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  • br References br Contents lists available at ScienceDirect b

    2020-08-18


    References
    Contents lists available at ScienceDirect
    Journal of Drug Delivery Science and Technology
    journal homepage: www.elsevier.com/locate/jddst
    Biotin decorated sunitinib loaded nanostructured lipid carriers for tumor targeted chemotherapy of lung cancer 
    T
    Somayeh Taymouria,∗, Maryam Alema, Jaleh Varshosaza, Mahboobeh Rostamib, Vajihe Akbaric, Loghman Firoozpourd a Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran b Department of Medicinal Chemistry, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran c Department of Pharmaceutical Biotechnology, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran d Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
    Keywords:
    Lung cancer
    Sunitinib
    Nanostructured lipid carrier
    Biotin
    Active targeting 
    Sunitinib (SUN) is an effective and extensively used anticancer agent, but its application is greatly limited by its adverse and undesirable systemic toxic effects. The targeted delivery of SUN could reduce systemic toxicity while maintaining local anti-tumoral efficacy. In this research, a novel nanostructured lipid carrier (NLC) modified with biotin has been designed to overcome this limitation. SUN loaded biotin targeted NLCs (biotin-SUN-NLCs) were prepared by emulsion-solvent diffusion and evaporation method and optimized using irregular factorial design. The morphology of optimized NLCs was studied using SEM. The cytotoxicity of free SUN, SUN-NLCs, and biotin-SUN-NLCs and blank NLCs was evaluated on A549 QC6352 by MTT assay. The optimized formulation pre-sented spherical particle with a mean size of 125.50 nm, 85.10% EE, zeta potential of 10.23 mV, drug release efficiency of about 62.85% during 8 h and PdI < 0.3. Cytotoxicity of biotin-SUN-NLCs was significantly en-hanced compared to that of free SUN and SUN-NLCs. The Flow cytometry and fluorescent microscope demon-strated that the biotin-NLCs exhibited higher cellular uptake in A549 human lung cells than non-targeted NLCs. In conclusion, it can be suggested that biotin-SUN-NLCs have advantages and potential for targeted lung cancer therapy.
    1. Introduction
    Lung cancer is a one of the most leading cause of cancer related death in both primary and metastasis neoplasms. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for approximately 85% of lung cancer [1]. The prognosis of lung cancer treated with conventional treatment such as surgical resection, che-motherapy, radiotherapy is unsatisfactory. Most anticancer drugs dis-tribute non-specifically throughout the body and can be harmful to healthy cells, leading to systemic toxicity and severe side effects. Therefore, to minimize side effects the novel, harmless and efficient treatments would be desirable. In the past decade, nano based drug delivery systems (DDS) have been extensively investigated for cancer treatment because nanoparticles (NPs) containing drug not only can increase stability of drugs during their transport in blood circulation but also protect normal tissues from toxicity. NPs can prolong blood cir-culation time, alter drug biodistribution profile, and allow passive
    tumor targeting via enhanced permeability and retention (EPR) effect [2]. Lipid NPs including liposomes, nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) are considered as one of the most promising DDS due to bio-acceptable, biodegradable nature of these systems, sustained release behavior, and possibility of production on large industrial scale [3]. NLCs have received growing scientific at-tention as an improved generation of SLNs to improve cancer treatment. NLCs are composed of solid lipid core along with certain content of liquid lipid (oil) which leads to amorphous state and imperfect lipid structure. Liquid lipids reduce polymorphic transition of solid lipid from disordered crystal structure to ordered crystal lattice resulting in decreasing or preventing common problems associated with SLNs such as drug leakage during storage and limitation in drug loading capacity [3]. Passive targeting is a prerequisite for NPs localization in the tumor interstitium occurs by the EPR effect. To promote uptake of NPs by cancer cells, active targeting can be an effective approach and can be achieved by surface modification of NPs with small targeting ligands
    ∗ Corresponding author. Department of Pharmaceutics, school of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Isfahan, PO Box 81745-359, Iran. E-mail address: [email protected] (S. Taymouri).
    S. Taymouri et al.
    such as biotin which widely overexpressed in many cancer cells such as lung cancer [4,5]. Several studies demonstrated that biotin-conjugated drug carriers exhibited high specificity in the receptor-mediated process and significantly increased the cytotoxicity of chemotherapeutic agent. For example, biotin-targeted Pluronic P123/F127 mixed micelles con-taining niclosamide showed enhanced cytotoxicity against A549 lung cancer cells [4]. SUN is a multi-targeted tyrosine kinase inhibitor with antitumor and anti-angiogenic activities. SUN blocks platelet derived growth factor receptor subtypes and all three vascular endothelial growth factor receptor subtypes (KIT, FLT3, and CSR-1R), glial cell line derived neurotropic factor receptor and colony stimulating factor 1 receptor which have a main role in tumor proliferation, angiogenesis and metastasis [6]. SUN has been successfully investigated for the treatment of imatinib resistant gastrointestinal stromal tumors, ad-vanced renal cell carcinoma and progressive, well-differentiated pan-creatic neuroendocrine tumors. Moreover, SUN exhibited clinical ac-tivity against NSCLC [7]. However, its application is greatly limited by its adverse and undesirable systemic toxic effects such as, fatigue, nausea, diarrhea, Heart burn, taste changes, severe cutaneous toxicity, hypertension, cardiac disorder, blood clot and low blood count [8]. The targeted delivery of SUN could reduce systemic toxicity while main-taining local anti-tumoral efficacy. Consequently, this study was in-tended to formulate and optimize a novel targeted NLCs containing SUN. To this end, we conjugated biotin as a target moiety on the stearylamine inserted in NLCs. Then, physicochemical properties such as particle size distribution, zeta potential, surface morphology, en-capsulation efficiency (EE), drug release profile, cellular uptake effi-ciency and cytotoxicity against A549 cells were investigated.