Microbial transglutaminase (mTGase) is an enzyme that catalyzes site-specific protein derivatization at specific glutamines. mTGase-mediated conjugation with PEG-NH2 to granulocyte colony stimulating factor (G-CSF) yields a site selective mono-derivative conjugate involving Gln135. The same enzymatic reaction of mTGase, i.e. the transfer of the Gln acyl group to an amino donor, was investigated by reversing the substrates. A specific acyl donor PEG derivative was synthesized by coupling the Z-QG mTGase substrate to PEG. The mTGase-mediated conjugation of this PEG-ZQG in the presence of G-CSF generated a high-yield PEG-G-CSF conjugate in which the polymer was selectively coupled to Lys41 of the protein. The PEG-K41-G-CSF conjugate was compared with the PEG-Q135-G-CSF one obtained through mTGase conjugation of PEG-NH2 to Gln135. Biophysical characterization showed that the two positional isomers have similar behaviors, and pharmacokinetic studies in rats demonstrated that they have comparable half-life extensions. Overall, the study demonstrates that mTGase protein derivatization is linked to inherent advantages because it carries with it the possibility of targeting lysines or glutamines, in both cases with a high site-selective specificity

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The targeted delivery of bioactive molecules to the appropriate site of action, one of the critical focuses of pharmaceutical research, improves therapeutic outcomes and increases safety at the same time; a concept envisaged by Ehrlich over 100 years ago when he described the "magic bullet" model. In the following decades, a considerable amount of research effort combined with enormous investment has carried selective drug targeting into clinical practice via the advent of monoclonal antibodies and antibody-drug conjugates derivatives. Additionally, a deeper understanding of physiopathological conditions of disease has permitted the tailored design of targeted drug delivery platforms that carry drugs, many copies of the same drug, and different drugs in combination to the appropriate site of action in a selective or at least preferential manner. The acquired know-how has provided the field with the design rationale to develop a successful delivery system that will provide new and improved means to treat many intractable diseases and disorders. In this review, we discuss a wide range of molecular platforms for drug delivery, and focus on those with more success in the clinic, given their potential for targeted therapies.

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