Mild Acid-Responsive "Nanoenzyme Capsule" Remodeling of the Tumor Microenvironment to Increase Tumor Penetration.
Dense extracellular matrix (ECM) severely impedes the spread of drugs in solid tumors and induces hypoxia, reducing chemotherapy efficiency. Different proteolytic enzymes, such as collagenase (Col) or bromelain, can directly attach to the surface of nanoparticles and improve their diffusion, but the method of ligation may also impair the enzymatic activity due to conformational changes or blockage of the active site. Herein, a "nanoenzyme capsule" was constructed by combining collagenase nanocapsules (Col-nc) with heavy-chain ferritin (HFn) nanocages encapsulating the chemotherapy drug doxorubicin (DOX) to enhance tumor penetration of the nanoparticles by hydrolyzing collagen from the ECM. Col-nc could protect the activity of the enzyme before reaching the site of action while being degraded under mildly acidic conditions in tumors, and the released proteolytic enzyme could digest collagen. In addition, HFn as a carrier could effectively load DOX and had a self-targeting ability, enabling the nanoparticles to internalize into cancer cells more effectively. From in vivo and in vitro studies, we found that collagen was effectively degraded by Col-nc/HFn(DOX) to increase the accumulation and penetration of nanoparticles in the solid tumor site and could alleviate hypoxia inside the tumor to enhance the antitumor effects of DOX. Therefore, the strategy of increasing nanoparticle penetration in this system is expected to provide a potential approach for the clinical treatment of solid tumors.
['Yao|Hanchun|H|', 'Guo|Xiaofang|X|', 'Zhou|Huijuan|H|', 'Ren|Jinjin|J|', 'Li|Ying|Y|', 'Duan|Songchao|S|', 'Gong|Xiaobao|X|', 'Du|Bin|B|http://orcid.org/0000-0002-9049-9313']
D000818:Animals D000970:Antineoplastic Agents D001052:Apoferritins D015687:Cell Hypoxia D045744:Cell Line, Tumor D003094:Collagen D017364:Collagenases D004317:Doxorubicin D004337:Drug Carriers D005109:Extracellular Matrix D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D006863:Hydrogen-Ion Concentration D008807:Mice, Inbred BALB C D053769:Nanocapsules D053758:Nanoparticles D009369:Neoplasms D018874:Spheroids, Cellular D059016:Tumor Microenvironment
tumor penetration extracellular matrix collagenase nanocapsule heavy-chain ferritin alleviate hypoxia