title: Photodynamic agents with anti-metastatic activities.
abstract: A new concept in multifunctional anticancer agents is demonstrated. Tetrakis-(diisopropyl-guanidino) zinc phthalocyanine (Zn-DIGP) exhibits excellent properties as a photodynamic therapy (PDT) agent, as well as potential anti-metastatic activities in vivo. Zn-DIGP exhibits good cellular uptake and low toxicity in the dark (EC50 > 80 μM) and is well tolerated upon its intravenous injection into mice at 8 mg/kg. Upon photoexcitation with red laser light (660 nm), Zn-DIGP exhibits a high quantum yield for singlet oxygen formation (Φ ≈ 0.51) that results in potent phototoxicity to cell cultures (EC50 ≈ 0.16 μM). Zn-DIGP is also capable of inhibiting the formation of tumor colonies in the lungs of C57BL/6 mice injected with B16F10 cells. Zn-DIGP therefore inhibits cancer growth by both light-dependent and light-independent pathways. The anti-metastatic activities of Zn-DIGP possibly result from its ability to interfere with the signaling between chemokine CXCL10 and the G protein-coupled receptor CXCR3. Zn-DIGP is a competitive inhibitor of CXCR3 activation (IC50 = 3.8 μM) and selectively inhibits downstream events such as CXCL10-activated cell migration. Consistent with the presence of feedback regulation between CXCR3 binding and CXCL10 expression, Zn-DIGP causes overexpression of CXCL10. Interestingly, Zn-DIGP binds to CXCR3 without activating the receptor yet is able to cause endocytosis and degradation of this GPCR. To the best of our knowledge, Zn-DIGP is the first PDT agent that can facilitate the photodynamic treatment of primary tumors while simultaneously inhibiting the formation of metastatic tumor colonies by a light-independent mode of action.
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Balayeshwanth R
authors.initials: BR
authors.lastname: Vummidi
authors.forename: Faiza
authors.initials: F
authors.lastname: Noreen
authors.forename: Jawad
authors.initials: J
authors.lastname: Alzeer
authors.forename: Karin
authors.initials: K
authors.lastname: Moelling
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Luedtke
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D008665:Metalloporphyrins / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; C587063:tetrakis(diisopropylguanidino) zinc phthalocyanine