Title:Improved Protein Toxin Delivery Based on ATTEMPTS Systems
Volume: 19
Issue: 4
关键词:
蛋白质毒素,核糖体失活蛋白,免疫毒素,细胞穿透肽(CPP),明胶,肿瘤靶向传递。
摘要: 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.