Article pubs.acs.org/cm
Cite This: Chem. Mater. 2018, 30, 5412−5421
A Bioenvironment-Responsive Versatile Nanoplatform Enabling Rapid Clearance and Effective Tumor Homing for Oxygen-Enhanced Radiotherapy Qiuhong Zhang,†,‡ Jingwen Chen,§ Ming Ma,† Han Wang,*,§,∥ and Hangrong Chen*,†
Downloaded via UNIV OF NEW ENGLAND on October 6, 2018 at 06:48:43 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P. R. China ‡ University of Chinese Academy of Sciences, Beijing 100049, P. R. China § Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P. R. China ∥ National Engineering Research Center for Nanotechnology, Shanghai 200241, P. R. China S Supporting Information *
ABSTRACT: Nanoradiosensitizer-augmented cancer radiotherapy (RT) has been widely investigated, whereas the desirable nanoradiosensitizer with the characteristics of rapid clearance, effective tumor homing, and tumor hypoxia relief is still lacking. Herein, bismuth sulfide−albumin composite nanospheres followed by catalase conjugation (denoted as BSNSs-CAT) have been well constructed as a bioenvironment-responsive nanoradiosensitizer platform. The BSNSs-CAT phagocytosed by normal cells demonstrate architectural disintegration into small ones in response to physiological pH, achieving small size-favored rapid clearance, which largely mitigates the concern of long-term toxicity of BSNSs-CAT in normal tissues. More importantly, benefiting from their large size-favored enhanced permeability and retention effect, BSNSs-CAT accumulate efficiently in tumors and remain architecturally stable in a mildly acidic tumor microenvironment (TME), which strongly favors a response with H2O2 overproduced TME. As a result, the produced intratumor oxygen could overcome tumor hypoxia-associated RT resistance, together with the radiosensitization effect of bismuth, collectively enhancing RT efficacy. This research demonstrates a versatile material solution by fully exploring its bioenvironment-responsive nature, offering a new strategy for nanomedicine design and application.
■
INTRODUCTION Radiotherapy (RT), which utilizes ionizing radiation (X-ray) to ablate tumor,1,2 has a unique advantage in being depthindependent, effectively favoring both superficial and deepseated tumor regression. Recently, inorganic nanomaterials containing high Z elements, such as rare earth elementcontaining upconversion nanoparticles,3−5 wolfram oxide nanoparticles,6 gold nanoparticles,7−9 etc., have been widely investigated as nanoradiosensitizers. In comparison with pure RT, during which high-energy X-rays are applied to tumorous regions to kill cancer cells, those nanoradiosensitizers that accumulate in tumorous regions can interact with X-rays, producing photoelectrons, compton electrons, and secondary charged particles to promote RT-induced cancer killing.8 In order to maximize the RT efficacy, the effective tumor homing of these nanoradiosensitizers through the enhanced permeability and retention (EPR) effect is highly desirable and, simultaneously, the rapid clearance to circumvent their longterm toxicity is also considerably expected; both of these features, as the growing body of evidence shows, are closely © 2018 American Chemical Society
related to their hydrodynamic size. On one hand, a hydrodynamic size in the range of 30−200 nm is quite beneficial for improved tumor homing through the EPR effect, but inevitably results in retention in reticuloendothelial systems (RES) such as liver and spleen,10 wherein long-term toxicity would be potentially amplified if without biodegradation and clearance.11−13 On the other hand, a hydrodynamic size of
