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Anti-Parkinsonian Therapy:Strategies for Crossing the Blood–Brain Barrier and Nano-Biological Effects of Nanomaterials

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Nano-Micro Letters 2022年第6期14卷 350-398页

作者： Guowang cheng Yujing Liu Rui Ma Guopan cheng Yucheng Guan Xiaojia chen Zhenfeng Wu Tongkai Chen Key Laboratory of Modern Preparation of Traditional Chinese Medicine Ministry of EducationJiangxi University of Chinese MedicineNanchang 330004People’s Republic of China Science and Technology Innovation Center Guangzhou University of Chinese MedicineGuangzhou 510405People’s Republic of China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078People’s Republic of China

Parkinson’s disease(PD),a neurodegenerative disease that shows a high incidence in older individuals,is becoming increasingly prevalent.Unfortunately,there is no clinical cure for PD,and novel anti-PD drugs are therefore urgently required.However,the selective permeability of the blood–brain barrier(BBB)poses a huge challenge in the development of such drugs.Fortunately,through strategies based on the physiological characteristics of the BBB and other modifications,including enhancement of BBB permeability,nanotechnology can offer a solution to this problem and facilitate drug delivery across the BBB.Although nanomaterials are often used as carriers for PD treatment,their biological activity is ignored.Several studies in recent years have shown that nanomaterials can improve PD symptoms via their own nano-bio effects.In this review,we first summarize the physiological features of the BBB and then discuss the design of appropriate brain-targeted delivery nanoplatforms for PD treatment.Subsequently,we highlight the emerging strategies for crossing the BBB and the development of novel nanomaterials with anti-PD nano-biological effects.Finally,we discuss the current challenges in nanomaterial-based PD treatment and the future trends in this field.Our review emphasizes the clinical value of nanotechnology in PD treatment based on recent patents and could guide researchers working in this area in the future.

关键词： Blood-brain barrier Parkinson’s disease Nasal delivery Biomimetic drug delivery Nano-biological effects

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Robust boron nanoplatform provokes potent tumoricidal activities via inhibiting heat shock protein

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Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 728-740页

作者： Yuying Zhao Ning Liu Piaoxue Liu Taojian Fan Rui Ma Huijie Hong Xiaojia chen Zhongjian Xie Han Zhang Qi Wang Tongkai Chen Science and Technology Innovation Center Guangzhou University of Chinese MedicineGuangzhou 510405China Institute of Microscale Optoelectronics Collaborative Innovation Centre for Optoelectronic Science&TechnologyKey Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong ProvinceCollege of Physics and Optoelectronic EngineeringShenzhen Key Laboratory of Micro-Nano Photonic Information TechnologyGuangdong Laboratory of Artificial Intelligence and Digital Economy(SZ)Shenzhen UniversityShenzhen 518060China College of Health Science and Environmental Engineering School of Shenzhen Technology UniversityShenzhen 518118China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China Institute of Pediatrics Shenzhen Children’s HospitalShenzhen 518038China Shenzhen International Institute for Biomedical Research Shenzhen 518116China

Near-infrared(NIR)-light-triggered photothermal therapy(PTT)is a promising treatment for breast cancer.However,its therapeutic efficiency is often compromised due to the heatinduced up-regulation of heat shock proteins,which confer photothermal resistance.To solve this urgent problem,PEGylated two-dimensional boron nanosheets(B-PEG)-which allow both multimodal imaging and photothermal conversion-were loaded with gambogic acid(GA),which can inhibit heat shock protein 90(Hsp90).Experimental findings indicated that this combination of B-PEG and GA could serve as an integrated drug delivery system for cancer diagnosis and treatment.It could be used to administer mild PTT as well as chemotherapy for breast cancer,provide improved anti-tumor effects,and reduce the toxicity of PTT,all while inhibiting breast cancer growth.This drug delivery system could offer a novel tool for administering chemotherapy combined with PTT while avoiding the adverse effects of traditional PTT.

关键词： Mild photothermal therapy Chemotherapy Boron nanosheets Heat shock proteins Breast cancer

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Intranasal delivery of paeoniflorin nanocrystals for brain targeting

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Asian Journal of Pharmaceutical Sciences 2020年第3期15卷 326-335页

作者： Chaoyin Wu Benyue Li Yi Zhang Tingting chen Chuangrong chen Wei Jiang Qi Wang Tongkai Chen Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510405China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou 510530China Science and Technology Department Guangzhou University of Chinese MedicineGuangzhou 510006China Department of Radiology Sun Yet-sen Memorial HospitalSun Yet-sen UniversityGuangzhou 510120China

Paeoniflorin(PA) is an anti-Parkinson Chinese medicine with inferior bioavailability and difficulty in delivery to the brain. This research is to develop an efficacious PA nanocrystal formulation(PA-NCs) that is suitable for intranasal administration to treat Parkinson’s disease(PD). PA-NCs were fabricated through an antisolvent precipitation method using TPGS as the stabilizer. The rod-shaped PA-NCs had particle size of 139.6 ± 1.3 nm and zeta potential of-23.2 ± 0.529 mV. A molecular dynamics simulation indicated that van der Waals forces are the primary drivers of interactions between PA and TPGS. In the ex vivo nasal mucosa permeation assay, the cumulative drug release at 24 h was 87.14% ± 5.34%,which was significantly higher than that of free PA. PA-NCs exhibited substantially improved cellular uptake as well as permeability on Calu-3 cells as compared to PA alone. FRET imaging analysis demonstrated that intact NCs could be internalized into Calu-3 cells.Moreover, PA-NCs conferred desirable protective effect against MPP+-induced SH-SY5Y cellular damage. Pharmacokinetic studies revealed a higher PA concentration in the brain following intranasal delivery of PA-NCs. In summary, the intranasal administration of PANCs is a promising treatment strategy for PD.

关键词： Intranasal delivery Nanocrystals Paeoniflorin Brain targeting Neuroprotective effect

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Ultrasmall Coordination Polymers for Alleviating ROS-Mediated Inflammatory and Realizing Neuroprotection against Parkinson's Disease

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Research 2022年第4期2022卷 531-546页

作者： Guowang cheng Xueliang Liu Yujing Liu Yao Liu Rui Ma Jingshan Luo Xinyi Zhou Zhenfeng Wu Zhuang Liu Tongkai Chen Yu Yang Key Laboratory of Modern Preparation of Traditional Chinese Medicine Ministry of EducationJiangxi University of Chinese MedicineNanchang 330004China Institute of Molecular Medicine(IMM) Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200240China Science and Technology Innovation Center Guangzhou University of Chinese MedicineGuangzhou 510405China School of Cellular and Molecular Medicine University of BristolBristol BS81THUK Institute of Functional Nano e Soft Materials Laboratory(FUNSOM) Soochow UniversitySuzhouJiangsu 215123China

Parkinson's disease(PD)is the second most common neurodegenerative disease globally,and there is currently no effective treatment for this condition.Excessive accumulation of reactive oxygen species(ROs)and neuroinflammation are major contributors to PD pathogenesis.Herein,ultrasmall nanoscale coordination polymers(NCPs)coordinated by ferric ions and natural product curcumin(Cur)were exploited,showing efficient neuroprotection by scavenging excessive radicals and suppressing neuroinflammation.In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse PD model,such ultrasmall Fe-Cur NCPs with prolonged blood circulation and BBB traversing capability could effectively alleviate oxidative stress,mitochondrial dysfunction,and inflammatory condition in the midbrain and striatum to reduce PD symptoms.Thus,this study puts forth a unique type of therapeutics-based NCPs that could be used for safe and efficient treatment of PD with potential in clinical translation.

关键词： inflammation pathogenesis clinical

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Cell Membrane Coating Technology:A Promising Strategy for Biomedical Applications

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Nano-Micro Letters 2019年第4期11卷 720-765页

作者： Yao Liu Jingshan Luo Xiaojia chen Wei Liu Tongkai Chen Science and Technology Innovation Center Guangzhou University of Chinese MedicineGuangzhou 510405People’s Republic of China Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510405People’s Republic of China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacaoPeople’s Republic of China Key Laboratory of Artificial Micro-and Nano-Structures of Ministry of Education School of Physics and TechnologyWuhan UniversityWuhan 430072People’s Republic of China

Cell membrane coating technology is an approach to the biomimetic replication of cell membrane properties,and is an active area of ongoing research readily applicable to nanoscale biomedicine.Nanoparticles(NPs)coated with cell membranes offer an opportunity to unite natural cell membrane properties with those of the artificial inner core material.The coated NPs not only increase their biocompatibility but also achieve effective and extended circulation in vivo,allowing for the execution of targeted functions.Although cell membrane-coated NPs offer clear advantages,much work remains before they can be applied in clinical practice.In this review,we first provide a comprehensive overview of the theory of cell membrane coating technology,followed by a summary of the existing preparation and characterization techniques.Next,we focus on the functions and applications of various cell membrane types.In addition,we collate model drugs used in cell membrane coating technology,and review the patent applications related to this technology from the past 10 years.Finally,we survey future challenges and trends pertaining to this technology in an effort to provide a comprehensive overview of the future development of cell membrane coating technology.

关键词： Cell membrane Biomimetic nanoparticles Cancer therapy Immune modulation Detoxification

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Preparation and characterization of pelletized solid dispersion of resveratrol with mesoporous silica microparticles to improve dissolution by fluid-bed coating techniques

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Asian Journal of Pharmaceutical Sciences 2016年第4期11卷 528-535页

作者： Jian Li Xiaoqing Miao Tongkai Chen Defang Ouyang Ying Zheng State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao

With hydrophilic surface and high surface area, porous silica has been applied to load insoluble drugs. Compared to solvent equilibrium method, resveratrol(RES)–mesoporous silica microparticles(MSM) solid dispersion prepared by fluid bed demonstrated higher drug loading and more complete dissolution. Pore volume and diameter have more remarkable effects than surface area to the drug loading and in vitro dissolution profiles. RES–polyethylene glycol solid dispersion with high drug loading showed fast but incomplete dissolution due to the recrystallization. The combination of fluid bed and MSM was an effective strategy to improve drug loading as well as dissolution for poorly water-soluble drugs.

关键词： Resveratrol (RES) Solid dispersion Mesoporous silica microparticles (MSM) Fluid bed Amorphous

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Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation

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Asian Journal of Pharmaceutical Sciences 2020年第4期15卷 518-528页

作者： Sha Xiong Wei Liu Yile Zhou Yousheng Mo Yao Liu Xiaojia chen Huafeng Pan Dongsheng Yuan QiWang Tongkai Chen Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510405China Institute of Chinese Medical Sciences University of MacaoMacaoChina

Resveratrol(RES),a non-flavonoid polyphenol extracted from a wide variety of plants,exhibits neuroprotective activities against Parkinson’s disease(PD).However,undesirable water solubility of RES reduces its oral bioavailability and demonstrates lowefficacy in blood and brain,thus limiting its application.In present study,a nanocrystal formulation of RES(RES-NCs)was developed to enhance its oral bioavailability and delivery into brain for PD treatment.RES-NCs were fabricated with hydroxypropyl methylcellulose(HPMC)stabilizer via antisolvent precipitation approach.The obtained RES-NCs displayed the particle size of 222.54±1.66 nm,the PDI of 0.125±0.035,the zeta potential of−9.41±0.37mV,and a rapid in vitro dissolution rate.Molecular dynamics simulation of RES and HPMC revealed an interaction energy of−68.09 kJ/mol and a binding energy of−30.98±0.388 kJ/mol,indicating that the spontaneous binding between the two molecules is through van der Waals forces.RES-NCs conferred enhanced cellular uptake as well as improved permeability relative to pure RES.In addition,RES-NCs were able to protect neurons against cytotoxicity induced by MPP+.Meanwhile,RES-NCs exerted no significant toxic effects on zebrafish embryos and larvae,and did not influence their survival and hatching rates.When orally administered to rats,RES-NCs exhibited more favorable pharmacokinetics than pure RES,with higher plasma and brain concentrations.More importantly,MPTP-induced PD mice showed notable improvements in behavior,attenuated dopamine deficiency,and elevated levels of dopamine and its metabolites after the treatment with RES-NCs.Furthermore,immunoblot analysis revealed that the neuroprotective role of RES-NCsmay be at least partially mediated by Akt/Gsk3βsignaling pathway.Taken altogether,RES-NCs can serve as a potential treatment modality for PD,offering means of improving RES oral bioavailability and brain accumulation.

关键词： Nanocrystals Resveratrol Oral absorption Brain permeability Anti-Parkinsonian efficacy

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Biomimetic manganese-based theranostic nanoplatform for cancer multimodal imaging and twofold immunotherapy

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Bioactive Materials 2023年第1期19卷 237-250页

作者： Yuyue Zhao Yuanwei Pan Kelong Zou Zhou Lan Guowang cheng Qiuying Mai Hao Cui Qianfang Meng Tongkai Chen Lang Rao Limin Ma Guangtao Yu Stomatological Hospital Southern Medical UniversityGuangzhou510280China Institute of Biomedical Health Technology and Engineering Shenzhen Bay LaboratoryShenzhen518132China Departments of Diagnostic Radiology SurgeryChemical and Biomolecular Engineeringand Biomedical EngineeringYong Loo Lin School of Medicine and Faculty of EngineeringNational University of SingaporeSingapore119074Singapore Science and Technology Innovation Center Guangzhou University of Chinese MedicineGuangzhou510405China Medical Research Center Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China

The limited clinical response and serious side effect have been challenging in cancer immunotherapy resulting from immunosuppressive tumor microenvironment(TME)and inferior drug targeting.Herein,an active targeting TME nanoplatform capable of revising the immunosuppressive TME microenvironment is designed.Briefly,gold nanorods(GNRs)are covered with silica dioxide(SiO_(2))and then coated manganese dioxide(MnO_(2))to obtain GNRs@SiO_(2)@MnO_(2)(GSM).Myeloid-derived suppressor cells(MDSCs)membrane is further camouflaged on the surface of GSM to obtain GNRs@SiO_(2)@MnO_(2)@MDSCs(GSMM).In this system,GSMM inherits active targeting TME capacity of MDSCs.The localized surface plasmon resonance of GNRs is developed in near-infraredⅡwindow by MnO_(2)layer coating,realizing NIR-Ⅱwindow photothermal imaging and photoacoustic imaging of GSMM.Based on the release of Mn^(2+)in acidic TME,GSMM can be also used for magnetic resonance imaging.In cancer cells,Mn^(2+)catalyzes H_(2)O_(2)into·OH for(chemodynamic therapy)CDT leading to activate cGAS-STING,but also directly acts on STING inducing secretion of typeⅠinterferons,pro-inflammatory cytokines and chemokines.Additionally,photothermal therapy and CDT-mediated immunogenic cell death of tumor cells can further enhance anti-tumor immunity via exposure of CRT,HMGB1 and ATP.In summary,our nanoplatform realizes multimodal cancer imaging and dual immunotherapy.

关键词： Biomimetic Manganese ions The second near-infrared window Cancer imaging Immunotherapy

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Rational Design of Thermosensitive Hydrogel to Deliver Nanocrystals with Intranasal Administration for Brain Targeting in Parkinson’s Disease

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Research 2021年第1期2021卷 1046-1058页

作者： Yun Tan Yao Liu Yujing Liu Rui Ma Jingshan Luo Huijie Hong Xiaojia chen Shengpeng Wang Chuntai Liu Yi Zhang Tongkai Chen Hunan Provincial Key Laboratory of Micro&Nano Materials Interface Science College of Chemistry and Chemical EngineeringCentral South UniversityChangsha 410083China Science and Technology Innovation Center Guangzhou University of Chinese MedicineGuangzhou 510405China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China Key Laboratory of Materials Processing and Mold Ministry of EducationZhengzhou UniversityZhengzhou 450002China

Mitochondrial dysfunction is commonly detected in individuals suffering from Parkinson’s disease(PD),presenting within the form of excessive reactive oxygen species(ROS)generation as well as energy metabolism.Overcoming this dysfunction within brain tissues is an effective approach to treat PD,while unluckily,the blood-brain barrier(BBB)substantially impedes intracerebral drug delivery.In an effort to improve the delivery of efficacious therapeutic drugs to the brain,a drug delivery platform hydrogel(MAG-NCs@Gel)was designed by complexing magnolol(MAG)-nanocrystals(MAG-NCs)into the noninvasive thermosensitive poly(Nisopropylacrylamide)(PNIPAM)with self-gelation.The as-prepared MAG-NCs@Gel exhibited obvious improvements in drug solubility,the duration of residence with the nasal cavity,and the efficiency of brain targeting,respectively.Above all,continuous intranasal MAG-NCs@Gel delivery enabled MAG to cross the BBB and enter dopaminergic neurons,thereby effectively alleviating the symptoms of MPTP-induced PD.Taking advantage of the lower critical solution temperature(LCST)behavior of this delivery platform increases its viscoelasticity in nasal cavity,thus improving the efficiency of MAG-NCs transit across the BBB.As such,MAG-NCs@Gel represented an effective delivery platform capable of normalizing ROS and adenosine triphosphate(ATP)in the mitochondria of dopaminergic neurons,consequently reversing the mitochondrial dysfunction and enhancing the behavioral skills of PD mice without adversely affecting normal tissues.

关键词： nasal drugs Rational

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Enhancement of Oral Bioavailability and Anti-Parkinsonian Efficacy of Resveratrol by a Nanocrystal Formulation

Enhancement of Oral Bioavailability and Anti-Parkinsonian Ef...

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2018年第十二届中国药物制剂大会

作者：熊莎 Wei Liu Xiaojia chen Qi Wang Dongsheng Yuan Tongkai Chen Institute of Clinical Pharmacology Guangzhou University of Chinese Medicine State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau

Resveratrol（RES）, a non-flavonoid polyphenol extracted from a wide variety of plants, possesses neuroprotective activity for the treatment of Parkinson’s disease（PD）. However, the poor water solubility of RES results in low oral bioavailability, which causes low exposure of RES in the blood and brain, and limits its anti-Parkinsonian efficacy and clinical application. In this study, a nanocrystal formulation of RES（RESNCs） was developed to improve its solubility and oral bioavailability and thus to treat PD. The RES-NCs were fabricated using an anti-solvent precipitation approach where hydroxypropyl methylcellulose（HPMC） was optimized as the stabilizer. The obtained RES-NCs had a particle size of 222.54 ± 1.66 nm with a PDI of 0.12 ± 0.03, and the RES-NCs exhibited a fast dissolution rate in vitro. Differential scanning calorimetry（DSC） and powder X-ray diffraction（PXRD） results demonstrated that the RES was maintained in the crystalline state in the fabricated nanocrystals. Molecular dynamics simulation of RES and HPMC exhibited an interaction and binding energy of-68.09 kJ/mol and-30.98 ± 0.388 kJ/mol, respectively with van der Waals interactions in the spontaneous binding. The cellular uptake and permeability of RES-NCs were much higher than those of the raw RES in Madin-Darby Canine Kidney（MDCK） cells（p＜0.01）. In addition, the RES-NCs afforded a significant neuroprotective effect against 1-methyl-4-phenylpyridinium ion（MPP+）-induced damage in SH-SY5 Y cells. Meanwhile, the zebrafish embryos and larvae treated with RES-NCs did not show any obvious toxic effects during the entire experiment. When RES-NCs were orally administrated to rats, the drug was absorbed quickly and a maximum plasma concentration of 2.97 ± 0.46 μg/ml was reached in 2.11 ± 0.05 h. Compared to the unformulated RES, the Cmax and AUC0-24 h of RES-NCs were increased nearly 3.09-and 3.52-fold, respectively, indicating that the RES-NCs could effectively enhance RES oral absorption. The RES-NCs also resulted in markedly higher brain Cmax and AUC0

关键词： Nanocrystals Resveratrol Oral bioavailability Anti-Parkinsonian Efficacy Parkinson’s disease

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