title: Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles.
abstract: Glioma is still hard to be treated due to their complex microenvironment. In this study, a gold nanoparticle-based delivery system was developed. The system, An-PEG-DOX-AuNPs, was loaded with doxorubicin (DOX) through hydrazone, an acid-responsive linker, and was functionalized with angiopep-2, a specific ligand of low density lipoprotein receptor-related protein-1 (LRP1), which could mediate the system to penetrate blood brain barrier and target to glioma cells. The particle size of An-PEG-DOX-AuNPs was 39.9 nm with a zeta potential of -19.3 mV, while the DOX loading capacity was 9.7%. In vitro, the release of DOX from DOX-AuNPs was pH-dependent. At lower pH values, especially 5.0 and 6.0, release of DOX was much quicker than that at pH 6.8 and 7.4. After coating with PEG, the acid-responsive release of DOX from PEG-DOX-AuNPs was almost the same as that from DOX-AuNPs. Cellular uptake study showed obviously higher intensity of intracellular An-PEG-DOX-AuNPs compared with PEG-DOX-AuNPs. In vivo, An-PEG-DOX-AuNPs could distribute into glioma at a higher intensity than that of PEG-DOX-AuNPs and free DOX. Correspondingly, glioma-bearing mice treated with An-PEG-DOX-AuNPs displayed the longest median survival time, which was 2.89-fold longer than that of saline. In conclusion, An-PEG-DOX-AuNPs could specifically deliver and release DOX in glioma and significantly expand the median survival time of glioma-bearing mice.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Ruan
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
authors.forename: Mingqing
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
authors.forename: Guanlian
authors.initials: G
authors.lastname: Hu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
authors.forename: Xingli
authors.initials: X
authors.lastname: Cun
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
authors.forename: Qianyu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China. Electronic address: qinhe@scu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China. Electronic address: gaohuile@scu.edu.cn.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006046:Gold / Q000737:chemistry*; D008297:Male; D053768:Metal Nanoparticles / Q000648:ultrastructure; D051379:Mice; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: C531860:Angiopep-2; D010455:Peptides; D011092:Polyethylene Glycols; D006046:Gold; D004317:Doxorubicin
keywords: Doxorubicin; Glioma; Gold nanoparticles; Sensitive release; Tumor microenvironment