Enzymatic Assemblies of Thiophosphopeptides Instantly Target Golgi Apparatus and Selectively Kill Cancer Cells**

Abstract

Changing an oxygen atom of the phosphoester bond in phosphopeptides by a sulfur atom enables instantly targeting Golgi apparatus (GA) and selectively killing cancer cells by enzymatic self-assembly. Specifically, conjugating cysteamine S-phosphate to the C-terminal of a self-assembling peptide generates a thiophosphopeptide. Being a substrate of alkaline phosphatase (ALP), the thiophosphopeptide undergoes rapid ALP-catalyzed dephosphorylation to form a thiopeptide that self-assembles. The thiophosphopeptide enters cells via caveolin-mediated endocytosis and macropinocytosis and instantly accumulates in GA because of dephosphorylation and formation of disulfide bonds in Golgi by themselves and with Golgi proteins. Moreover, the thiophosphopeptide potently and selectively inhibits cancer cells (HeLa) with the IC 50 (about 3 mM), which is an order of magnitude more potent than that of the parent phosphopeptide.

Precise Control of Self‐assembly in vivo Based on Polymer‐Peptide Conjugates†

“…The endoplasmic reticulum (ER) and Golgi may be a new strategy for cancer therapy. Xu and co‐workers [ 102‐103 ] reported the alkaline phosphatase (ALP)‐responsive self‐assembly of peptide to target the ER in cancer cells. The self‐assembled peptide consists of D ‐peptide backbone (Nap‐ffky) and L ‐peptide branch (KYDKKKKDG), which can form into assemblies under the ER of OVSAHO cells with overexpression of typsin‐1 (PRSS1), leading to the ER stress and eventual cell death.…”

Assembly Transformation Jointly Driven by the LAP Enzyme and GSH Boosting Theranostic Capability for Effective Tumor Therapy

“…Over the past decades, with the rapid development of nanobiotechnology and nanomedicine, dynamic nanoassembly-based drug delivery systems have attracted great research interest and have been recognized as a promising means to improve the enrichment of drugs locally for achieving effective cancer diagnosis and treatment. − Such nanosystems have great potential to improve the specificity, accumulation, and retention time of antitumor agents. Stimulus-induced self-assembly, which enables molecules to assemble locally at the disease site of interest, has been demonstrated to be an efficient way to realize the purpose of imaging signal amplification, , enhanced therapeutic effects, and improved biosafety. , For example, the enzyme-induced self-assembled supramolecular hydrogels developed by Xu and coworkers have proven the capability to enhance the accumulation and retention time of small-molecule peptides for improved cancer imaging and treatment. − Alternatively, Rao and Liang groups innovatively proposed a concept of an enzyme/GSH-mediated self-assembly approach based on a biorthogonal CBT-Cys condensation reaction, which has been successfully and widely applied for bioimaging applications. − Recently, Wang and coworkers reported a peptide-assembled nanosystem with the assembly-induced retention (AIR) effect to improve the tumor accumulation and antitumor efficacy in vivo. − Nevertheless, the metabolism and the ultimate therapeutic effect of the nanoassembly in living organisms greatly depend on the physical and chemical properties of materials, − especially the particle morphology, , which is one of the most critical factors for boosting the effects of the cellular uptake rate, tumor accumulation, and tissue penetration depth.…”