Preparation and evaluation of a CD13/APN-targeting and hydrolase-resistant conjugate that comprises pingyangmycin and NGR motif-integrated apoprotein.

We have chemically synthesized NGR-LDP-PYM, a novel CD13/aminopeptidase (APN)-targeting and hydrolase-resistant conjugate by cross-linking of the antitumor antibiotic pingyangmycin (bleomycin A5, PYM) to an engineered NGR motif-integrated apoprotein (NGR-LDP) with a noncleavable linker. This protein–drug conjugate not only basically retains the original properties of PYM but also can specifically deliver PYM to the CD13/APN-expressing tumor cells. Furthermore, the resulting conjugate exhibits more resistance to hydrolysis of recombinant human bleomycin hydrolase than parental PYM. These results may be useful for improving the therapeutic efficacy of PYM and have implications in the treatment of PYM-refractory and CD13/APN-overexpressing tumors. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1204–1213, 2014