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1
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Zhang Y, Jiang Y, Shang K, Ge C, Fang J, Liu S. Updated pharmaceutical progress on plant antibiotic rhein and its analogs: Bioactivities, structure-activity relationships and future perspectives. Bioorg Med Chem 2024; 113:117895. [PMID: 39259985 DOI: 10.1016/j.bmc.2024.117895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/14/2024] [Accepted: 08/20/2024] [Indexed: 09/13/2024]
Abstract
Rhein, as a plant antibiotic, demonstrates a broad spectrum of pharmacological effects. Nevertheless, its limited water solubility, low bioavailability, and potential hepatotoxicity and nephrotoxicity making it difficult to directly become a medicine, thereby imposing significant constraints on its clinical application. In recent decades, extensive researches have been proceeded on the multifaceted structural modifications of rhein, resulting in notable improvements on pharmacological activities and druggabilities. This review offers a comprehensive overview and advanced update on the biological potential and structural-activity relationships (SARs) of various rhein derivatives, delineating the sites of structural modification and corresponding activity trends of rhein derivatives for future.
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Affiliation(s)
- Yindi Zhang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 42008, China; The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, China
| | - Yueping Jiang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 42008, China; The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, China
| | - Kaiqi Shang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 42008, China; The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, China
| | - Chengyu Ge
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 42008, China; The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, China
| | - Jing Fang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 42008, China; The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, China.
| | - Shao Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 42008, China; The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, China.
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2
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Qiu Q, Fu F, Wu Y, Han C, Pu W, Wen L, Xia Q, Du D. Rhei Radix et Rhizoma and its anthraquinone derivatives: Potential candidates for pancreatitis treatment. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155708. [PMID: 38733906 DOI: 10.1016/j.phymed.2024.155708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/22/2024] [Accepted: 05/02/2024] [Indexed: 05/13/2024]
Abstract
BACKGROUND Pancreatitis is a common exocrine inflammatory disease of the pancreas and lacks specific medication currently. Rhei Radix et Rhizoma (RR) and its anthraquinone derivatives (AQs) have been successively reported for their pharmacological effects and molecular mechanisms in experimental and clinical pancreatitis. However, an overview of the anti-pancreatitis potential of RR and its AQs is limited. PURPOSE To summarize and analyze the pharmacological effects of RR and its AQs on pancreatitis and the underlying mechanisms, and discuss their drug-like properties and future perspectives. METHODS The articles related to RR and its AQs were collected from the Chinese National Knowledge Infrastructure, Wanfang data, PubMed, and the Web of Science using relevant keywords from the study's inception until April first, 2024. Studies involving RR or its AQs in cell or animal pancreatitis models as well as structure-activity relationship, pharmacokinetics, toxicology, and clinical trials were included. RESULTS Most experimental studies are based on severe acute pancreatitis rat models and a few on chronic pancreatitis. Several bioactive anthraquinone derivatives of Rhei Radix et Rhizoma (RRAQs) exert local protective effects on the pancreas by maintaining pancreatic acinar cell homeostasis, inhibiting inflammatory signaling, and anti-fibrosis, and they improve systemic organ function by alleviating intestinal and lung injury. Pharmacokinetic and toxicity studies have revealed the low bioavailability and wide distribution of RRAQs, as well as hepatotoxicity and nephrotoxicity. However, there is insufficient research on the clinical application of RRAQs in pancreatitis. Furthermore, we propose effective strategies for subsequent improvement in terms of balancing effectiveness and safety. CONCLUSION RRAQs can be developed as either candidate drugs or novel lead structures for pancreatitis treatment. The comprehensive review of RR and its AQs provides references for optimizing drugs, developing therapies, and conducting future studies on pancreatitis.
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Affiliation(s)
- Qi Qiu
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fei Fu
- Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610213, China
| | - Yaling Wu
- Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610213, China
| | - Chenxia Han
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Weiling Pu
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Li Wen
- State Key Laboratory of Complex, Severe, and Rare Diseases, Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100073, China
| | - Qing Xia
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Dan Du
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China; Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610213, China.
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3
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Li J, Ye E, Huang J, Xu M, Zhang J, Zhang J, Cai H, Zhang J. Cysteine-modified PEGylated nanoparticles for targeted delivery of methylprednisolone to pancreatitis. Eur J Pharm Biopharm 2024; 195:114179. [PMID: 38199584 DOI: 10.1016/j.ejpb.2024.114179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/24/2023] [Accepted: 01/03/2024] [Indexed: 01/12/2024]
Abstract
The timely suppression of inflammatory mediator production and mitigation of their effects on pancreatic acinar cells are crucial for the successful management of acute pancreatitis. To achieve effective treatment, we present a novel approach utilizing cysteine modified PEG nanoparticles for both precise accumulation at the site of pancreatitis and specific targeting of acinar cells. Methylprednisolone, a nonsteroidal anti-inflammatory drug, was tailored to enhance its circulation time in the bloodstream, preferentially accumulate in the pancreas and enhance cell uptake efficiency by acinar cells through specifically targeting L-Type amino acid transporter 1. The nanosystem significantly downregulated pro-inflammatory cytokines in plasma, resulting in the effective suppression of inflammation in acinar cells within an acute pancreatitis rat model. The utilization of the dual targeted therapy strategy holds considerable potential for the clinical management of pancreatitis.
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Affiliation(s)
- Jianbo Li
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ertai Ye
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jingwen Huang
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Meng Xu
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; School of Basic Medical Science, Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China
| | - Jieke Zhang
- Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Junrong Zhang
- Department of Pathogen Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Huijie Cai
- Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jinjie Zhang
- Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
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Liu L, Zhang Y, Li X, Deng J. Microenvironment of pancreatic inflammation: calling for nanotechnology for diagnosis and treatment. J Nanobiotechnology 2023; 21:443. [PMID: 37996911 PMCID: PMC10666376 DOI: 10.1186/s12951-023-02200-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 11/07/2023] [Indexed: 11/25/2023] Open
Abstract
Acute pancreatitis (AP) is a common and life-threatening digestive disorder. However, its diagnosis and treatment are still impeded by our limited understanding of its etiology, pathogenesis, and clinical manifestations, as well as by the available detection methods. Fortunately, the progress of microenvironment-targeted nanoplatforms has shown their remarkable potential to change the status quo. The pancreatic inflammatory microenvironment is typically characterized by low pH, abundant reactive oxygen species (ROS) and enzymes, overproduction of inflammatory cells, and hypoxia, which exacerbate the pathological development of AP but also provide potential targeting sites for nanoagents to achieve early diagnosis and treatment. This review elaborates the various potential targets of the inflammatory microenvironment of AP and summarizes in detail the prospects for the development and application of functional nanomaterials for specific targets. Additionally, it presents the challenges and future trends to develop multifunctional targeted nanomaterials for the early diagnosis and effective treatment of AP, providing a valuable reference for future research.
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Affiliation(s)
- Lu Liu
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1 South Maoyuan Street, Nanchong, 637001, China
| | - Yiqing Zhang
- Institute of Burn Research Southwest Hospital State Key Lab of Trauma Burn and Combined Injury Chongqing Key Laboratory for Disease Proteomics Army Medical University, Chongqing, 400038, China
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese PLA General Hospita, PLA Medical College, 28 Fu Xing Road, Beijing, 100853, China
| | - Xinghui Li
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1 South Maoyuan Street, Nanchong, 637001, China.
| | - Jun Deng
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1 South Maoyuan Street, Nanchong, 637001, China.
- Institute of Burn Research Southwest Hospital State Key Lab of Trauma Burn and Combined Injury Chongqing Key Laboratory for Disease Proteomics Army Medical University, Chongqing, 400038, China.
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Chen Y, Tao H, Chen R, Pan Y, Wang J, Gao R, Chen J, Yang J. Biomimetic Nanoparticles Loaded with Ulinastatin for the Targeted Treatment of Acute Pancreatitis. Mol Pharm 2023; 20:4108-4119. [PMID: 37349264 DOI: 10.1021/acs.molpharmaceut.3c00238] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/24/2023]
Abstract
Ulinastatin is commonly used in the clinic to treat acute pancreatitis (AP), but its therapeutic effect was limited by the presence of the blood-pancreas barrier (BPB) and low specificity. Here, we prepared a macrophage biomimetic nanoparticle (MU) that delivered ulinastatin to address the above issues. Macrophage membrane was used as a shell for a mixture of PEG-PLGA and ulinastatin. It was found that MU showed good stability and biocompatibility in vitro and in vivo. According to in vivo fluorescence imaging, MU displayed a great inflammation targeting effect both in a subcutaneous inflammation model and in situ pancreatitis mouse model, which was ascribed to the presence of adhesion proteins. In vitro and in vivo results demonstrated that MU have a superior AP treatment effect by inhibiting pro-inflammatory factors and keeping cells viability. It was suggested the MU could provide a new strategy for targeted AP treatment.
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Affiliation(s)
- Yunlong Chen
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Haisu Tao
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832000, China
| | - Rui Chen
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
- Biliary Surgical Department of West China Hospital, Sichuan University, Chengdu, Sichuan 610064, China
| | - Yingying Pan
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- Department of Medical Ultrasound, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Junfeng Wang
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Rongkang Gao
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Jingqin Chen
- Research Laboratory for Biomedical Optics and Molecular Imaging, CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Jian Yang
- Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
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Yin Z, Zhang Z, Gao D, Luo G, Ma T, Wang Y, Lu L, Gao X. Stepwise Coordination-Driven Metal-Phenolic Nanoparticle as a Neuroprotection Enhancer for Alzheimer's Disease Therapy. ACS APPLIED MATERIALS & INTERFACES 2023; 15:524-540. [PMID: 36542560 DOI: 10.1021/acsami.2c18060] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Current therapeutic strategies for Alzheimer's disease (AD) mainly focus on inhibition of aberrant amyloid-β peptide (Aβ) aggregation. However, these strategies cannot repair the side symptoms (e.g., high neuronal oxidative stress) triggered by Aβ accumulation and thus show limited effects on suppressing Aβ-induced neuronal apoptosis. Herein, we develop a stepwise metal-phenolic coordination approach for the rational design of a neuroprotection enhancer, K8@Fe-Rh/Pda NPs, in which rhein and polydopamine are effectively coupled to enhance the treatment of AD in APPswe/PSEN1dE9 transgenic (APP/PS1) mice. We discover that the polydopamine inhibits the aggregation of Aβ oligomers, and rhein helps repair damage to neurons triggered by Aβ aggregation. Based on molecular docking, we demonstrate that the polydopamine has a strong interaction with Aβ monomers/fibrils through its multiple recognition sites (e.g., catechol groups, imine groups, and indolic/catecholic π-systems), thereby reducing Aβ burden. Further investigation of the antioxidant mechanisms suggests that K8@Fe-Rh/Pda NPs promote the mitochondrial biogenesis via activating the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathway. This finally inhibits neuronal apoptosis. Moreover, an intravenous injection of these nanoparticles potently improves the cognitive function in APP/PS1 mice without adverse effects. Overall, our work provides a promising approach to develop advanced nanomaterials for multi-target treatment of AD.
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Affiliation(s)
- Zhihui Yin
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing102488, China
| | - Zhixin Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing102488, China
| | - Demin Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing102488, China
| | - Gan Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing102488, China
| | - Tao Ma
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing100078, China
| | - Ying Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing102488, China
| | - Lehui Lu
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun130022, China
| | - Xiaoyan Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing102488, China
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He S, Gui J, Xiong K, Chen M, Gao H, Fu Y. A roadmap to pulmonary delivery strategies for the treatment of infectious lung diseases. J Nanobiotechnology 2022; 20:101. [PMID: 35241085 PMCID: PMC8892824 DOI: 10.1186/s12951-022-01307-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/17/2022] [Indexed: 12/18/2022] Open
Abstract
Pulmonary drug delivery is a highly attractive topic for the treatment of infectious lung diseases. Drug delivery via the pulmonary route offers unique advantages of no first-pass effect and high bioavailability, which provides an important means to deliver therapeutics directly to lung lesions. Starting from the structural characteristics of the lungs and the biological barriers for achieving efficient delivery, we aim to review literatures in the past decade regarding the pulmonary delivery strategies used to treat infectious lung diseases. Hopefully, this review article offers new insights into the future development of therapeutic strategies against pulmonary infectious diseases from a delivery point of view.
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Affiliation(s)
- Siqin He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Jiajia Gui
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Kun Xiong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Meiwan Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Huile Gao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
| | - Yao Fu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
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8
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Gong GW, Tang WH, Zhou Z, Jiang YW, Wang CZ, Cheng H, Cao Y, Jiang ZW. Potential Efficacious Materials Investigation of Yi-Yi Mixture Based on Metabolome-oriented Network Pharmacology Strategy. J Chromatogr B Analyt Technol Biomed Life Sci 2022; 1197:123199. [DOI: 10.1016/j.jchromb.2022.123199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/13/2022] [Accepted: 02/24/2022] [Indexed: 02/07/2023]
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Zhang J, Wang S, Cai H, Feng T, Liu Z, Xu Y, Li J. Hydrophobic ion-pairing assembled liposomal Rhein with efficient loading for acute pancreatitis treatment. J Microencapsul 2021; 38:559-571. [PMID: 34637365 DOI: 10.1080/02652048.2021.1993363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
AIM The present study aimed to develop liposomal Rhein by employing a hydrophobic ion-pairing technique (HIP) for improved pancreatitis therapy. METHODS F127 modified liposomal Rhein (F127-RPC-Lip) was prepared using a two-step process consisting of complexation first, followed by a film-ultrasonic dispersion step. The drug-phospholipid interaction was characterised by FT-IR and P-XRD. Particle size and morphology were investigated using DLS and TEM, respectively. Biodistribution and therapeutic efficacy of F127-RPC-Lip were evaluated in a rat model of acute pancreatitis. RESULTS F127-RPC-Lip achieved efficient drug encapsulation after complexation with lipids through non-covalent interactions and had an average hydrodynamic diameter of about 141 nm. F127-RPC-Lip demonstrated slower drug release (55.90 ± 3.60%, w/w) than Rhein solution (90.27 ± 5.11%) within 24 h. Compared with Rhein, F127-RPC-Lip exhibited prolonged systemic circulation time, superior drug distribution, and attenuated injury in the pancreas of rats post-injection. CONCLUSIONS HIP-assembled liposomes are a promising strategy for Rhein in treating pancreatitis.
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Affiliation(s)
- Jinjie Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Targeting Therapy and Diagnosis of Critical Diseases, Zhengzhou, Henan Province, China.,Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan Province, China
| | - Shuaishuai Wang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Targeting Therapy and Diagnosis of Critical Diseases, Zhengzhou, Henan Province, China.,Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan Province, China
| | - Huijie Cai
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Targeting Therapy and Diagnosis of Critical Diseases, Zhengzhou, Henan Province, China.,Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan Province, China
| | - Tiange Feng
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Targeting Therapy and Diagnosis of Critical Diseases, Zhengzhou, Henan Province, China.,Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan Province, China
| | - Zhilei Liu
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China.,BGI College, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yaru Xu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Targeting Therapy and Diagnosis of Critical Diseases, Zhengzhou, Henan Province, China.,Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, Henan Province, China
| | - Jianbo Li
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China.,BGI College, Zhengzhou University, Zhengzhou, Henan Province, China
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Li GM, Chen JR, Zhang HQ, Cao XY, Sun C, Peng F, Yin YP, Lin Z, Yu L, Chen Y, Tang YL, Xie XF, Peng C. Update on Pharmacological Activities, Security, and Pharmacokinetics of Rhein. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:4582412. [PMID: 34457021 PMCID: PMC8387172 DOI: 10.1155/2021/4582412] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 07/30/2021] [Indexed: 12/11/2022]
Abstract
Rhein, belonging to anthraquinone compounds, is one of the main active components of rhubarb and Polygonum multiflorum. Rhein has a variety of pharmacological effects, such as cardiocerebral protective effect, hepatoprotective effect, nephroprotective effect, anti-inflammation effect, antitumor effect, antidiabetic effect, and others. The mechanism is interrelated and complex, referring to NF-κB, PI3K/Akt/MAPK, p53, mitochondrial-mediated signaling pathway, oxidative stress signaling pathway, and so on. However, to some extent, its clinical application is limited by its poor water solubility and low bioavailability. Even more, rhein has potential liver and kidney toxicity. Therefore, in this paper, the pharmacological effects of rhein and its mechanism, pharmacokinetics, and safety studies were reviewed, in order to provide reference for the development and application of rhein.
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Affiliation(s)
- Gang-Min Li
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Jun-Ren Chen
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Hui-Qiong Zhang
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Xiao-Yu Cao
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Chen Sun
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Fu Peng
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yan-Peng Yin
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Ziwei Lin
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Lei Yu
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Yan Chen
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Yun-Li Tang
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
- Guangxi University of Traditional Chinese Medicine, Nanning 530200, China
| | - Xiao-Fang Xie
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Cheng Peng
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
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11
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Jiang X, Zheng YW, Bao S, Zhang H, Chen R, Yao Q, Kou L. Drug discovery and formulation development for acute pancreatitis. Drug Deliv 2020; 27:1562-1580. [PMID: 33118404 PMCID: PMC7598990 DOI: 10.1080/10717544.2020.1840665] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Acute pancreatitis is a sudden inflammation and only last for a short time, but might lead to a life-threatening emergency. Traditional drug therapy is an essential supportive method for acute pancreatitis treatment, yet, failed to achieve satisfactory therapeutic outcomes. To date, it is still challenging to develop therapeutic medicine to redress the intricate microenvironment promptly in the inflamed pancreas, and more importantly, avoid multi-organ failure. The understanding of the acute pancreatitis, including the causes, mechanism, and severity judgment, could help the scientists bring up more effective intervention and treatment strategies. New formulation approaches have been investigated to precisely deliver therapeutics to inflammatory lesions in the pancreas, and some even could directly attenuate the pancreatic damages. In this review, we will briefly introduce the involved pathogenesis and underlying mechanisms of acute pancreatitis, as well as the traditional Chinese medicine and the new drug option. Most of all, we will summarize the drug delivery strategies to reduce inflammation and potentially prevent the further development of pancreatitis, with an emphasis on the bifunctional nanoparticles that act as both drug delivery carriers and therapeutics.
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Affiliation(s)
- Xue Jiang
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.,Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ya-Wen Zheng
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shihui Bao
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hailin Zhang
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Children's Respiration Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ruijie Chen
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qing Yao
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Longfa Kou
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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12
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Xu T, Liang C, Zheng D, Yan X, Chen Y, Chen Y, Li X, Shi Y, Wang L, Yang Z. Nuclear delivery of dual anticancer drug-based nanomedicine constructed by cisplatinum-induced peptide self-assembly. NANOSCALE 2020; 12:15275-15282. [PMID: 32644059 DOI: 10.1039/d0nr00143k] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Nuclear delivery of anticancer drugs, particularly dual complementary anticancer drugs, can significantly improve chemotherapy efficacy. However, successful examples are rare. We reported a novel dual anticancer drug-based nanomedicine with nuclear accumulation properties. The nanomedicine was formed by chelation between a drug peptide amphiphile Rh-GFFYERGD (Rh represents Rhein, 1,8-dihydroxy-3-carboxy anthraquinonea) and cisplatinum (Pt). A single molecule of the drug peptide amphiphile could chelate up to 8 equiv. of cisplatinum in the resulting nanofibers. The nanofibers with a 1 : 4 ratio of Rh-GFFYERGD to cisplatinum demonstrated remarkable cellular uptake, and more significantly, superior nuclear accumulation properties. Additionally, the nanofibers could also bind to the DNA molecule more efficiently than those formed by the drug peptide amphiphile. Thus the nanofibers exhibited excellent anticancer properties both in vitro and in vivo. We envision a significant therapeutic potential of the dual anticancer drug-based nanomedicine with cisplatinum in cancer.
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Affiliation(s)
- Tengyan Xu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, P. R. China.
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13
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Chen Y, Wang L, Luo S, Hu J, Huang X, Li PW, Zhang Y, Wu C, Tian BL. Enhancement of Antitumor Efficacy of Paclitaxel-Loaded PEGylated Liposomes by N,N-Dimethyl Tertiary Amino Moiety in Pancreatic Cancer. Drug Des Devel Ther 2020; 14:2945-2957. [PMID: 32801636 PMCID: PMC7398872 DOI: 10.2147/dddt.s261017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/26/2020] [Indexed: 02/05/2023] Open
Abstract
Introduction Pancreatic cancer, or pancreatic duct adenocarcinoma (PDAC), remains one of the most lethal cancers and features insidious onset, highly aggressive behavior and early distant metastasis. The dense fibrotic stroma surrounding tumor cells is thought to be a shield to resist the permeation of chemotherapy drugs in the treatment of PDAC. Thus, we synthesized a pancreas-targeting paclitaxel-loaded PEGylated liposome and investigated its antitumor efficacy in the patient-derived orthotopic xenograft (PDOX) nude mouse models of PDAC. Methods The PTX-loaded PEGylated liposomes were prepared by film dispersion-ultrasonic method and modified by an N,N-dimethyl tertiary amino residue. Morphology characteristics of the PTX-loaded liposomes were observed by transmission electron microscope (TEM). The PDOX models of PDAC were established by orthotopic implantation and imaged by a micro positron emission tomography/computed tomography (PET/CT) imaging system. The in vivo distribution and antitumor study were then carried out to observe the pancreas-targeting accumulation and the antitumor efficacy of the proposed PTX liposomes. Results PTX loaded well into both modified (PTX-Lip2N) and unmodified (PTX-Lip) PEGylated liposomes with spherical shapes and suitable parameters for the endocytosis process. The PDOX nude mouse models were successfully created in which high 18F-FDG intaking regions were observed by micro-PET/CT. In addition to higher cellular uptakes of PTX-Lip2N by the BxPC-3 cells, the proposed nanoparticle had a notable penetrating ability towards PDAC tumor tissues, and consequently, the antitumor ability of PTX-Lip2N was significantly superior to the unmodified PTX-Lip in vivo PDOX models and even more effective than nab-PTX in restraining tumor growth. Conclusion The modified pancreas-targeting PTX-loaded PEGylated liposomes provide a promising platform for the treatment of pancreatic cancer.
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Affiliation(s)
- Yang Chen
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - Li Wang
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - Shi Luo
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Jun Hu
- Laboratory of Basic Scientific Research, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - Xing Huang
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - Pei-Wen Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yi Zhang
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - Chao Wu
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - Bo-Le Tian
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
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Sundar V, Senthil Kumar KA, Manickam V, Ramasamy T. Current trends in pharmacological approaches for treatment and management of acute pancreatitis – a review. J Pharm Pharmacol 2020; 72:761-775. [DOI: 10.1111/jphp.13229] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022]
Abstract
Abstract
Objectives
Acute pancreatitis (AP) is an inimical disorder associated with overall mortality rates between 10-15%. It is a disorder of the exocrine pancreas which is characterized by local and systemic inflammatory responses primarily driven by oxidative stress and death of pancreatic acinar cells. The severity of AP ranges from mild pancreatic edema with complete recuperative possibilities to serious systemic inflammatory response resulting in peripancreatic/pancreatic necrosis, multiple organ failure, and death.
Key findings
We have retrieved the potential alternative approaches that are developed lately for efficacious treatment of AP from the currently available literature and recently reported experimental studies. This review summarizes the need for alternative approaches and combinatorial treatment strategies to deal with AP based on literature search using specific key words in PubMed and ScienceDirect databases.
Summary
Since AP results from perturbations of multiple signaling pathways, the so called “monotargeted smart drugs” of the past decade is highly unlikely to be effective. Also, the conventional treatment approaches were mainly involved in providing palliative care instead of curing the disease. Hence, many researchers are beginning to focus on developing alternate therapies to treat AP effectively. This review also summarizes the recent trends in the combinatorial approaches available for AP treatment.
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Affiliation(s)
- Vaishnavi Sundar
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | | | - Venkatraman Manickam
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Tamizhselvi Ramasamy
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
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15
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Li PW, Luo S, Xiao LY, Tian BL, Wang L, Zhang ZR, Zeng YC. A novel gemcitabine derivative-loaded liposome with great pancreas-targeting ability. Acta Pharmacol Sin 2019; 40:1448-1456. [PMID: 31015736 DOI: 10.1038/s41401-019-0227-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 03/14/2019] [Indexed: 02/05/2023]
Abstract
Gemcitabine (Gem) is a standard first-line treatment for pancreatic cancer (PC). However, its chemotherapeutic efficacy is hampered by various limitations such as short half-life, metabolic inactivation, and lack of tumor localizing. We previously synthesized a lipophilic Gem derivative (Gem formyl hexadecyl ester, GemC16) that exhibited improved antitumor activity in vitro. In this study, a target ligand N,N-dimethyl-1,3-propanediamine was conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[hydroxyl succinimidyl (polyethylene glycol-2000)] (DSPE-PEG-NHS) to form DSPE-PEG-2N. Then, pancreas-targeting liposomes (2N-LPs) were prepared using the film dispersion-ultrasonic method. GemC16-loaded 2N-LPs displayed near-spherical shapes with an average size distribution of 157.2 nm (polydispersity index (PDI) = 0.201). The encapsulation efficiency of GemC16 was up to 97.3% with a loading capacity of 8.9%. In human PC cell line (BxPC-3) and rat pancreatic acinar cell line (AR42J), cellular uptake of 2N-LPs was significantly enhanced compared with that of unmodified PEG-LPs. 2N-LPs exhibited more potent in vitro cytotoxicity against BxPC-3 and AR42J cell lines than PEG-LPs. After systemic administration in mice, 2N-LPs remarkably increased drug distribution in the pancreas. In an orthotopic tumor mouse model of PC, GemC16-bearing liposomes were more effective in preventing tumor growth than free GemC16. Among these treatments, 2N-LPs showed the best curative effect. Together, 2N-LPs represent a promising nanocarrier to achieve pancreas-targeting drug delivery, and this work would provide new ideas for the chemotherapy of PC.
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16
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Sun M, Zhang X, Gao Z, Liu T, Luo C, Zhao Y, Liu Y, He Z, Wang J, Sun J. Probing a dipeptide-based supramolecular assembly as an efficient camptothecin delivering carrier for cancer therapy: computational simulations and experimental validations. NANOSCALE 2019; 11:3864-3876. [PMID: 30758022 DOI: 10.1039/c8nr07014h] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Short peptide-based supramolecular assemblies have drawn much attention in the field of drug delivery. However, the progress still remains limited owing to the inefficient drug loading capacity of conventional short peptide-based materials. In this study, based on coordinated intramolecular π-π stacking, we customize a dipeptide-based rhein derivative (rhein-diphenylalanine peptide, RDP), which could spontaneously form spherical nanoassemblies for drug delivery. A structure-based virtual screening of a library of small molecules is conducted to identify the suitable compounds which could be effectively delivered by this nanocarrier. Sorted by binding energy results, fifteen superior and five inferior molecules are found. Subsequently, the co-assembly capacity of high-affinity molecules (camptothecin, CPT) and low-affinity molecules (norcantharidin, NCTD) with the dipeptide-based carrier is predicted via dissipative particle dynamics (DPD) simulation. Consistent with computational results, the in vitro experimental results show that CPT-encapsulated nanoassemblies have significant advantages in the particle size distribution and recrystallization-inhibitory effect compared with NCTD. Furthermore, in vivo experiments were conducted to determine whether CPT is precisely delivered to tumor sites by using the dipeptide-based nanoassemblies. The CPT-loaded nanoassemblies show better effects in terms of drug biodistribution and in vivo anti-tumor efficacy compared to free CPT. The cooperative computational and experimental strategies (in vitro and in vivo) used in this work lay a good foundation to systematically understand short peptide-based assemblies for precise drug delivery.
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Affiliation(s)
- Mengchi Sun
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.
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17
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Zhou X, Cao X, Tu H, Zhang ZR, Deng L. Inflammation-Targeted Delivery of Celastrol via Neutrophil Membrane-Coated Nanoparticles in the Management of Acute Pancreatitis. Mol Pharm 2019; 16:1397-1405. [PMID: 30753778 DOI: 10.1021/acs.molpharmaceut.8b01342] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Celastrol (CLT)-loaded PEG-PLGA nanoparticles (NPs/CLT) coated with neutrophil membranes (NNPs/CLT) were explored for the management of acute pancreatitis (AP). PEG-PLGA nanoparticles sized around 150 nm were proven to selectively accumulate in the pancreas in rats with AP. NNPs were found to overcome the blood-pancreas barrier and specifically distributed to the pancreatic tissues. Moreover, NNPs showed more selective accumulation in the pancreas than nanoparticles without any membrane coating in AP rats. Compared to CLT solution and the NPs/CLT group, NNPs/CLT significantly downregulated the levels of serum amylase and pancreatic myeloperoxidase in AP rats. Also, using NNPs as the delivery vehicle significantly reduced the systemic toxicity of CLT in AP rats. Together, these results suggest that NNPs/CLT represent a highly promising delivery vehicle for the targeted therapy of AP.
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Affiliation(s)
- Xu Zhou
- Sichuan Provincial Orthopedic Hospital , Chengdu 610041 , China.,Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Xi Cao
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - He Tu
- Sichuan Provincial Orthopedic Hospital , Chengdu 610041 , China
| | - Zhi-Rong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Li Deng
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
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18
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Phytoceuticals in Acute Pancreatitis: Targeting the Balance between Apoptosis and Necrosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:5264592. [PMID: 29686719 PMCID: PMC5857302 DOI: 10.1155/2018/5264592] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 11/29/2017] [Accepted: 12/20/2017] [Indexed: 12/11/2022]
Abstract
Despite recent advances in understanding the complex pathogenesis of pancreatitis, the management of the disease remains suboptimal. The use of phytoceuticals (plant-derived pleiotropic multitarget molecules) represents a new research trend in pancreatology. The purpose of this review is to discuss the phytoceuticals with pancreatoprotective potential in acute pancreatitis and whose efficacy is based, at least in part, on their capacity to modulate the acinar cell death. The phytochemicals selected, belonging to such diverse classes as polyphenols, flavonoids, lignans, anthraquinones, sesquiterpene lactones, nitriles, and alkaloids, target the balance between apoptosis and necrosis. Activation of apoptosis via various mechanisms (e.g., inhibition of X-linked inhibitor of apoptosis proteins by embelin, upregulation of FasL gene expression by resveratrol) and/or inhibition of necrosis seem to represent the essential key for decreasing the severity of the disease. Apart from targeting the apoptosis/necrosis balance, the phytochemicals displayed other specific protective activities: inhibition of inflammasome (e.g., rutin), suppression of neutrophil infiltration (e.g., ligustrazine, resveratrol), and antioxidant activity. Even though many of the selected phytoceuticals represent a promising therapeutic alternative, there is a shortage of human evidence, and further studies are required to provide solid basis to justify their use in the treatment of pancreatitis.
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19
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Zhu L, Li JY, Zhang YM, Kang HX, Chen H, Su H, Li J, Tang WF. Pharmacokinetics and pharmacodynamics of Shengjiang decoction in rats with acute pancreatitis for protecting against multiple organ injury. World J Gastroenterol 2017; 23:8169-8181. [PMID: 29290653 PMCID: PMC5739923 DOI: 10.3748/wjg.v23.i46.8169] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/24/2017] [Accepted: 11/14/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the pharmacokinetics and pharmacodynamics of Shengjiang decoction (SJD) in rats with acute pancreatitis (AP) for protecting against multiple organ injury.
METHODS An AP model was established by retrograde perfusion of 3.5% sodium taurocholate into the biliopancreatic duct, and a control group (CG) received 0.9% sodium chloride instead. Twelve male Sprague-Dawley rats were randomly divided into a CG treated with SJD (CG + SJD) and a model group treated with SJD (MG + SJD), both of which were orally administered with SJD (5 g/kg) 2 h after surgery. Blood samples were collected via the tail vein at 10, 20, and 40 min and 1, 2, 3, 4, 6, 8, and 12 h after a single dose of SJD to detect its main components using high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were compared. In the pharmacodynamic experiment, 18 male Sprague-Dawley rats were randomly divided into a CG, an AP model group (MG), and an SJD treated AP group (SJDG). Serum amylase, lipase, and inflammatory cytokines were measured, and heart, lung, liver, spleen, pancreas, kidney, and intestine tissues were collected for pathological examination.
RESULTS The MG + SJD displayed significantly shorter mean residence time (MRT) and higher clearance (CL) for emodin and aloe-emodin; significantly shorter time of maximum concentration and T1/2 and a lower area under curve (AUC) for aloe-emodin; a significantly higher AUC and lower CL for rhein; and longer MRT and lower CL for chrysophanol than the CG + SJD. In the pharmacodynamic experiment, the amylase, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α levels in the MG were higher than those in the CG (P < 0.05). After the herbal decoction treatment, the SJDG had higher IL-10 and lower TNF-α levels than the MG (P < 0.05). The MG had the highest pathological scores, and the pathological scores of the lung, pancreas, kidney, and intestine in the SJDG were significantly lower than those in the MG (P < 0.05).
CONCLUSION AP may have varying effects on the pharmacokinetics of the major SJD components in rats. SJD might alleviate pathological injuries of the lung, pancreas, kidney, and intestine in rats with AP via regulating pro- and anti- inflammatory responses, which might guide the clinical application of SJD for AP treatment.
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Affiliation(s)
- Lv Zhu
- Sichuan Provincial Pancreatitis Center, Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jun-Yi Li
- Department of Traditional Chinese Medicine, Wuhan Union Hospital, Wuhan 430000, Hubei Province, China
| | - Yu-Mei Zhang
- Sichuan Provincial Pancreatitis Center, Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hong-Xin Kang
- Sichuan Provincial Pancreatitis Center, Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Huan Chen
- Sichuan Provincial Pancreatitis Center, Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hang Su
- Sichuan Provincial Pancreatitis Center, Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Juan Li
- Sichuan Provincial Pancreatitis Center, Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Fu Tang
- Sichuan Provincial Pancreatitis Center, Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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20
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Luo S, Li P, Li S, Du Z, Hu X, Fu Y, Zhang Z. N,N-Dimethyl Tertiary Amino Group Mediated Dual Pancreas- and Lung-Targeting Therapy against Acute Pancreatitis. Mol Pharm 2017; 14:1771-1781. [PMID: 28247763 DOI: 10.1021/acs.molpharmaceut.7b00028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Acute pancreatitis (AP) is a sudden inflammation of the pancreas with high mortality rate worldwide. As a severe complication to AP, acute lung injury has been the major cause of death among patients with AP. Poor penetration across the blood pancreas barrier (BPB) and insufficient drug accumulation at the target site often result in poor therapeutic outcome. Our previous work successfully demonstrated a dual-specific targeting strategy to pancreas and lung using a phenolic propanediamine moiety. Inspired by this, a simplified ligand structure, N,N-dimethyl tertiary amino group, was covalently conjugated to celastrol (CLT) to afford tertiary amino conjugates via either an ester (CP) or an amide linkage (CTA). With sufficient plasma stability, CTA was subjected to the following studies. Compared to CLT, CTA exhibited excellent cellular uptake efficiency in both rat pancreatic acinar cell line (AR42J) and human pulmonary alveolar epithelial cell line (A549). Organic cation transporters were proven to be responsible for this active transport process. Given systemically, CTA specifically distributed to pancreases and lungs in rats thus resulting in a 2.59-fold and 3.31-fold increase in tissue-specific accumulation as compared to CLT. After CTA treatment, tissue lesions were greatly alleviated and the levels of proinflammatory cytokines were downregulated in rats with sodium taurocholate induced AP. Furthermore, CTA demonstrated marginal adverse effect against major organs with reduced cardiac toxicity compared to CLT. Together, tertiary amine mediated dual pancreas- and lung-targeting therapy represents an efficient and safe strategy for AP management.
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Affiliation(s)
- Shi Luo
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Peiwen Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Sha Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Zhengwu Du
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Xun Hu
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Yao Fu
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Zhirong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
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21
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Zhang L, Liu ZH, Cheng XG, Xia Z, Liu Y, Yu Y. Docetaxel-Loaded Lecithoid Nanoparticles with Enhanced Lung Targeting Efficiency and Reduced Systemic Toxicity: Developed by Solid Dispersion and Effervescent Techniques. Chem Pharm Bull (Tokyo) 2017; 65:959-966. [DOI: 10.1248/cpb.c17-00515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Li Zhang
- Research Laboratory of Medicinal Chemistry and Biomaterials, Chongqing Pharmaceutical Engineering Research Center, School of Pharmacy, Chongqing Medical University
| | - Zhong-hong Liu
- Research Laboratory of Medicinal Chemistry and Biomaterials, Chongqing Pharmaceutical Engineering Research Center, School of Pharmacy, Chongqing Medical University
| | - Xun-guan Cheng
- Research Laboratory of Medicinal Chemistry and Biomaterials, Chongqing Pharmaceutical Engineering Research Center, School of Pharmacy, Chongqing Medical University
| | - Zhu Xia
- Department of Nuclear Medicine, The First Affiliated Hospital of Chongqing Medical University
| | - Yu Liu
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University
| | - Yu Yu
- Research Laboratory of Medicinal Chemistry and Biomaterials, Chongqing Pharmaceutical Engineering Research Center, School of Pharmacy, Chongqing Medical University
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22
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Zhou M, Li J, Li C, Guo L, Wang X, He Q, Fu Y, Zhang Z. Tertiary amine mediated targeted therapy against metastatic lung cancer. J Control Release 2016; 241:81-93. [PMID: 27639682 DOI: 10.1016/j.jconrel.2016.09.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 08/11/2016] [Accepted: 09/14/2016] [Indexed: 01/13/2023]
Abstract
In this work, two tertiary amine-derived 4'-demethylepipodophyllotoxin (DMEP) conjugates (DC and DP) have been designed and synthesized using N,N,N'-trimethyl-N'-(4-carboxyl benzyl)-1,3-propanediamine (CPDM) and 4-(4-methylpiperazinomethyl)benzoic acid (PBA) as the targeting ligands. Both DC and DP exhibited strong in vitro cytotoxicity against small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines. Cellular uptake efficiencies of DC and DP in human alveolar type II epithelial cells were significantly enhanced compared to DMEP and etoposide (VP-16), which were demonstrated to be concentration-, time- and energy-dependent. The active transport process of DC and DP might be mediated by organic cation transporters (OCTs). After systemic administration in mice, both DC and DP selectively accumulated in the lung, displaying the highest Cmax and AUC0-t values of all tested tissues. Compared with DMEP and VP-16, DC and DP remarkably reduced the lung weight and the number of lung metastases of B16 melanoma in mice, and further prolonged the survival of tumor-bearing mice. Also, DC and DP exhibited comparable levels of cell cycle arrest and cell apoptosis. Furthermore, DC and DP demonstrated minimum toxicity towards vital organs and reduced gastrointestinal injury compared to DMEP and VP-16. Taken together, tertiary amine-derived moieties such as CPDM and PBA represent an efficient yet safe strategy to achieve lung-targeted drug delivery.
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Affiliation(s)
- Meiling Zhou
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Jianbo Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Chunhong Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Ling Guo
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xinyi Wang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Qin He
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yao Fu
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| | - Zhirong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
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