A safe, simple and efficient doxorubicin prodrug hybrid micelle for overcoming tumor multidrug resistance and targeting delivery.
A pH-sensitive prodrug, TPGS-CHN-DOX, was introduced by conjugating anticancer drug, doxorubicin (DOX), onto d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) via a cleavable Schiff base linkage. The prodrug was mixed with a PEGylated lipid to form a simple but multifunctional hybrid micelle system, which can realize high drug loading capability and biocompatibility, extended blood circulation time, inhibited drug resistance in cancer cells, improved therapeutic response, reduced side effects, and easy functionalities for targeting delivery. The hybrid micelles exhibited in vitro pH-sensitive drug release, enhanced cellular uptake and strengthened cytotoxicity on both drug-sensitive human breast cancer MCF-7 and resistant MCF-7/ADR cells. P-glycoprotein functional inhibition and mitochondria-associated cell apoptosis induced by TPGS were thought to play an important role in overcoming the multidrug resistance. As a result, the hybrid micelles demonstrated good anticancer efficacy in MCF-7/ADR xenograft model. Additionally, after modifying with a tumor-specific targeting peptic ligand, cRGD, the tumor growth/metastasis inhibition was further evidenced in integrin receptor overexpressed melanoma cancer B16F10 and even murine hepatocarcinoma H22 models. This TPGS-based pH-sensitive prodrug provides a safe and "Molecular economical" way in the rational design of prodrugs for overcoming multidrug resistance and targeting delivery, which can improve the potency for clinical use.
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
Yuling
Y
Bao
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
Mingxing
M
Yin
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
Xiaomeng
X
Hu
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
Xiangting
X
Zhuang
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
Yu
Y
Sun
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
Yuanyuan
Y
Guo
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: tansongwei@gmail.com.
Songwei
S
Tan
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Engineering Research Centre for Novel Drug Delivery System, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: zhipingzhang@mail.hust.edu.cn.
Zhiping
Z
Zhang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D016503:Drug Delivery Systems; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008810:Mice, Inbred C57BL; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D047368:Tumor Burden / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D008823:Micelles; D011355:Prodrugs; D014810:Vitamin E; D004317:Doxorubicin; C014225:tocophersolan
4-Formylbenzoic acid (PubChem CID: 12088); D-Alpha-tocopherol succinate (PubChem CID: 20353); D-α-tocopherol polyethylene glycol 1000 succinate; DSPE-mPEG-2000 (PubChem CID: 86278269); Doxorubicin hydrochloride (PubChem CID: 443939); Drug resistance; Prodrug; RGD peptide (PubChem CID: 104802); Targeting; pH-sensitive