Mild Acid-Responsive “Nanoenzyme Capsule” Remodeling of theTumor Microenvironment to Increase Tumor Penetration

【作者】 Hanchun Yao, Xiaofang Guo, Huijuan Zhou, Jinjin Ren, Ying Li, Songchao Duan, Xiaobao Gong,and Bin Du

【期刊名】 ACS Applied Materials & Interfaces

【影响因子】 2020年:8.456

【作者单位】 School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China

【年，卷(期)：页码】2020, 12(18): 20214−20227

【关键词】 extracellular matrix, heavy-chain ferritin, collagenase nanocapsule, tumor penetration, alleviate hypoxia

【摘要】Dense extracellular matrix (ECM) severely impedes thespread of drugs in solid tumors and induces hypoxia, reducing chemotherapyefficiency. Different proteolytic enzymes, such as collagenase (Col) orbromelain, can directly attach to the surface of nanoparticles and improvetheir diffusion, but the method of ligation may also impair the enzymaticactivity due to conformational changes or blockage of the active site. Herein,a “nanoenzyme capsule” was constructed by combining collagenasenanocapsules (Col-nc) with heavy-chain ferritin (HFn) nanocagesencapsulating the chemotherapy drug doxorubicin (DOX) to enhancetumor penetration of the nanoparticles by hydrolyzing collagen from theECM. Col-nc could protect the activity of the enzyme before reaching thesite of action while being degraded under mildly acidic conditions in tumors,and the released proteolytic enzyme could digest collagen. In addition, HFnas a carrier could effectively load DOX and had a self-targeting ability, enabling thenanoparticles to internalize into cancer cells moreeffectively. From in vivo and in vitro studies, we found that collagen was effectively degraded by Col-nc/HFn(DOX) to increase theaccumulation and penetration of nanoparticles in the solid tumor site and could alleviate hypoxia inside the tumor to enhance theantitumor effects of DOX. Therefore, the strategy of increasing nanoparticle penetration in this system is expected to provide apotential approach for the clinical treatment of solid tumors.

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