title: Integrating Enzymatic Self-Assembly and Mitochondria Targeting for Selectively Killing Cancer Cells without Acquired Drug Resistance.
abstract: Targeting organelles by modulating the redox potential of mitochondria is a promising approach to kill cancer cells that minimizes acquired drug resistance. However, it lacks selectivity because mitochondria perform essential functions for (almost) all cells. We show that enzyme-instructed self-assembly (EISA), a bioinspired molecular process, selectively generates the assemblies of redox modulators (e.g., triphenyl phosphinium (TPP)) in the pericellular space of cancer cells for uptake, which allows selectively targeting the mitochondria of cancer cells. The attachment of TPP to a pair of enantiomeric, phosphorylated tetrapeptides produces the precursors (L-1P or D-1P) that form oligomers. Upon dephosphorylation catalyzed by ectophosphatases (e.g., alkaline phosphatase (ALP)) overexpressed on cancer cells (e.g., Saos2), the oligomers self-assemble to form nanoscale assemblies only on the surface of the cancer cells. The cancer cells thus uptake these assemblies of TPP via endocytosis, mainly via a caveolae/raft-dependent pathway. Inside the cells, the assemblies of TPP-peptide conjugates escape from the lysosome, induce dysfunction of mitochondria to release cytochrome c, and result in cell death, while the controls (i.e., omitting TPP motif, inhibiting ALP, or removing phosphate trigger) hardly kill the Saos2 cells. Most importantly, the repeated stimulation of the cancers by the precursors, unexpectedly, sensitizes the cancer cells to the precursors. As the first example of the integration of subcellular targeting with cell targeting, this study validates the spatial control of the assemblies of nonspecific cytotoxic agents by EISA as a promising molecular process for selectively killing cancer cells without inducing acquired drug resistance.
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02453, United States.|State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Collaborative Innovation Center of Chemical Science, Nankai University , Tianjin 300071, P.R. China.
authors.forename: Huaimin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02453, United States.
authors.forename: Zhaoqianqi
authors.initials: Z
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Collaborative Innovation Center of Chemical Science, Nankai University , Tianjin 300071, P.R. China.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02453, United States.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Collaborative Innovation Center of Chemical Science, Nankai University , Tianjin 300071, P.R. China.
authors.forename: Zhimou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02453, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism*; D055162:Biocatalysis; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D010755:Organophosphates; D000469:Alkaline Phosphatase; C005445:triphenyl phosphate