ATTEMPTS system: a macromolecular prodrug strategy for cancer drug delivery.
In order to reduce systemic toxicity and effectively deliver macromolecular drug into tumor cells, a system termed "ATTEMPTS" (antibody targeted, [protamine] triggered, electrically modified prodrug-type strategy) was developed in our laboratory. This approach was adapted from our previously reported heparin/protamine-based system for controlled delivery of protease drugs such as tissue- specific plasminogen activator (tPA). In this "ATTEMPTS" system, the cell-permeable protein drugs are synthesized by conjugating proteins to cell-penetrating peptides (CPPs). Cell penetration ability of such CPP-protein conjugates would initially be disabled, acting as a "prodrug", by forming polyelectrolyte complexes with a functionalized heparin-antibody moiety. The complexes would accumulate in tumor sites by the antibody targeting function, and then the local release of CPP-protein conjugates would be triggered by protamine. We applied this system to the macromolecular anticancer agents, such as the protein drugs (gelonin and asparaginase) as well as the polymerdrugs (polyrotaxane-doxorubicin and polyrotaxane-camptothecin). Both in vitro and preliminary in vivo studies demonstrated the regulable cell penetration behavior based on the competitive ionic interactions between CPP/heparin and heparin/protamine. Thus, this ATTEMPTS approach provides a multi-functionalized system incorporating the features of targeting, prodrug-like, triggerable release, and cell penetration ability for the delivery of macromolecular anticancer agents. A summary of our work on "ATTEMPTS" is presented in this review.
Huang
Yongzhuo
Y
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
Park
Yoon Shin
YS
Wang
Jianxin
J
Moon
Cheol
C
Kwon
Young Min
YM
Chung
Hee Sun
HS
Park
Yoon Jeong
YJ
Yang
Victor C
VC
D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000502:physiology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D046911:Macromolecular Substances / Q000008:administration & dosage / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D011479:Protamines / Q000008:administration & dosage
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D046911:Macromolecular Substances; D011355:Prodrugs; D011479:Protamines; D006493:Heparin