Mastocarcinoma therapy synergistically promoted by lysosome dependent apoptosis specifically evoked by 5-Fu@nanogel system with passive targeting and pH activatable dual function.
This manuscript describes a synergistic therapy for mastocarcinoma by pH and temperature dual-sensitive nanogel, and effects of microstructure, composition and properties of nanogel on the cellular response mechanism. The extracellular internalization of nanogels was obviously enhanced, due to the passive targeting function at T>VPTT. Interestingly, the increased cytotoxicity was further synergistically enhanced by an unexpected apoptosis as evoked by the 5-fluorouracil loaded nanogel (FLNG). The systemically evaluation of the effectors generated from different sub-cellular organelles including endosome, lysosome, autophagosome confirmed that it was a lysomal dependent apoptosis. Such specific apoptosis was mainly attributed to its activatable protonated PEI at low pH, which caused lysosomal membrane destruction and lysosomal enzyme cathepsin B (Cat B) leakage. This Cat B was then translocated to the mitochondria resulting in mitochondrial membrane permeability increase and mitochondrial membrane potential (MMP) decrease, followed by cytochrome c (Cyt C) release. Cyt C was the main molecule that evoked apoptosis as reflected by overexpression of caspase 9. Additionally, such lysosome dependent, apoptosis was further enhanced by the passive cellular targeting at T>VPTT. Thus, the tumor growth inhibition was synergistically enhanced by the extracellular temperature dependent passive targeting and intracellular pH activatable lysosomal dependent apoptosis.
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Xiandi
X
Zhu
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Yn
Y
Sun
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Di
D
Chen
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Jingfeng
J
Li
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Xia
X
Dong
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China; College of Pharmacy, Liaocheng University, 1Hunan Road, Liaocheng, Shandong 25000, China.
Jie
J
Wang
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Huaiwen
H
Chen
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Ying
Y
Wang
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Fulei
F
Zhang
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China.
Jinaxin
J
Dai
3B's Research Group-Biomaterials, Biodegradables, and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS-3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Rogério P
RP
Pirraco
College of Pharmacy, Liaocheng University, 1Hunan Road, Liaocheng, Shandong 25000, China.
Shangjing
S
Guo
3B's Research Group-Biomaterials, Biodegradables, and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS-3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Alexandra P
AP
Marques
3B's Research Group-Biomaterials, Biodegradables, and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal; ICVS-3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Rui L
RL
Reis
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, China; College of Pharmacy, Liaocheng University, 1Hunan Road, Liaocheng, Shandong 25000, China. Electronic address: liwei@smmu.edu.cn.
Wei
W
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D053453:Caspase 9 / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D045304:Cytochromes c / Q000378:metabolism; D004337:Drug Carriers; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D005782:Gels; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007097:Imines / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D049329:Nanostructures / Q000737:chemistry*; D010316:Particle Size; D011095:Polyethylenes / Q000737:chemistry
D000970:Antineoplastic Agents; D004337:Drug Carriers; D005782:Gels; D007097:Imines; D011095:Polyethylenes; C505405:poly(ethylene imine); D045304:Cytochromes c; D053453:Caspase 9; D002401:Cathepsin B; D005472:Fluorouracil
Apoptosis; Drug delivery; Mastocarcinoma therapy; Nanogel; Passive targeting