Folate-targeted liposomal nitrooxy-doxorubicin: An effective tool against P-glycoprotein-positive and folate receptor-positive tumors

JOURNAL OF CONTROLLED RELEASE

卷:270

Article

Gazzano, Elena¹  Rolando, Barbara²  Chegaev, Konstantin²  Salaroglio, Iris C.¹  Kopecka, Joanna¹  Pedrini, Isabella²  Saponara, Simona³  Sorge, Matteo⁴  Buondonno, Ilaria¹  Stella, Barbara²  Marengo, Alessandro²  Valoti, Massimo³  Brancaccio, Mara⁴  Fruttero, Roberta²  Gasco, Alberto²  Arpicco, Silvia²  Riganti, Chiara¹ 

[1] Univ Turin, Dept Oncol, Via Santena 5 Bis, I-10126 Turin, Italy

[2] Univ Turin, Dept Drug Sci & Technol, Via Pietro Giuria 9, I-10125 Turin, Italy

[3] Univ Siena, Dept Life Sci, Via Aldo Moro 2, I-53100 Siena, Italy

[4] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Via Nizza 52, I-10126 Turin, Italy

关键词: Liposomes;    Doxorubicin;    Folic acid;    P-glycoprotein;    Chemoresistance;    Breast cancer;   

DOI  :  10.1016/j.jconrel.2017.11.042

来源: Elsevier

【 摘 要 】

Drug efflux transporters, in particular P-glycoprotein (Pgp), limit the success of chemotherapy. We previously found that synthetic doxorubicin conjugated with nitric oxide (NO)-releasing group overcomes resistance by inducing a NO-mediated inhibition of Pgp. Here we produced the first liposomal formulations of this nitrooxy-doxorubicin decorated with folic acid (FA), termed LNDF, in order to improve their active targeting against Pgp-expressing tumors. Folate was inserted onto liposomes surface using two different methods and the formulations were compared with respect to their technological features and in vitro behavior. By analyzing human and murine breast cancer cells with different expression of FA receptor (FAR) and Pgp, we demonstrated that LNDF are internalized in a FAR-dependent manner and achieve maximal anti-tumor efficacy against FAR-positive/Pgppositive cells. Upon uptake of LNDF, nitrooxy-doxorubicin was delivered within nucleus, where it induced cell cycle arrest and DNA damages, and mitochondria, where it impaired the mitochondrial energy metabolism and triggered mitochondria-dependent apoptosis. LNDF reduced the growth of FAR-positive/ Pgp-positive tumors and prevented tumor formation in mice, whereas doxorubicin and Caelyx (R) failed. LNDF cardiotoxicity was comparable to Caelyx (R). The sensitivity to LNDF was maintained in tumors exposed to repeated cycles of the drug and in cells derived from the exposed tumors, excluding the onset of secondary resistance. By combining an innovative multitarget cargo drug, conceived to achieve high efficacy against Pgp-expressing cells, and appropriate strategies of liposome formulation and decoration, we produced a therapeutic tool that may represent a significant advancement in the treatment of FAR-positive/ Pgp-positive tumors.

【 授权许可】

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