Disulfide-crosslinked nanomicelles confer cancer-specific drug delivery and improve efficacy of paclitaxel in bladder cancer

被引:35
|
作者
Pan, Amy [1 ,6 ]
Zhang, Hongyong [2 ]
Li, Yuanpei [1 ]
Lin, Tzu-yin [2 ]
Wang, Fuli [2 ,7 ]
Lee, Joyce [2 ]
Cheng, Mingshan [3 ]
Dall'Era, Marc [4 ]
Li, Tianhong [2 ,5 ]
White, Ralph deVere [4 ]
Pan, Chong-Xian [2 ,4 ,5 ]
Lam, Kit S. [1 ,2 ]
机构
[1] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Sacramento, CA 95817 USA
[2] Univ Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
[3] Jackson Lab, 4910 Raley Blvd, Sacramento, CA 95838 USA
[4] Univ Calif Davis, Ctr Canc, Dept Urol, Sacramento, CA 95817 USA
[5] VA Northern Calif Hlth Care Syst, 10535 Hosp Way, Mather, CA 95655 USA
[6] Univ Calif San Diego, Dept Psychol, La Jolla, CA 92093 USA
[7] Four Mil Med Sch, Dept Urol, Xian, Peoples R China
关键词
bladder cancer; nanomicelle; paclitaxel; targeted delivery; MULTIFUNCTIONAL MICELLES; PHASE; CHEMOTHERAPY; STATISTICS;
D O I
10.1088/0957-4484/27/42/425103
中图分类号
TB3 [工程材料学];
学科分类号
0805 ; 080502 ;
摘要
Chemotherapy commonly used in the treatment of advanced bladder cancer is only moderately effective and associated with significant toxicity. There has been no appreciable improvement in overall survival over the last three decades. The goal of this project is to develop and characterize bladder cancer-specific nanometer-scale micelles loaded with the chemotherapeutic drug paclitaxel (PTX) and determine the anti-tumor activity and toxicity. Micelle-building-material telodendrimers were synthesized through the stepwise conjugation of eight cholic acid units at one terminus of polyethylene glycol (PEG) and a bladder cancer-specific targeting peptide named PLZ4 at the other terminus. To synthesize disulfide-crosslinked PLZ4 nanomicelles (DC-PNM), cysteine was introduced between the cholic acid and PEG. DC-PNM-PTX was synthesized through the evaporation method by loading PTX in the core. The loading capacity of PTX in DC-PNM was 25% (W/W). The loading efficiency was over 99%. DC-PNM-PTX was spherical with the median size of 25 nm. The stability of DC-PNM-PTX was determined in a solution containing sodium docecyl sulfate (SDS). It was stable in a SDS solution, but dissolved within 5 min after the addition of glutathione at the physiological intracellular concentration of 10 mM. In vivo targeting and anti-tumor activity were determined in immunodeficient mice carrying patient-derived bladder cancer xenografts (PDXs). After intravenous administration, DC-PNM specifically targeted the bladder cancer PDXs, but very little to the lung cancer xenografts in the same mice (p < 0.001). DC-PNM loaded with PTX overcame cisplatin resistance, and improved the median survival from 55 d with free PTX to 69.5 d ( p = 0.03) of mice carrying PDXs. In conclusion, DC-PNM remained stable in the SDS solution, specifically targeted the bladder cancer xenografts in vivo, and improved the anti-cancer efficacy of PTX.
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页数:9
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