title: Copper sulfide nanoparticle-based localized drug delivery system as an effective cancer synergistic treatment and theranostic platform.
abstract: Localized cancer treatment with combination therapy has attracted increasing attention for effective inhibition of tumor growth. In this work, we introduced diffusion molecular retention (DMR) tumor targeting effect, a new strategy that employed transferrin (Tf) modified hollow mesoporous CuS nanoparticles (HMCuS NPs) to undergo extensive diffuse through the interstitium and tumor retention after a peritumoral (PT) injection. Herein, HMCuS NPs with strong near-infrared (NIR) absorption and photothermal conversion efficiency could serve as not only a drug carrier but also a powerful contrast agent for photoacoustic imaging to guide chemo-phototherapy. The iron-dependent artesunate (AS), which possessed profound cytotoxicity against tumor cell, was used as model drug. As a result, this AS loaded Tf-HMCuS NPs (AS/Tf-HMCuS NPs) system could specially target to tumor cells and synchronously deliver AS as well as irons into tumor to achieve enhanced antitumor activity. It was found that AS/Tf-HMCuS NPs was taken up by MCF-7 cells via Tf-mediated endocytosis, and could effectively convert NIR light into heat for photothermal therapy as well as generated high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, in vivo antitumor efficacy studies showed that tumor-bearing mice treated with AS/Tf-HMCuS NPs through peritumoral (PT) injection under NIR laser irradiation displayed the strongest inhibition rate of about 74.8%, even with the reduced frequency of administration. Furthermore, to demonstrate DMR, the optical imaging, photoacoustic tomography and immunofluorescence after PT injection were adopted to track the behavior of AS/Tf-HMCuS NPs in vivo. The results exhibited that Tf-HMCuS NPs prolonged the local accumulation and retention together with slow vascular uptake and extensive interstitial diffusion, which was consistent with the biodistribution studies of AS/Tf-HMCuS NPs. Therefore, the approach of localized delivery through DMR combined with multi-mechanism therapy may be a promising method for cancer treatment.
  
  
  
  In recent years, localized cancer treatment using different biomaterials has attracted increasing attention for effective inhibition of tumor growth. However, it is still challenging for this kind of system to achieve a high drug loading, overcome biological barriers from the site of injection to the site of action, and combine synergetic therapy with diagnosis without adversely affecting the formation process. This study provides a localized diffusion molecular retention (DMR) tumor targeting drug delivery system based on hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) entrapment of anticancer drug for the first time, which can achieve high drug loading, improve local drug accumulation and retention, accomplish synergistic combination of chemo-phototherapy, and finally enhance antitumor effect. In addition, HMCuS NPs also possesses the property suitable for photoacoustic imaging, which could offer us a theranostic platform.
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Hou
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Shan
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Hao
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China.
authors.forename: Qianhua
authors.initials: Q
authors.lastname: Feng
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China. Electronic address: zhangzz_pharm@163.com.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D003287:Contrast Media / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology; D000068936:Theranostic Nanomedicine / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D013440:Sulfides; D003300:Copper
keywords: Combination therapy; Diffusion molecular retention; Hollow mesoporous CuS; Localized delivery; Tumor-targeted