life by decreasing
the kidney clearance, suggesting that PEGylated proteins could
markedly impact drug behavior in vivo . In addition, the decrease in
side eff ects with less frequent dosing has enabled PEGylated protein
therapeutics to serve as significant part of the protein therapeutics
platform [125]. Several proteins with therapeutic relevance, such as
(i) antibodies, (ii) cytokines, (iii) growth factors, and (iv) enzymes,
have been conjugated to PEG. In here, an example of each group will
be presented.