Journal
ACS APPLIED NANO MATERIALS
Volume 1, Issue 2, Pages 595-608Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsanm.7b00087
Keywords
halloysite; nanotube; targeting therapy; cancer; folate; intravenous injection
Funding
- National High Technology Research and Development Program of China [2015AA020915]
- National Natural Science Foundation of China [51473069, 81622050, 51502113]
- Guangdong Natural Science Funds for Distinguished Young Scholar [S2013050014606]
- Science and Technology Program of Guangzhou, China [2013J4100100, 201610010026]
- Guangdong Special Support Program [2014TQ01C127, 2014TQ01R229]
- Fundamental Research Funds for the Central Universities [21615204]
- Guangdong Province Ocean and Fisheries Bureau-Key Technology Research and Development Program [A201701A02]
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To carry doxorubicin (DOX) on breast cancer site effectively, halloysite nanotubes conjugated with poly(ethylene glycol) and folate (HNTs-PEG-FA) is designed as a targeted drug delivery system. Halloysite nanotubes (HNTs) are shortened to similar to 200 nm by ultrasonic scission and functionalized with amide groups to conjugate with N-hydroxylsuccinimide-polyethylene glycol carboxylic acid (NHS-PEG-COOH) and folate (FA). DOX@HNTs-PEG-FA is prepared by loading DOX on HNTs-PEG-FA via physical adsorption. The sustained and controlled release of DOX from DOX@HNT5-PEG-FA is up to 35 h in an acidic environment (pH 5.3). DOX@HNTs-PEG-FA, performed as a new nanodelivery system, shows significant inhibition of proliferation and induction of death in MCF-7 cells with positive FA receptor but not in L02 cells with negative FA receptor. Results of acridine orange/ethidium bromide and flow cytometric assay indicate that DOX@HNTs-PEG-FA induces cell death through apoptosis. Compared to the same dose of DOX, DOX@HNTs-PEG-FA generates more reactive oxygen species (ROS) in MCF-7 cells, which lead to mitochondrial damage and apoptosis. Furthermore, with fluorescence images and transmission electron microscopy, uptake of DOX@HNTs-PEG-FA by tumor cells is both through endocytosis and direct penetration mechanism. The in vivo antibreast cancer activity of DOX@HNTs-PEG-FA is further confirmed in 4T1-bearing mice. In contrast to DOX, DOX@HNT5-PEG-FA effectively reduces heart toxicity and inhibits solid tumor growth with higher cleaved caspase-3 protein level in tumor tissue of 4T1-bearing mice. DOX@HNTs-PEG-FA reveals a higher DOX fluorescence intensity in tumor tissue than in other normal tissues including heart, spleen, lung, and kidney at different time points. All these results suggest that FA-conjugated HNTs may be designed to be a novel drug delivery system for targeted therapy of breast cancer via intravenous injection.
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