SiLinker Technology

  • SiLinker Technology

    At BlinkBio we have discovered and developed novel, tunable linkers based upon proprietary disilylether-based chemistries that offer significant improvements over contemporary linker systems. They are designed to rapidly and completely release payloads in the modestly acidic conditions found within cancer cells (endosomal/lysosomal compartment) and in other hypoxic regions of the tumor microenvironment, while being stable at physiological pH and in human plasma. The released payloads are silanol adducts which generally improves permeability compared to the parent payload molecule.

  • SiLinker Figure_769p

  • We have validated the performance of our SiLinkers using model systems in the test tube, in cells and in mouse anti-tumor models. The differentiation of our linker system hinges on the exquisite and tunable sensitivity of the linkers to cleavage under modestly acidic conditions such as those that might be encountered in the endosomal and lysosomal compartments of a cell and in the acidic microenvironment of solid tumors. As shown below, model SiLinkers exhibit good stability at 37°C in pH7.4 buffer (and human or rodent plasma) but show rapid hydrolysis at pH ~5.5 to 6.5 (with half-lives in the 15 minute to 120 minute range).

    SiLinker Model System_769

  • We first sought to demonstrate that model SMDCs could be constructed that bound to cells, were internalized and then released payload in the endosomal compartment. To do this we constructed an SMDC comprising a folic acid ligand with two fluorescent dyes (BODIPY and Rhodamine) positioned on either side of a SiLinker. As such we would expect to see precise overlap of images for an intact SMDC and separation into two components after cleavage of the SiLinker following dosing of the model SMDC to cells overexpressing the folic acid receptor. The figure below summarizes the results.

    Model SMDC Imaging Data_769p

  • We then constructed Folic acid ligand-SiLinker-vinblastine model SMDCs with which to establish cellular and in vivo proof-of-concept. In cellular studies we tested our SMDCs in cell lines that overexpress FAR and were able to show that the observed cytotoxicity was blocked by excess Folic Acid. Subsequent in vivo studies, using a nude mouse xenograft model, demonstrated appreciable antitumor activity for these prototype (unoptimized) SMDCs as summarized below. BB-01 showed a clear dose response and had cures in 3 out of 5 mice after 24 days in this study.

    BB01 in vivo data_st_769p