title: Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival.
abstract: Most current cancer therapies focus on killing malignant cells, but these cells are often genetically unstable and can become resistant to chemotherapy. Tumor-associated macrophages (TAMs) facilitate disease progression by promoting angiogenesis and tumor cell growth, as well as by suppressing the adaptive immune response. TAMs are therefore potential targets for adjuvant anticancer therapies. However, resident macrophages are critical to host defense, and preferential ablation of TAMs remains challenging. Macrophage activation is broadly categorized as classically activated, or M1, and alternatively activated, or M2, and TAMs in the tumor microenvironment have been shown to adopt the anti-inflammatory, M2-like phenotype. To date, there are no methods for specific molecular targeting of TAMs. In this work, we report the discovery of a unique peptide sequence, M2pep, identified using a subtractive phage biopanning strategy against whole cells. The peptide preferentially binds to murine M2 cells, including TAMs, with low affinity for other leukocytes. Confocal imaging demonstrates the accumulation of M2pep in TAMs in vivo after tail vein injection. Finally, tail vein injection of an M2pep fusion peptide with a proapoptotic peptide delays mortality and selectively reduces the M2-like TAM population. This work therefore describes a molecularly targeted construct for murine TAMs and provides proof of concept of this approach as an anticancer treatment. In addition, M2pep is a useful tool for murine M2 macrophage identification and for modulating M2 macrophages in other murine models of disease involving M2 cells.
authors.affiliation: Departments of Bioengineering and Medical Genetics, University of Washington, Seattle, WA 98195.
authors.forename: Maryelise
authors.initials: M
authors.lastname: Cieslewicz
authors.forename: Jingjing
authors.initials: J
authors.lastname: Tang
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Yu
authors.forename: Hua
authors.initials: H
authors.lastname: Cao
authors.forename: Maja
authors.initials: M
authors.lastname: Zavaljevski
authors.forename: Koka
authors.initials: K
authors.lastname: Motoyama
authors.forename: Andre
authors.initials: A
authors.lastname: Lieber
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Raines
authors.forename: Suzie H
authors.initials: SH
authors.lastname: Pun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D016503:Drug Delivery Systems / Q000379:methods*; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000276:immunology*; D019151:Peptide Library; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D019151:Peptide Library; D010455:Peptides
keywords: flow cytometry; immunomodulation; macrophage polarization; peptide phage display; tumor targeting
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