ATTEMPTS System: A Macromolecular Prodrug Strategy for Cancer Drug Delivery

Title: ATTEMPTS System: A Macromolecular Prodrug Strategy for Cancer Drug Delivery

Volume: 16 Issue: 21

Author(s): Yongzhuo Huang, Yoon Shin Park, Jianxin Wang, Cheol Moon, Young Min Kwon, Hee Sun Chung, Yoon Jeong Park and Victor C. Yang

Affiliation:

Keywords: ATTEMPTS, prodrug, cell-penetrating peptide, CPP, protein drug delivery, cancer

Abstract: 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.

Cite this article as:

Huang Yongzhuo, Shin Park Yoon, Wang Jianxin, Moon Cheol, Min Kwon Young, Sun Chung Hee, Jeong Park Yoon and C. Yang Victor, ATTEMPTS System: A Macromolecular Prodrug Strategy for Cancer Drug Delivery, Current Pharmaceutical Design 2010; 16 (21) . https://dx.doi.org/10.2174/138161210791920441