WANG ET AL. VOL. 9 ’ NO. 2 ’ 1788–1800 ’ 2015 www.acsnano.org 1788 January 20, 2015 C 2015 American Chemical Society Plasmonic Copper Sulfide Nanocrystals Exhibiting Near-Infrared Photothermal and Photodynamic Therapeutic Effects Shunhao Wang, †,§,# Andreas Riedinger, ‡,^,# Hongbo Li, ^ Changhui Fu, † Huiyu Liu, * ,† Linlin Li, † Tianlong Liu, † Longfei Tan, † Markus J. Barthel, ^ Giammarino Pugliese, ^ Francesco De Donato, ^ Marco Scotto D’Abbusco, ^ Xianwei Meng, † Liberato Manna, ^ Huan Meng, * , ) and Teresa Pellegrino * ,^ † Laboratory of Controllable Preparation and Application of Nanomaterials, Research Center for Micro & Nano Materials and Technology, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, People's Republic of China, ‡ Optical Materials Engineering Laboratory, ETH Zurich, 8092 Zurich, Switzerland, § University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China, ^ Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy, and ) Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, California 90095, United States. # These authors have contributed equally. P hotodynamic therapy (PDT) refers to phototherapy and photochemother- apy in which photosensitizers (PSs) are used to generate highly reactive oxygen species (ROS) by means of photoexcitation, such as hydroxyl radicals ( 3 OH), singlet oxy- gen ( 1 O 2 ), as well as peroxides (ROO 3 ) which irreversibly damage a target of inter- est, for example, cancer cells. 1,2 In clinical applications, the excitation of an ideal PS should occur at a wavelength at which the PS alone and not the tissue absorbs the photon energy. 3 Here, the NIR range of the spectrum (7001100 nm) is of particular interest since the human tissue is consid- ered to be “transparent” to photons in this energy level. 3 Although many PSs are used in clinics to treat a variety of diseases, PDT in cancer therapy is still hampered by numer- ous limitations. Organic or metalorganic dyes often have poor water solubility 4 and undergo rapid decomposition under laser irradiation. 5 Other limiting factors include low targeted accumulation 6 and inefficient excitation in the NIR due to low absorption cross sections and/or low extinction coeffi- cients at these wavelengths. 7 In this regard, nanoparticle-based systems represent a potentially useful solution to significantly improve the performance in PDT, with the possibility to overcome all these limitations at once. 6,8,9 Another novel cancer treatment is repre- sented by photothermal therapy (PTT). Here a therapeutic agent absorbs energy from photons and dissipates it partially in the form of heat. When the therapeutic agent is located in close vicinity 10 to the tumor site, the temperature increase can lead to tumor cell death via cellular structure disruption, apoptosis, and/or necrosis medi- ated mechanisms. Research on PTT has made a huge progress thanks to various NIR light absorbing (plasmonic) nanomater- ials that have been developed in the past years. Especially noble metal nanostructures, * Address correspondence to liuhy@mail.ipc.ac.cn, hmeng@mednet.ucla.edu, teresa.pellegrino@iit.it. Received for review November 24, 2014 and accepted January 20, 2015. Published online 10.1021/nn506687t ABSTRACT Recently, plasmonic copper sulfide (Cu 2x S) nanocrystals (NCs) have attracted much attention as materials for photothermal therapy (PTT). Previous reports have correlated photoinduced cell death to the photothermal heat mechanism of these NCs, and no evidence of their photodynamic properties has been reported yet. Herein we have prepared physiologically stable near-infrared (NIR) plasmonic copper sulfide NCs and analyzed their photothermal and photodynamic properties, including therapeutic potential in cultured melanoma cells and a murine melanoma model. Interestingly, we observe that, besides a high PTT efficacy, these copper sulfide NCs additionally possess intrinsic NIR induced photodynamic activity, whereupon they generate high levels of reactive oxygen species. Furthermore, in vitro and in vivo acute toxic responses of copper sulfide NCs were also elicited. This study highlights a mechanism of NIR light induced cancer therapy, which could pave the way toward more effective nanotherapeutics. KEYWORDS: copper sulfide nanocrystals . near-infrared light . photothermal therapy . photodynamic therapy ARTICLE