Acid-Induced Activated Cell-Penetrating Peptide-Modified Cholesterol-Conjugated Polyoxyethylene Sorbitol Oleate Mixed Micelles for pH-Triggered Drug Release and Efficient Brain Tumor Targeting Based on a Charge Reversal Mechanism

被引:44
|
作者
Tian, Yu [1 ]
Mi, Gujie [2 ]
Chen, Qian [1 ]
Chaurasiya, Birendra [1 ]
Li, Yanan [1 ]
Shi, Di [2 ]
Zhang, Yong [3 ]
Webster, Thomas J. [2 ]
Sun, Chunmeng [1 ]
Shen, Yan [1 ]
机构
[1] China Pharmaceut Univ, Sch Pharm, Dept Pharmaceut, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China
[2] Northeastern Univ, Dept Chem Engn, Snell Engn Ctr 313, 360 Huntington Ave, Boston, MA 02115 USA
[3] Nanjing Med Univ, Childrens Hosp, Nanjing 210008, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
polyoxyethylene sorbitol oleate; pH-responsive micelles; acid-induced activated; cell penetrating peptide; charge shielding; brain tumor targeting; POLYMERIC MICELLES; MEDIATED TRANSPORT; DELIVERY; NANOPARTICLES; GLIOBLASTOMA; BARRIER; STRATEGIES; RECEPTOR; DESIGN; TEMOZOLOMIDE;
D O I
10.1021/acsami.8b15147
中图分类号
TB3 [工程材料学];
学科分类号
0805 ; 080502 ;
摘要
Glioblastoma multiforme is the most devastating malignant brain tumor in adults. Even with the standard care of therapy, the prognosis remains dismal due to tumor heterogeneity, tumor infiltration, and, more importantly, the restrictive nature of the blood-brain barrier (BBB). To overcome the challenge of effectively delivering therapeutic cargo into the brain, herein a "smart", multifunctional polymeric micelle was developed using a cholesterol-conjugated polyoxyethylene sorbitol oleate. A cell-penetrating peptide, arginine-glycine repeats (RG)(5), was incorporated into the micelles to improve cellular uptake, while a pH-sensitive masking sequence, histidine-glutamic acid repeats (HE)(5), was introduced for charge shielding to minimize nonspecific binding and uptake at physiological pH. Results demonstrated that (RG)(5)- and (HE)(5)-modified mixed micelles were optimized using this strategy to effectively mask the cationic charges of the activated cell-penetrating peptide (RG)(5) at physiological pH, i.e., limiting internalization, and were selectively triggered in response to a mildly acidic microenvironment in vitro based on a charge reversal mechanism. In vivo results further confirmed that such micelles preferentially accumulated in both brain and tumor tissues in both xenograft and orthotropic glioma mouse models. Furthermore, micelles significantly inhibited tumor growth with limited toxicity to peripheral tissues. The combination of BBB penetration, tumor targeting, potent efficacy, and high tolerance of these micelles strongly suggests that they could be a promising candidate for safe and effective drug delivery to the brain.
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页码:43411 / 43428
页数:18
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