Date Published: February 22, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Zhen Lu Yang, Wei Tian, Qing Wang, Ying Zhao, Yun Lei Zhang, Ying Tian, Yu Xia Tang, Shou Ju Wang, Ying Liu, Qian Qian Ni, Guang Ming Lu, Zhao Gang Teng, Long Jiang Zhang.
Oxygen (O2) plays a critical role during photodynamic therapy (PDT), however, hypoxia is quite common in most solid tumors, which limits the PDT efficacy and promotes the tumor aggression. Here, a safe and multifunctional oxygen‐evolving nanoplatform is costructured to overcome this problem. It is composed of a prussian blue (PB) core and chlorin e6 (Ce6) anchored periodic mesoporous organosilica (PMO) shell (denoted as PB@PMO‐Ce6). In the highly integrated nanoplatform, the PB with catalase‐like activity can catalyze hydrogen peroxide to generate O2, and the Ce6 transform the O2 to generate more reactive oxygen species (ROS) upon laser irradiation for PDT. This PB@PMO‐Ce6 nanoplatform presents well‐defined core–shell structure, uniform diameter (105 ± 12 nm), and high biocompatibility. This study confirms that the PB@PMO‐Ce6 nanoplatform can generate more ROS to enhance PDT than free Ce6 in cellular level (p < 0.001). In vivo, the singlet oxygen sensor green staining, tumor volume of tumor‐bearing mice, and histopathological analysis demonstrate that this oxygen‐evolving nanoplatform can elevate singlet oxygen to effectively inhibit tumor growth without obvious damage to major organs. The preliminary results from this study indicate the potential of biocompatible PB@PMO‐Ce6 nanoplatform to elevate O2 and ROS for improving PDT efficacy.
Photodynamic therapy (PDT) has been proven to be a potential therapeutic strategy for cancers1 via the reaction between photosensitizers and oxygen (O2) under laser to generate cytotoxic reactive oxygen species (ROS) for killing cancer cells.2, 3, 4, 5, 6 Compared to traditional cancer therapy strategies, such as surgery, chemotherapy, and radiotherapy, PDT emerges as a promising treatment method with less invasiveness, fewer side effects, and higher selectivity and efficacy.2, 4, 7, 8, 9 Because the PDT process is dependent on O2 concentration, tumor hypoxia originating from the rapid tumor growth and abnormal tumor vessels3, 10, 11 limits the efficacy of PDT and promotes therapeutic resistance and cancer progression.12, 13
In order to overcome hypoxia during PDT, we synthesized a safe, simple, integrated, and multifunctional nanoplatform, PB@PMO‐Ce6, to achieve the enhancement of PDT efficacy by first making use of the catalase‐like activity of PB. PB and PMO are both with excellent biocompatibility,28 which makes this nanoplatform suitable for application in vivo. The nanoparticle presents well‐defined core–shell structure, uniform diameter (105 ± 12 nm), and high biocompatibility. Owing to the PB cores and conjugated photosensitizer, the nanoparticles can effectively catalyze abundant but undesirable H2O2 into O2 and sequentially generate more ROS for PDT in the same system. A higher level of singlet oxygen and better therapeutic efficacy are present in group of PB@PMO‐Ce6 than Ce6 only both in vitro and in vivo, which indicates the ability of the nanosystem to enhance PDT. There are no obvious weight loss and organs damage by analyzing body weight and H&E staining sections of important organs of mice, which ensure the safety of this nanoparticles. Additionally, the preliminary PA and MR imaging results support its potentials to act as a contrast agent for imaging. The results from our study highlight the potential of the PB@PMO‐Ce6 nanoplatform to enhance PDT efficacy by elevating O2 and ROS in a highly integrated and simple nanosystem.
Chemicals and Reagents: Potassium hexacyanoferrate (II) trihydrate (K4[Fe(CN)6] · 3H2O), iron (III) chloride anhydrous (FeCl3), tetraethyl orthosilicate (TEOS), hexadecyltrimethyl ammonium bromide (CTAB, 25wt%), dioxane, and triphenylphosphine were obtained from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Citric acid monohydrate, N,N‐dimethylformamide (DMF), anhydrous ethanol, concentrated ammonia aqueous solution (25 wt%), and hydrogen peroxide (30 wt%) were obtained from Nanjing Chemical Reagent Co., Ltd. (Nanjing, China). Acetone was acquired from Nanjing Aojia Chemical Co., Ltd. (Nanjing, China). TESPTS, N‐Carbamoylmaleimide, N‐hydroxysulfosuccinimide sodium salt (NHS), N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride (EDC), Chlorin e6, and 2′,7′‐dichlorofluorescin diacetate (DCFH‐DA) were bought from Sigma‐Aldrich (St. Louis, MO, USA). Concentrated hydrochloric acid (HCl) (37%) was obtained from Shanghai Jiuyi Chemical Reagent Co., Ltd. (Shanghai, China). Tris(4,7‐diphenyl‐1,10‐phenanthroline)rutheniuM(II) dichloride (Ru(dpp)3Cl2) was obtained from Meryer (Shanghai) Chemical Technology Co., Ltd. (Shanghai, China). SOSG was purchased from Invitrogen (USA). Deionized water (Millipore) with a resistivity of 18 MΩ cm was used for all experiments. Dimethyl sulfoxide, Dulbecco’s Modified Eagle’s Medium (DMEM) and cell counting kit‐8 (CCK‐8) were bought from Nanjing Keygen Biotech. Co., Ltd. (Nanjing, China). Trypsin‐EDTA (0.25%), heat‐inactivated fetal bovine serum (FBS), and penicillin‐streptomycin solution were bought from Gibco Laboratories (NY, USA). U87MG cells were acquired from American Type Culture Collection (ATCC, Manassas, VA).
The authors declare no conflict of interest.