title: Self-assembled tumor-targeting hyaluronic acid nanoparticles for photothermal ablation in orthotopic bladder cancer.
abstract: Bladder cancer is one of the most frequent malignancies in the urinary system. Radical cystectomy is inevitable when bladder cancer progresses to a muscle-invasive disease. However, cystectomy still causes a high risk of death and a low quality of life (such as ureter-abdomen ostomy, uroclepsia for ileal-colon neobladder). Therefore, more effective treatments as well as bladder preservation are needed. We developed self-assembled tumor-targeting hyaluronic acid-IR-780 nanoparticles for photothermal ablation in over-expressing CD44 (the receptor for HA) bladder cancer, which show high tumor selectivity, high treatment efficacy, good bioavailability, and excellent biocompatibility. The nanoparticles demonstrated a stable spherical nanostructure in aqueous conditions with good mono-dispersity, and their average size was 171.3±9.14nm. The nanoparticles can be degraded by hyaluronidase when it is over-expressed in bladder cells; therefore, they appear to have a hyaluronidase-responsive "OFF/ON" behavior of a fluorescence signal. HA-IR-780 NPs also showed high photothermal efficiency; 2.5, 5, 10 and 20μg/mL of NPs had a maximum temperature increase of 11.2±0.66°C, 18.6±0.75°C, 26.8±1.11°C and 32.3±1.42°C. The in vitro cell viability showed that MB-49 cells could be efficiently ablated by combining HA-IR-780 NPs with 808nm laser irradiation. Then, in vivo biodistribution showed the HA-IR-780 NPs are targeted for accumulation in bladder cancer cells but have negligible accumulation in normal bladder wall. The photothermal therapeutic efficacy of HA-IR-780 NPs in the orthotopic bladder cancer model showed tumors treated with NPs had a maximum temperature of 48.1±1.81°C after 6min of laser irradiation. The tumor volume was approximately 65-75mm3prior to treatment. After 12days, the tumor sizes for the PBS, PBS plus laser irradiation and HA-IR-780 NPs-treated groups were 784.75mm3, 707.5mm3, and 711.37mm3, respectively. None of the tumors in the HA-IR-780 NPs plus laser irradiation-treated group were visible to the naked eye. A toxicity study showed HA-IR-780 NPs (2.5-20mg/kg, i.v.) were nontoxic and safe for in vivo applications. HA-IR-780 nanoparticles address current clinical challenges, treating locally aggressive lesions and preserving the bladder. They have enormous potential to improve the bladder cancer treatment strategies in clinic.
  
  
  
  1) Bladder cancer is one of the most frequent malignancies in the urinary system. Radical cystectomy is inevitable while bladder cancer progress to muscle-invasive disease. 2) We developed self-assembled tumor-targeting hyaluronic acid-IR-780 nanoparticles for photothermal ablation in over-expressing CD44 (the receptor for HA) bladder cancer. 3) Photothermal therapeutic efficacy of HA-IR-780 NPs in orthotopic bladder cancer model showed tumors were completely ablated. 4) HA-IR-780 nanoparticles address current clinical challenges, treating locally aggressive lesions as well as for bladder preservation.
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Tingsheng
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, Jiangsu, China.
authors.forename: Ahu
authors.initials: A
authors.lastname: Yuan
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Huibo
authors.initials: H
authors.lastname: Lian
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Junlong
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Wenmin
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, Jiangsu, China.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, Jiangsu, China.
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China. Electronic address: dr.ghq@nju.edu.cn.
authors.forename: Hongqian
authors.initials: H
authors.lastname: Guo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003460:Crystallization / Q000379:methods; D005260:Female; D006820:Hyaluronic Acid / Q000737:chemistry*; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000737:chemistry; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C548458:2-(2-(2-chloro-3-((1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene)-1-cyclohexen-1-yl)ethenyl)-3,3-dimethyl-1-propylindolium; D007211:Indoles; D053769:Nanocapsules; D017319:Photosensitizing Agents; D006820:Hyaluronic Acid
keywords: Hyaluronic acid (HA); IR-780; Orthotopic bladder cancer; Photothermal ablation; Self-assembled nanoparticles