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    anticancer therapeutic efficacy for HER2 positive breast cancer cells and probably could reduce the side effects of the therapies.
    This research was financially supported by Iran National Science Foundation (INSF) (Grant No. 94018445) and Tarbiat Modares Univer-sity (TMU).
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    Process Biochemistry
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    Arginyl-glycyl-aspartic LLY507 (RGD) containing nanostructured lipid carrier T co-loaded with doxorubicin and sildenafil citrate enhanced anti-cancer effects and overcomes drug resistance
    Hamed Hajipoura, Marjan Ghorbanib, Houman Kahrobac,d, Farideh Mahmoodzadehe, Reza Zolfaghari Emamehf, Ramezan Ali Taheri a, a Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran b Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran c Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran e Halal Research Center of IRI, FDA, Tehran, Iran f Department of Energy and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), 14965/161, Tehran, Iran
    Sildenafil citrate
    Nanostructured lipid carriers
    Resistance to anticancer agents is considered as the main cause of chemotherapy failure. This study is aimed to prepare and optimize [Doxorubicin (Dox) + Sildenafil citrate (SC)]-coloaded Arginyl-glycyl-aspartic acid (RGD)-containing nanostructured lipid carriers (NLC-RGD) to overcome multidrug resistance limitation and improve cancer treatments. Consequently, [DOX + SC]-coloaded NLC-RGD were fabricated by homogenization method and characterized by several techniques. Then, cytotoxicity, cellular uptake, apoptosis, and expression level of some multi-drug resistance related genes were evaluated in [DOX + SC]-coloaded NLC-RGD treated cells. As results, particles with nano-size, narrow size distribution and suitable encapsulation efficiency (∼56% for DOX and ∼81% for SC) were prepared. Our Results also demonstrated that co-delivery of DOX and SC by NLC-RGD promotes uptake and accumulation of drugs by integrin mediated endocytosis and possible ABC transporter inhibition. Cytotoxicity and apoptosis experiments revealed that co-delivery of DOX and SC by NLC-RGD is more effective approach for induction of apoptosis in comparison to individual treatment and delivery. Gene ex-pression experiments revealed that SC reduces expression of ABCC1 and Nrf2. These findings indicated that NLC-RGD can be considered as an appropriate delivery system for co-delivery of DOX and SC to overcome DOX resistance to improve treatment efficacy in cancer.
    1. Introduction
    cancer is known as second leading cause of death next to cardio-vascular diseases [1]. Following surgery, the chemotherapy is con-sidered as the convenient treatment approach for cancer [2]. However, this option is LLY507 limited by acquired extrinsic or intrinsic resistance to chemotherapy agents [3]. Overexpression of ATP-binding cassette (ABC) transporters, including ABCB1 (P-glycoprotein/MDR1), ABCCs [multidrug resistance–associated proteins (MRP)], and ABCG2 (BCRP/ MXR/ABCP) is one of the key players in establishment of chemoresis-tance [4]. Overexpression of ABC transporters in cancerous cells leads to extrusion of chemotherapeutic agents, thereby lowering intracellular drug concentration and resulting in an attenuated chemotherapeutic effects (2). Therefore, discovery of novel strategies to overcome ATP-
    Corresponding author.
    transporters-based chemoresistance may provide more efficacious cancer treatment. Recently it has been reported that Sildenafil citrate (SC), an inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), inhibits the activity of ABC trans-porters such as ABCB1, ABCC4, ABCC5 and ABCG2 [5]. However, poor water solubility of SC is a limitation in therapeutic application [6]. Line of evidence indicate that approximately 71 percent of oral dose of SC has first pass hepatic and intestinal metabolism which results in low bioavailability of SC [7,8]. Moreover, oral administration of SC is concomitant with numerous side effects such as headaches, blood pressure reduction, flushing, and nasal congestion [8]. Therefore, na-noparticulate delivery systems are suggested to reduce side effects of SC and enhance bioavailability. Protection of encapsulated bioactive compounds from degradation, enhanced permeability and retention