Xingyu Hou1, Dan Zhong1, Yunkun Li1, Hongli Mao2, Jun Yang3, Hu Zhang4, Kui Luo1, Qiyong Gong1, Zhongwei Gu5,6. 1. Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China. 2. Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Nanjing Tech University, Nanjing, 211816, People's Republic of China. 3. The Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, Tianjin, 300071, People's Republic of China. 4. Amgen Bioprocessing Centre, Keck Graduate Institute, Claremont, CA, 91711, USA. 5. Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China. zwgu@scu.edu.cn. 6. Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Nanjing Tech University, Nanjing, 211816, People's Republic of China. zwgu@scu.edu.cn.
Abstract
BACKGROUND: Nanocarriers-derived antitumor therapeutics are often associated with issues of limited tumor penetration and dissatisfactory antitumor efficacies. Some multistage delivery systems have been constructed to address these issues, but they are often accompanied with complicated manufacture processes and undesirable biocompatibility, which hinder their further application in clinical practices. Herein, a novel dual-responsive multi-pocket nanoparticle was conveniently constructed through self-assembly and cross-linking of amphiphilic methoxypolyethylene glycol-lipoic acid (mPEG-LA) conjugates to enhance tumor penetration and antitumor efficacy. RESULTS: The multi-pocket nanoparticles (MPNs) had a relatively large size of ~ 170 nm at physiological pH which results in prolonged blood circulation and enhanced accumulation at the tumor site. But once extravasated into acidic tumor interstices, the increased solubility of PEG led to breakage of the supramolecular nanostructure and dissolution of MPNs to small-sized (< 20 nm) nanoparticles, promoting deep penetration and distribution in tumor tissues. Furthermore, MPNs exhibited not only an excellent stable nanostructure for antitumor doxorubicin (DOX) loading, but rapid dissociation of the nanostructure under an intracellular reductive environment. With the capacity of long blood circulation, deep tumor penetration and fast intracellular drug release, the DOX-loaded multi-pocket nanoparticles demonstrated superior antitumor activities against large 4T1 tumor (~ 250 mm3) bearing mice with reduced side effect. CONCLUSIONS: Our facile fabrication of multi-pocket nanoparticles provided a promising way in improving solid tumor penetration and achieving a great therapeutic efficacy.
BACKGROUND: Nanocarriers-derived antitumor therapeutics are often associated with issues of limited tumor penetration and dissatisfactory antitumor efficacies. Some multistage delivery systems have been constructed to address these issues, but they are often accompanied with complicated manufacture processes and undesirable biocompatibility, which hinder their further application in clinical practices. Herein, a novel dual-responsive multi-pocket nanoparticle was conveniently constructed through self-assembly and cross-linking of amphiphilic methoxypolyethylene glycol-lipoic acid (mPEG-LA) conjugates to enhance tumor penetration and antitumor efficacy. RESULTS: The multi-pocket nanoparticles (MPNs) had a relatively large size of ~ 170 nm at physiological pH which results in prolonged blood circulation and enhanced accumulation at the tumor site. But once extravasated into acidic tumor interstices, the increased solubility of PEG led to breakage of the supramolecular nanostructure and dissolution of MPNs to small-sized (< 20 nm) nanoparticles, promoting deep penetration and distribution in tumor tissues. Furthermore, MPNs exhibited not only an excellent stable nanostructure for antitumor doxorubicin (DOX) loading, but rapid dissociation of the nanostructure under an intracellular reductive environment. With the capacity of long blood circulation, deep tumor penetration and fast intracellular drug release, the DOX-loaded multi-pocket nanoparticles demonstrated superior antitumor activities against large 4T1 tumor (~ 250 mm3) bearing mice with reduced side effect. CONCLUSIONS: Our facile fabrication of multi-pocket nanoparticles provided a promising way in improving solid tumor penetration and achieving a great therapeutic efficacy.
Entities:
Keywords:
Disulfide cross-linking; Drug delivery; Facile preparation; Particle size; Tumor penetration
Authors: H Cabral; Y Matsumoto; K Mizuno; Q Chen; M Murakami; M Kimura; Y Terada; M R Kano; K Miyazono; M Uesaka; N Nishiyama; K Kataoka Journal: Nat Nanotechnol Date: 2011-10-23 Impact factor: 40.523