Sono-Photodynamic　therapy　(SPDT)　utilizing　ultrasound　and　light　has　been　demonstrated　that　this　novel　approach　can　lower　dosage　resulting　in　reduction　of　the　potential　side　effects　caused　by　sensitizers.　Recently,　a　new　formulation　of　rose　bengal　(RB)　as　an　intralesional　injection　has　completed　clinical　trials　phase　II　for　PDT　treatment　of　melanoma　cancer.　However,　the　inherent　unfavorable　pharmacological　properties　of　RB　hindered　its　extensive　clinical　development.　With　the　aim　to　identify　new　RB　derivatives　(RBDs)　with　enhanced　photodynamic　and　sonodynamic　anticancer　efficiency,　a　series　of　amphiphilic　RBDs　have　been　designed,　synthesized　and　biological　characterized.　Among　them,　RBD4　significantly　improved　cellular　uptake　and　enhanced　intracellular　ROS　generation　efficiency　upon　light　and　ultra-sound　irradiation,　resulting　in　dramatically　improved　anticancer　potency.　Notably,　RBD4　has　a　relative　potency　similar　to　sinoporphyrin　sodium　(DVDMS),　indicating　its　further　potential　application　for　SPDT.　(C)　2018　Elsevier　Masson　SAS.　All　rights　reserved.