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Brain Delivery of Curcumin Using Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Preparation, Optimization and Pharmacokinetic Evaluation Soroor Sadegh Malvajerd, Amir Azadi, Zhila Izadi, Masoumeh Kurd, Tahereh Dara, Maryam Dibaei, Mohammad Sharif Zadeh, Hamid Akbari-Javar, and Mehrdad Hamidi ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00510 • Publication Date (Web): 17 Oct 2018 Downloaded from http://pubs.acs.org on October 18, 2018
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ACS Chemical Neuroscience
Brain Delivery of Curcumin Using Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Preparation, Optimization, and Pharmacokinetic Evaluation Soroor Sadegh Malvajerda, Amir Azadib, Zhila Izadic, Masoumeh Kurdd, Tahereh Darae, Maryam Dibaeie, Mohammad Sharif Zadehf, Hamid Akbari Javare,g*, Mehrdad Hamidid,h* a
Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14174, Iran b
Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. c
Pharmacutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. d
Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, 45139-56184 Zanjan, Iran. e
Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. f
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, 13169-43551 Tehran, Iran. g
Tehran Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, 13169-43551 Tehran, Iran. h
Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, 45139-56184 Zanjan, Iran.
* Corresponding authors: (MH) email:
[email protected],
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Abstract Curcumin is a multi-therapeutic agent with great therapeutic potential in the central nervous system (CNS) diseases. In the current study, curcumin was encapsulated in solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for the purpose of increasing the brain accumulation. The preparation processes have been optimized using experimental design and multi-objective optimization method. Entrapment efficiency of curcumin in SLNs and NLCs was found to be 82% ± 0.49 and 94% ± 0.74, respectively. The pharmacokinetic studies showed that the amount of curcumin available in the brain were significantly higher in curcumin-loaded NLCs (AUC0-t = 505.76 ng/gr h) compared to free curcumin (AUC0-t = 0.00 ng/gr h) and curcumin-loaded SLNs (AUC0-t = 116.31 ng/gr h) (P < 0.005), after intravenous (IV) administration of 4 mg/kg dose of curcumin in rat. The results of the DSC and XRD showed that, curcumin has been dispersed as amorphous in the nano-carriers. SEM images confirmed the nanoscale size and spherical shape of the nanoparticles. The DPPH free radical scavenging study indicated that preparation processes do not have any significant effect on the anti-oxidant activity of curcumin. The results of this study are promising for the use of curcumin-loaded NLCs in more studies and using curcumin in the treatment of CNS diseases.
Keywords: Curcumin; Alzheimer’s disease; Nanostructured lipid carriers; Optimization; Solid lipid nanoparticles; Pharmacokinetic
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Introduction Despite the advances in the field of prevention and treatment of dementia, Alzheimer's International Center statistics revealed that; currently, 47 million people worldwide are suffering from dementia (1). Alzheimer's Disease (AD) is the most common form of neurodegenerative diseases among elderly people, which is characterized by a gradual loss of memory and perceived skills (2). This disorder seems to be progressive, irreversible and currently untreatable (3-5). Due to the aging population, it is estimated that, if no therapeutic or preventive measures are introduced, the number of people affected by the AD will be tripled by 2050, especially in developing countries (6, 7). The AD is associated with a consistent reduction in cognitive function and the presence of two distinct types of pathologic lesions in the brain. Extracellular plaques consisting of a large fibrillary form of beta-amyloid (Aβ) and tau protein derived from microtubule inside neurons can lead to a neurologic impairment (8, 9). It seems that oxidative and inflammatory stress plays a major role in this regard. However, the main mechanism of the AD is still unknown (10). So far, only a few drugs have been discovered with little effect on the progression of the AD and in fact, those are used to treat cognitive impairment and behavioral abnormalities in the AD. The main strategies for treatment of cognitive deficits in AD include the inhibition of acetylcholinesterase (AChE) activity (11), neurotransmitting and anti-amyloid therapies (12, 13), neurogenesis (14, 15), and the use of antioxidants and anti-inflammatory drugs (16, 17). Despite such treatments, no disease-modifying remedies are currently available due to the multifactorial nature of the disease. However, the biggest challenge in treating neurodegenerative diseases is the presence of bloodbrain barrier (BBB) (18). The brain has very advanced protective systems, including the skull, meningeal layers, and BBB. The latter is able to protect the brain cells against different harmful chemicals. The BBB consists of endothelial cells of the capillaries of the brain, which are joined together by tight junctions with high electrical resistance and limited permeability (19). In addition, there are a set of carriers and enzymes with a complex and coordinated function of the BBB to protect the CNS from harmful chemicals and metabolites (20, 21). Several protein carriers exist in the endothelial cell membrane, such as P-glycoproteins (P-gp) that pump materials across the BBB to circulate again (22-24). Unfortunately, the presence of the BBB also restricts the permeability of drugs into the brain and has a negative effect on drug efficacy: necessitating administration of a high dose of the drug to achieve an effective concentration in the brain. However, the high dose of the drug can bring more side effects and problems for patients. In recent years, curcumin has
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been considered widely for its unique features in treating and reducing the complications of AD. Curcumin with a wide range of advantages and neuroprotective functions including anti-Aβaggregation, anti-inflammatory, and anti-oxidant activities can be used as a multi-therapeutic agent in the treatment of AD and other diseases (25-31). However, curcumin has negligible water solubility, high-grade metabolism and rapid elimination from the circulatory system, and has very low plasma concentration. Furthermore, because of the specific properties of the BBB, the only trace amount of curcumin transports across the BBB. Many studies have been done to overcome BBB and facilitate the entry of curcumin into the brain using adjuvants such as piperine, liposomal curcumin, and curcumin loaded polymeric nanoparticles (32, 33). Nanoparticle systems are appropriate choices to overcome the problems of the brain drug delivery and can act as a "Trojan Horse" for the transport of active molecules across the BBB (34-36). Lipid-based nanoparticles as one of the effective drug delivery systems (DDS) offer an attractive means of drug delivery to brain due to their unique features, especially for hydrophobic drugs (37-40). SLNs and NLCs are classes of lipid-based nanoparticles with low toxicity and more stability compared to liposomal and polymeric nanoparticles that can effectively control drug release and act as an excellent nanocarrier for drug targeting (41-43). Therefore, the main objective of this research was to design and prepare optimized curcumin-loaded lipid-based nanoparticles as a means of CNS drug delivery using a simple high-performance preparation method. Our results will strengthen the hope that a low dose of the drug could pass through the BBB with high efficacy and minimum side effects. Moreover, in vivo investigations were carried out using an integrated plot analysis to estimate the brain uptake clearance of curcumin. Results and Discussion Experimental design and D-optimal design Identifying the experimental conditions that lead to the best results is the main goal in optimization studies. Because the number of effective factors in Curcumin-loaded solid lipid nanoparticles (CurSLNs) preparation were high, D-optimal design and multi-objective optimization (MOO) were used in order to optimize the process. Based on preliminary study, the most influential factors include drug-to-lipid ratio (A), surfactant concentration (B) and homogenization rate (C) and four dependent variables consist of particle size (PS), polydispersity index (PI), drug loading efficiency (LE), and drug loading capacity (LC) have opted and 20 experimental runs were conducted. The
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design and results of the experiments are shown in Table 1. Our optimization processes had multiple responses with multi-objective nature which, an increase in one can cause a decrease in the other. To overcome this problem, the desirability function method which was first introduced in 1980 by Derringer and Suich (44, 45) has been used. First, an individual desirability function (di) was introduced for each response and then composite desirability function (CDF) was calculated for each experiment by computing the geometric mean of individual desirabilities via the equation below: 1
𝐶𝐷𝐹 = [𝑑1 × 𝑑2 × … × 𝑑𝑖] 𝑛
0 F PS Model 1772.89 43.11
