Ko, Young Ji Lee, Jong Won Kim, Hyosuk Cho, EunJi Yang, Yoosoo Kim, In-San Kim, Sun Hwa Kwon, Ick Chan 2024-01-19T17:04:11Z 2024-01-19T17:04:11Z 2021-09-05 2020-07 0168-3659 https://pubs.kist.re.kr/handle/201004/118440 Signal-regulatory protein alpha (SIRPα) engaged by CD47, that is overexpressed in a wide range of human solid tumors, serves as a ‘Don't eat me’ signal for phagocytic cells such as macrophages and dendritic cells. The SIRPα-CD47 interactions have recently attracted increasing attention in both cancer diagnosis and cancer immunotherapy. Herein, we designed and suggested a lysosomal enzyme-activatable vSIRPα-probe (vSIRPα-probe) capable of facilitating CD47-targeted cancer imaging and eliciting anti-cancer immune responses depending on phagocytosis as a versatile platform for potential cancer theranostic applications. For more efficient and precise cancer targeting, a recombinant SIRPα variant (vSIRPα) having a 50,000-fold higher binding affinity to CD47 than wild-type SIRPα was used to fabricate the vSIRPα-probe by conjugating to a dark-quenched fluorogenic peptide that is a substrate of lysosomal endopeptidases. The vSIRPα-probe could specifically bind to CD47 in different types of cancer cells and be activated by dequenching after cellular internalization. By interrupting the SIRPα-CD47 interaction between macrophages and cancer cells, the vSIRPα-probe promoted the destruction of cancer cells by macrophage-mediated phagocytosis, which was highly comparable to the un-modified vSIRPα recombinant protein. In the mouse tumor-xenografts treated with intravenous injection of the vSIRPα-probe, its enhanced in vivo tumor-targeting and imaging abilities drastically diminished after blocking the SIRPα-CD47 interaction via intratumoral administration of anti-CD47 antibodies. This study demonstrates that our vSIRPα-probe provides a promising tumor-targeted immunotheranostic probe for a novel cancer diagnostic and therapeutic strategy. English Elsevier BV Versatile activatable vSIRPα-probe for cancer-targeted imaging and macrophage-mediated phagocytosis of cancer cells Article 10.1016/j.jconrel.2020.04.037 1 Journal of Controlled Release, v.323, pp.376 - 386 Journal of Controlled Release 323 376 386 N scie scopus 000540694200005 2-s2.0-85084116745 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article INTEGRIN-ASSOCIATED PROTEIN POOR-PROGNOSIS SIRP-ALPHA CD47 OVEREXPRESSION ANTIBODIES CLEARANCE DELIVERY PREVENT LIGAND Activatable probe CD47-mediated endocytosis Macrophage-mediated phagocytosis of tumor cells Signal-regulatory protein alpha (SIRPα) Tumor-targeted imaging