A safe, simple and efficient doxorubicin prodrug hybrid micelle for overcoming tumor multidrug resistance and targeting delivery
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- 作者：Yuling Baoa ; Mingxing Yina ; Xiaomeng Hua ; Xiangting Zhuanga ; Yu Suna ; Yuanyuan Guoa ; Songwei Tana ; b ; tansongwei@gmail.com" class="auth_mail" title="E-mail the corresponding author ; Zhiping Zhanga ; b ; c ; zhipingzhang@mail.hust.edu.cn" class="auth_mail" title="E-mail the corresponding author
- 关键词：D-Alpha-tocopherol succinate (PubChem CID ; 20353) ; RGD peptide (PubChem CID ; 104802) ; Doxorubicin hydrochloride (PubChem CID ; 443939) ; 4-Formylbenzoic acid (PubChem CID ; 12088) ; DSPE-mPEG-2000 (PubChem CID ; 86278269)
- 刊名：Journal of Controlled Release
- 出版年：2016
- 出版时间：10 August 2016
- 年：2016
- 卷：235
- 期：Complete
- 页码：182-194
- 全文大小：2762 K
文摘
A pH-sensitive prodrug, TPGS-CH
N-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.
N-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.