PEGylation Technology in Nanomedicine - Polymers in Nanomedicine - page 115

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
2 PEGylation Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
2.1 Site-Specific PEGylation . ............................................................ 118
2.2 Enzymatic PEGylation ................................................................ 119
2.3 Heterobifunctional PEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................. 120
2.4 Linear and Branched PEGs . . . ........................................................ 121
2.5 Releasable PEGylation . ............................................................... 122
3 Effect of PEGylation on Pharmaceuticals .................................................. 124
3.1 Reduction of Renal Clearance ........................................................ 124
3.2 Molecular Recognition of PEGylated Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.3 PEGylation on the Surface ........................................................... 126
4 PEGylated Drugs . . .......................................................................... 127
4.1 Small Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
4.2 Peptides, Proteins, Antibodies, and Antibody Fragments . . . . . ...................... 131
4.3 Oligonucleotide-PEG Conjugates .................................................... 131
4.4 PEGylated Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5 Conclusions and Future Prospects .......................................................... 135
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

1 Introduction

In 1977, Abuchowski et al. reported that covalent attachment of polyethylene glycol
(PEG) to albumin reduced the immunogenicity of albumin [ 1 ]. Subsequently, this
group also found that PEGylated biomolecules had a longer blood circulation time
than the corresponding normal biomolecules [ 2 ]. On the basis of this discovery,
PEGylation has been widely recognized as one of the more promising methods for
exploration of therapeutic drugs. This exploration includes developments in the
methodologies of PEGylation [ 3 ]. In the first generation of PEGylated molecules,
the target molecule was nonspecifically and irreversibly PEGylated with linear PEG
chains (Fig. 1 ). In the second generation, the molecule was PEGylated with
branched PEG chains at specific positions and covalently bound, so that PEG
could be released by stimuli from the outside environment. A variety of molecules,
including small molecules, peptides, proteins, enzymes, antibodies, antibody
fragments, and nanoparticles have been modified with PEG. At present, 11
PEGylated drugs have been approved for clinical use by the US Food and Drug
Administration (FDA) and several more trials in clinical settings are ongoing.

2 PEGylation Chemistry

At present, the most frequently used methods for PEGylation are chemical conju-
gation between reactive groups in the drug, such as the primary amine of lysine in
protein, and end-reactive PEG derivatives, such as the N -hydroxysuccinimide-