Autophagy inhibitior autophagy-related 7 small interfering RNA and doxorubicin dual-loaded nanostructured lipid carrier
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Autophagy inhibitior autophagy-related 7 small interfering RNA and doxorubicin dual-loaded nanostructured lipid carrier to combat multidrug resistance Liwen Zhanga), Bowen Xu Department of Surgical Oncology, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, 3100200, Zhejiang Province, China a)Address all correspondence to this author. e-mail: [email protected] Received: 31 March 2020; accepted: 3 August 2020
The multidrug resistance (MDR) is a widely observed phenotype that contributed to the major obstacle of impairing the outcome of cancer chemotherapy. With the aim to reverse MDR in the breast cancer cell line, the autophagy-related 7 (ATG7) small interfering RNA (siRNA) capable of downregulating the cellular autophagy level was loaded into a cationic nanostructured lipid carrier (NLC) with doxorubicin (Dox) to build a platform (NLC/D-R) for effective chemotherapy of breast cancer. Our results revealed that NLC/D-R was well-dispersed nanoparticles with satisfy protection to siRNA. In addition, NLC/D-R also exerted a sufficient drug release of both cargos under an acidic environment with high stability and biocompatibility at the physiological environment. Furthermore, NLC/D-R showed a preferable transfection profile to PEI 25k. The downregulated autophagy level in NLCF-7/Adr cells resulted in reverse of MDR and accumulated Dox retention in cells. The in vitro cytotoxicity using both cells on flat surfaces and multicellular tumor spheroid (NLCTS) model confirmed that NLC/D-R showed much elevated anticancer performance than NLC/Dox or NLC/siRNA, which suggested the synergistic effect between anti-autophagy and chemotherapy.
Introduction The multidrug resistance (MDR) is reported to a common phenotype in various cancer types which acquired along with the progress of cancers. It plays significant roles in the survival of cancer cells upon the treatment of chemotherapeutics which finally resulted in the poor performance of chemotherapy [1, 2]. Recent studies have identified the important contribution of the ATP-binding cassette transporter (ABCT) in MDR due to its indistinctive reverse transport nature of cytoplasmic drugs [2, 3]. Among various identified ABCTs, p-glycoprotein (P-gp) is widely recognized as the most potent one due to its overexpression in most MDR cancer cell lines [4, 5], although the inhibition or downregulation of the P-gp level using specific drug molecules has shown some positive effects on cancer chemotherapy [6, 7]. However, due to complicated constitution of ABCT family, the drug molecules targeting P-gp might also be excreted by other ABCT members which finally resulted in the limited outcome in many previous studies [8, 9].
The small interfering RNA (siRNA) is a recently discovered class of star molecules which was characterized as small, endogenous and double-strand RNAs with a length of 20–25 nucleotides [10, 11]. It usually binds to the 3′ -untranslated region (3′ -UTR) of their target mRNAs to negatively regulate the following protein expression due to its silencing effect
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