Improved Protein Toxin Delivery Based on ATTEMPTS Systems

Title:Improved Protein Toxin Delivery Based on ATTEMPTS Systems

Volume: 19 Issue: 4

Author(s): Yingzhi Chen, Meng Zhang, Kyoung Ah Min, Huiyuan Wang, Meong Cheol Shin*, Feng Li, Victor C. Yang and Yongzhuo Huang*

Affiliation:

• University of Michigan College of Pharmacy, Ann Arbor, MI,United States

• Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai,China

Keywords: Protein toxin, ribosome-inactivating protein, immunotoxin, cell-penetrating peptide (CPP), gelonin, tumortargeting delivery.

Abstract: Background: Ribosome-inactivating proteins (RIPs) are wildly found in multiple species of plants, bacteria and fungi. As a special family of protein toxins, RIPs can inhibit protein synthesis and induce cell death via inactivating ribosome in eukaryotic cells. Thus, RIPs have been applied for anti-tumor therapy in the past two decades. However, because of poor cell permeability, nonselective mode of action for tumor cells, poor pharmacokinetic profiles and immunogenicity, their clinical application has been severely constrained. As an effort to overcome these obstacles, tumor-specific monoclonal antibodies (mAb) have been conjugated to RIPs (forming so called “immunotoxins”) specifically to increase their cytotoxicity and provide tumor targeting. Nevertheless, immunotoxins yet have not fully resolved all the issues and critical challenges still remain, such as immunogenicity and inability to penetrate into the deep site of tumor.

Objective: To overcome the constrain of immunotoxins, the novel cell-penetrating peptide (CPP)- modified ATTEMPTS systems based on combination of CPP-mediated penetration and antibodymediated tumor targeting, with triggerable drug release function, were developed to achieve effective and safe delivery of protein toxin.

Results: The CPP-modified ATTEMPTS systems showed effective protamine-triggered CPP-toxin release and thus enhanced CPP-mediated cellular uptake and cytotoxicity. It also showed antibodymediated in vivo tumor targeting and significantly increased in vivo tumor growth suppression with limited systematic toxicity.

Conclusion: The CPP-modified ATTEMPTS systems were developed and demonstrated as a proof-ofconcept for CPP-based protein toxin delivery with triggerable antibody targeting to improve the druggability of protein toxin drugs. The systems showed the potential application of protein toxin clinical translation in anticancer treatment.

Cite this article as:

Chen Yingzhi, Zhang Meng , Min Ah Kyoung , Wang Huiyuan , Shin Cheol Meong *, Li Feng , Yang C. Victor and Huang Yongzhuo *, Improved Protein Toxin Delivery Based on ATTEMPTS Systems, Current Drug Targets 2018; 19 (4) . https://dx.doi.org/10.2174/1389450118666170302094758