Multidrug resistance (MDR) is a common cause of failure in chemotherapy for malignant diseases. MDR is either acquired as a result of previous repeated exposure to cytostatic drugs (P388/MDR cells) or naturally, as some tumors are congenitally resistant to chemotherapy (CT26 cells). One of the most common mechanisms of MDR is upregulation of P-glycoprotein (P-gp) expression. Here, we used HPMA copolymer conjugates, whereby the cytostatic drug doxorubicin (Dox) or the derivative of the P-gp inhibitor reversin 121 (R121) or both were covalently bound through a degradable pH-sensitive hydrazone bond. We proved that R121, when bound to a polymeric carrier, is capable of inhibiting P-gp in P388/MDR cells and sensitizing them in relation to the cytostatic activity of Dox. Conjugate bearing both Dox and R121 was found to be far more potent in P388/MDR cells than conjugate bearing Dox alone or a mixture of conjugates bearing either Dox or R121 when cytostatic activity in vitro, cell cycle arrest, accumulation of Dox in cells and induction of apoptosis were determined. Importantly, conjugate bearing R121 is also effective in vivo as it inhibits P-gp in P388/MDR tumors after intraperitoneal administration, while both the conjugate bearing Dox and R121 induces apoptosis in P388/MDR tumors more effectively than conjugate bearing Dox alone. Only conjugate bearing Dox and R121 significantly inhibited P388/MDR tumor growth and led to the prolonged survival of treated mice. However, the most dramatic antitumor activity of this conjugate was found in the CT26 tumor model where it completely cured six out of eight experimental mice, while conjugate bearing Dox alone cured no mice. (C) 2016 Elsevier Ltd. All rights reserved.
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E China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R ChinaE China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China
Qian, F
Wei, DZ
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E China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R ChinaE China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China
Wei, DZ
Zhang, Q
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E China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R ChinaE China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China
Zhang, Q
Yang, SL
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E China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R ChinaE China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China
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Shanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
Luo, Fei
Li, Huiyu
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Shanxi Acad Med Sci, Shanxi Dayi Hosp, Dept Gen Surg, 99 Longcheng Main St, Taiyuan 030032, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
Li, Huiyu
Liang, Jianfang
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Shanxi Med Univ, Dept Pathol, Hosp 1, Taiyuan 030001, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
Liang, Jianfang
Jia, Hongyan
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Shanxi Med Univ, Dept Gen Surg, Hosp 1, Taiyuan 030001, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
Jia, Hongyan
Li, Xiaoyu
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Shanxi Canc Hosp, Dept Mol Biol, Taiyuan 030013, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
Li, Xiaoyu
Xiao, Hong
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Shanxi Med Univ, Dept Pathol, Hosp 1, Taiyuan 030001, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
Xiao, Hong
He, Xuehua
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Shanxi Acad Med Sci Shanxi Dayi Hosp, Dept Blood Transfus, Taiyuan 030032, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
He, Xuehua
He, Jiefeng
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Shanxi Acad Med Sci, Shanxi Dayi Hosp, Dept Gen Surg, 99 Longcheng Main St, Taiyuan 030032, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
He, Jiefeng
Tian, Yanzhang
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Shanxi Acad Med Sci, Shanxi Dayi Hosp, Dept Gen Surg, 99 Longcheng Main St, Taiyuan 030032, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
Tian, Yanzhang
Zhao, Haoliang
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Shanxi Acad Med Sci, Shanxi Dayi Hosp, Dept Gen Surg, 99 Longcheng Main St, Taiyuan 030032, Shanxi, Peoples R ChinaShanxi Canc Hosp, Dept Breast Surg, Taiyuan 030013, Shanxi, Peoples R China
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Univ Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, ItalyUniv Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, Italy
Riganti, Chiara
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Contino, Marialessandra
Guglielmo, Stefano
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Univ Torino, Dipartimento Sci & Tecnol Farmaco, Via P Giuria 9, I-10125 Turin, ItalyUniv Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, Italy
Guglielmo, Stefano
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Perrone, Maria G.
Salaroglio, Iris C.
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Univ Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, ItalyUniv Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, Italy
Salaroglio, Iris C.
Milosevic, Vladan
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Univ Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, ItalyUniv Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, Italy
Milosevic, Vladan
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Giampietro, Roberta
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Leonetti, Francesco
Rolando, Barbara
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Univ Torino, Dipartimento Sci & Tecnol Farmaco, Via P Giuria 9, I-10125 Turin, ItalyUniv Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, Italy
Rolando, Barbara
Lazzarato, Loretta
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Univ Torino, Dipartimento Sci & Tecnol Farmaco, Via P Giuria 9, I-10125 Turin, ItalyUniv Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, Italy
Lazzarato, Loretta
Colabufo, Nicola A.
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Univ Bari ALDO MORO, Dipartimento Farm Sci Farmaco, Via Orabona 4, I-70125 Bari, Italy
Spin Off Univ Bari ALDO MORO, Biofordrug Sr1, Via Orabona 4, I-70125 Bari, ItalyUniv Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, Italy
Colabufo, Nicola A.
Fruttero, Roberta
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Univ Torino, Dipartimento Sci & Tecnol Farmaco, Via P Giuria 9, I-10125 Turin, ItalyUniv Torino, Dipartimento Oncol, Via Santena 5 Bis, I-10126 Turin, Italy