Application of "ATTEMPTS" for drug delivery.
A novel enzyme drug delivery system, Antibody, Targeted, Triggered, Electrically, Modified, Prodrug, Type, Strategy ("ATTEMPTS"), was developed in our laboratory to attenuate the toxicity associated with drug activity at non-targeted tissues. Tissue plasminogen activator is a prime example of an enzyme drug that exhibits systemic toxicity due to its indiscriminate activation of both targeted (i.e., clot-bound) and non-targeted (i.e., systemic) plasminogen. In brief, tissue plasminogen activator (t-PA) was modified to contain positive surface charges and then rendered inactive upon electrostatic binding with a negatively charged heparin-antifibrin antibody conjugate. After targeting the complex to the clot site, t-PA activity was restored by administration of protamine, a clinical heparin antidote. Cation-modified t-PA (CM-tPA) was obtained by chemical conjugation of t-PA with a poly(Arg)7Cys peptide using the crosslinker N-succinimidyl 3-2-(pyridlydithio)propionate (SPDP). Anti-fibrin IgG was chemically conjugated with heparin via oxidation of the carbohydrate moiety on its Fc region. Both in vitro characterization and in vivo studies using a rat thrombosis model clearly demonstrated that heparin-IgG conjugate induced inhibition of CM-tPA could be effectively reversed upon addition of protamine. Overall, the ATTEMPTS system was proven to induce clot dissolution without causing t-PA associated systemic toxicity due to the degradation of critical plasma factors by systemic plasmin production.
Naik
Sarita S
SS
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA.
Liang
Jun-Feng
JF
Park
Yoon Jeong
YJ
Lee
Won Kyu
WK
Yang
Victor C
VC
D000818:Animals; D016503:Drug Delivery Systems; D005341:Fibrinolysin / Q000096:biosynthesis; D005342:Fibrinolysis / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
D011355:Prodrugs; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin