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Barnase*Barstar-guided two-step targeting approach for drug delivery to tumor cells in vivo

To reduce side effects in the process of oncotherapy, it seems promising to use two-step targeting delivery of active agents, or pre-targeting: at the first stage, a non-toxic targeting module (also including antibody or non-immunoglobulin scaffolds) is selectively delivered to a cell of a certain molecular profile, and at the second stage, a cytotoxic agent capable of specifically interacting with the first module is administrated into the organism.

Targeted delivery, HER2, DARPin, Barstar, barnase, Pretargeting

Grigorov A.S.

Shramova EI, Shilova MV, Ryabova AV, Dzhalilova DS, Zolotova NA, Telegin GB, Deyev SM, Proshkina GM

A team of scientists from the Laboratory of molecular immunology IBCh RAS and Nursery for laboratory animals in collaboration with colleagues from other Russian institutes for the first time proposed the use of Barnase-Barstar pair as a «molecular glue» for precise ligation of a targeting and cytotoxic moiety. Targeting was mediated through the use of a scaffold protein DARPin_9–29 specific for the human epidermal receptor 2 (HER2) antigen that is highly expressed on some types of cancer and Barnase*Barstar native bacterial proteins interacted with each other with Kd 10-14 M. The approach proposed consists of prelabeling a target tumor with hybrid protein DARPin-Barnase prior to administration of cytotoxic component-loaded liposomes that have Barstar covalently attached to their outer surface. Based on in vivo bioimaging we have proven that DARPin-based Barnase*Barstar-mediated pretargeting possesses precise tumor-targeting capability as well as antitumor activity leading to apparent tumor-growth inhibition of primary tumors and distant metastases in experimental animals. The results obtained indicate that the new system combining DARPin and Barnase*Barstar can be useful both for the drug development and for monitoring the response to treatment in vivo in preclinical studies.

This work was published in the Journal of Controlled Release.

Figure 1. A schematic representation of the concept of Barnase*barstar-guided two-step targeting approach. At the first pretargeting step, non-toxic HER2-specific module DARPin-Barnase is administrated into tumor-bearing animals. After accumulation in the tumor and cleaning from the blood (~10 h), the second, cytotoxic component based on Barstar-Lip (PE40) is injected. Due to high affinity of Barnase and Barstar, quick and precise ligation of the two modules occurs in vivo leading to targeting cancer cells elimination.

november 19