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Rhynchophylline Loaded-Mpeg-PLGA Nanoparticles Coated with Tween-80 for Preliminary Study in Alzheimer's Disease

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Rhynchophylline Loaded-Mpeg-PLGA Nanoparticles Coated with Tween-80 for Preliminary Study in Alzheimer's Disease International Journal of Nanomedicine Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Rhynchophylline Loaded-mPEG-PLGA Nanoparticles Coated with Tween-80 for Preliminary Study in Alzheimer’sDisease This article was published in the following Dove Press journal: International Journal of Nanomedicine Ruiling Xu1 Purpose: Alzheimer’s disease (AD) is a growing concern in the modern society. The current Junying Wang1 drugs approved by FDA are not very promising. Rhynchophylline (RIN) is a major active Juanjuan Xu1 tetracyclic oxindole alkaloid stem from traditional Chinese medicine uncaria species, which fi Xiangrong Song2 has potential activities bene cial for the treatment of AD. However, the application of Hai Huang 2 rhynchophylline for AD treatment is restricted by the low water solubility, low concentration in brain tissue and low bioavailability. And there is no study of brain-targeting therapy with Yue Feng 3 RIN. In this work, we prepared rhynchophylline loaded methoxy poly (ethylene glycol)–poly Chunmei Fu1 (dl-lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPS-RIN), which coupled with 1Key Laboratory of Drug-Targeting and Tween 80 (T80) further for brain targeting delivery (T80-NPS-RIN). Drug Delivery System of the Education Methods: Preparation and characterization of T80-NPS-RIN were followed by the detection Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced of transportation across the blood–brain barrier (BBB) model in vitro, biodistribution and Drug and Sichuan Research Center for neuroprotective effects of nanoparticles. Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan Results: The results indicated T80-NPS-RIN could usefully assist RIN to pass through the University, Chengdu 610041, People’s BBB to the brain. T80-NPS-RIN treatment regulated the activity of neurons in vitro. 2 Republic of China; State Key Laboratory Conclusion: The presented data confirmed that rhynchophylline encapsulated mPEG-PLGA of Biotherapy/Geriatrics and Cancer fi Center, West China Hospital, Sichuan nanoparticles coated with Tween 80 could across through the BBB and exhibited ef cient University, and Collaborative Innovation neuroprotective effects. The T80-NPS-RIN nanoparticles have a chance to be an alternative Center for Biotherapy, Sichuan drug to the therapy of AD. University, Chengdu, People’s Republic of China; 3College of Pharmacy, Southwest Keywords: Alzheimer’s disease, rhynchophylline, nanoparticles, blood–brain barrier, University for Nationalities, Chengdu neuroprotective effect 610041, People’s Republic of China Introduction Nowadays, Alzheimer’s disease (AD) is a serious social problem among the neurode- generative diseases.1 With the increasing incidence of AD, the prevention and treat- ment of AD has become a global focus. The neuropathological characteristics of AD mainly include age-related Aβ deposition, synapses and neuronal loss and neurofibril- lary tangles.2–4 Accumulated soluble Aβ-induced abnormal neuronal network activity Correspondence: Chunmei Fu fi 5,6 Key Laboratory of Drug-Targeting and has been considered to play a signi cant role in the development of AD. At present, Drug Delivery System of the Education only five FDA-approved medicines are able to temporarily reduce AD symptoms.7 Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Furthermore, it should be noticed that these approved drugs cannot cure or delay the Drug and Sichuan Research Center for progression of AD, but only improve some symptoms for a limited time.8 Therefore, Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan the development of new AD therapeutics agents is urgently needed. ’ University, Chengdu 610041, People s Traditional Chinese medicine (TCM) has been used to prevent and treat cognitive Republic of China 9–11 12,13 Email [email protected] decline. The anti-AD agents from TCM have been developed for a long time. submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2020:15 1149–1160 1149 DovePress © 2020 Xu et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php – http://doi.org/10.2147/IJN.S236922 and incorporate the Creative Commons Attribution Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Xu et al Dovepress Rhynchophylline (RIN) is a major active tetracyclic oxindole nanoparticles coated Tween 80 can across through the BBB alkaloid stem from traditional Chinese medicine uncaria via LRPs mediated transcytosis.25 The schematic diagram of species.14 RIN has been used commonly in the treatment T80-NPS-RIN crossing BBB is shown in Figure 1.Inthis of central nervous system diseases including hypertension, work, we utilized methoxy poly (ethylene glycol)–poly (dl- convulsions, stroke, as well as AD.15 RIN has great potential lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles for the in the treatment of AD because it could inhibit soluble Aβ- load of RIN with prolonged blood residence. Rhynchophylline induced hyperexcitability of hippocampal neurons.16,17 loaded in mPEG-PLGA nanoparticles coated with Tween 80 Although RIN shows some good therapeutic effects was investigated and preliminarily evaluated for treatment in AD, its application is limited by its low solubility, low of AD in cell model in vitro. T80-NPS-RIN exhibited concentration in brain tissue and low bioavailability with increased therapeutic efficacy against nerve injury with high low permeability through blood–brain barrier (BBB).18,19 concentration of rhynchophylline accumulation in brain and Nanotechnology-based drug delivery systems with good solu- higher bioavailability. bility, high bioavailability, less patient variability and pro- longed circulation time provide new therapeutic strategy Materials and Methods for AD with brain targeting TCM delivery across through Materials – the BBB.20 22 Rhynchophylline (purity>98%) was purchased from A substance assisting in targeting drug delivery into the Beisite Biotechnology Co., Ltd. (Chengdu, China). For brain is Tween 80 (polysorbate 80), which is commonly coat- in vitro cell studies, rhynchophylline was dissolved in ing the surfaces of nanoparticles for drug load and delivery.23 dimethyl sulfoxide (DMSO) and further diluted in culture Tween 80 can adsorb apolipoprotein E and enable the binding medium (DMEM with 10% fetal bovine serum) to the to the lipoprotein receptor-related proteins (LRPs).24 The required concentration with the final concentration of Figure 1 Diagrammatical representation of T80-NPS-RIN cross BBB. Intravenously administered nanoparticles went to the brain and cross the BBB due to apolipoprotein E (ApoE) receptor-mediated transendocytosis. 1150 submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2020:15 DovePress Dovepress Xu et al DMSO concentration <0.1% (v/v). Cell culture plates and W1 Drug load ¼ Â 100% transwell plates were obtained from Corning INC. W2 (Corning, NY, USA). Hoechst 33258 staining kit was W À W purchased from Beyotime Biotechnology Co., Ltd. Encapsulation efficiency ¼ 3 4 Â 100% W (Shanghai, China). mPEG-PLGA (MW = 15 kDa; LA/ 3 GA = 75:25; PEG MW = 2 kDa) was purchased from where W1 is the weight of drug (RIN) in the nanoparticles, Jinan Daigang Biomaterial Co., Ltd. (Jinan, China). Poly W2 is the gross weight of nanoparticles, W3 is the total (vinyl alcohol) (PVA, MW=30–70 kDa, HD, 80%), weight of drug, and W4 is the weight of drug (RIN) that 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bro- remained in the liquid medium after encapsulation. mide (MTT) and Tween 80 were purchased from Chengdu Real Biotechnology Co., Ltd. All other reagents were of Particle Size and TEM Analysis analytical grade and were used as supplied. The particle size and polydispersity index (PDI) were ana- lyzed using a Mastersizer (Zetasizer NanoZS 90). The tested Animals samples were diluted 10 times for measurements. Each sam- C57BL/6 mice (aged 6–8 weeks, male and weighed 22–25 g, ple was measured three times in parallel. The morphology of SPF grade) and adult healthy male Sprague-Dawley rats the nanoparticles was observed using transmission electron (body weight range 200–250 g, SPF grade) were purchased microscopy (TEM) at 200 kV. For TEM analysis, 10 μLof from Dashuo Biotechnology Company, Ltd. (Chengdu, the nanoparticle solution was spotted on the copper micro- Sichuan, China). All the experiments on animals were grid and waited for the solution to dry. After that, the data approved and supervised by the West China School of were obtained at an accelerating voltage. Pharmacy Animal Care and Use Committee (Sichuan University). All animals were kept in the environment of In vitro Hemolysis Assay – 12:12 hrs light dark cycle at the temperature 22 ± 1°C and Red blood cells (RBCs) of healthy rabbit were used for the relative humidity remained at 55 ± 10%. evaluating the hemolytic potential of T80-NPS-RIN. 2% of erythrocyte suspension was obtained by centrifuging the Preparation of T80-NPS-RIN blood samples and re-dissolving in normal saline. Next, RIN loaded mPEG-PLGA nanoparticles (NPS) were pre- 2.5 mL of the erythrocyte dispersion solution was mixed pared by nanoprecipitation method using PVA as an aqueous with free RIN solution and nanoparticles with a total phase. RIN (60 mg/mL) and mPEG-PLGA (120 mg/mL) in volume of 5 mL. Distilled water was employed as the ratio of 1:2 were dissolved in N,N-Dimethylformamide a positive control, and saline solution was employed for (DMF). The organic phase containing RIN (100 μL) and the negative control group. All tubes were incubated at 37° mPEG-PLGA (100 μL) mixture was added drop by drop to C for 3 hrs.
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