Science Advances
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2020
·Vol. 6
·期 41
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IF 13.117
Di Liu,Gaofeng Shu,Feiyang Jin,Jing Qi,Xiaoling Xu,Yan Du,Hui Yu,Jun Wang,Mingchen Sun,Yuchan You,Minxia Zhu,Meixuan Chen,Luwen Zhu,Qiying Shen,Xiaoying Ying,Xuefang Lou,Saiping Jiang,Yongzhong Du
The development of drugs with rapid distribution in the kidney and long-term retention in the renal tubule is a breakthrough for enhanced treatment of acute kidney injury (AKI). Here, l-serine–modified chitosan (SC) was synthesized as a potential AKI kidney–targeting agent due to the native cationic property of chitosan and specific interaction between kidney injury molecule–1 (Kim-1) and serine. Results indicated that SC was rapidly accumulated and long-term retained in ischemia-reperfusion–induced AKI kidneys, especially in renal tubules, which was possibly due to the specific interactions between SC and Kim-1. SC-TK-SS31 was then prepared by conjugating SS31, a mitochondria-targeted antioxidant, to SC via reactive oxygen species (ROS)–sensitive thioketal linker. Because of the effective renal distribution combined with ROS-responsive drug release behavior, the administration of SC-TK-SS31 led to an enhanced therapeutic effect of SS31 by protecting mitochondria from damage and reducing the oxidative stress, inflammation, and cell apoptosis.
研究领域:
药学
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肾病学
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药物递送系统
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材料科学
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DOI
PubMed
高影响因子
BIOMATERIALS
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2023
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IF 14
Yuquan Li,Junxu Yang,Xiaoming Chen,Hao Hu,Nihan Lan,Jinmin Zhao,Li Zheng
Mitochondrial reactive oxygen species (mROS) play a crucial role in the process of osteoarthritis (OA), which may be a promising target for therapy of OA. In this study, novel mitochondrial-targeting and SOD-mimic Mn 3 O 4 @PDA@Pd-SS31 nanozymes with near-infrared (NIR) responsiveness and synergistic cascade to scavenge mROS were designed for the therapy of OA. Results showed that the nanozymes accelerated the release of Pd and Mn 3 O 4 under NIR irradiation, exhibiting enhanced activities of SOD and CAT mimic enzymes with reversed mitochondrial dysfunction and promoted mitophagy to effectively scavenge mROS from chondrocytes, modulate the microenvironment of oxidative stress, and eventually inhibit the inflammatory response. Nanozymes were excreted in vivo through intestinal metabolic pathway and had good biocompatibility, effectively reducing the inflammatory response and relieving articular cartilage degeneration in OA joints, with a reduction of 93.7 % and 93.8 % in OARSCI scores for 4 and 8 weeks respectively. Thus, this study demonstrated that the mitochondria targeting and NIR responsive Mn 3 O 4 @PDA@Pd-SS31 nanozymes could efficiently scavenge mROS, repair damaged mitochondrial function and promote cartilage regeneration, which are promising for the treatment of OA in clinical applications.
研究领域:
生物医学工程
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纳米技术
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骨科
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药学
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DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
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2024
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IF 10.7
Kang Qian,Peng Yang,Yixian Li,Ran Meng,Yunlong Cheng,Lingling Zhou,Jing Wu,Shuting Xu,Xiaoyan Bao,Qian Guo,Pengzhen Wang,Minjun Xu,Dongyu Sheng,Qizhi Zhang
Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms. Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology. However, clinical translation of peptide drugs is greatly hampered by their low permeability into brain. Herein, a hybrid peptide HNSS is generated by merging two therapeutic peptides (SS31 and S-14G Humanin (HNG)), using a different approach from the classical shuttle-therapeutic peptide conjugate design. HNSS demonstrated increased bio-permeability, with a 2-fold improvement in brain distribution over HNG, thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides. HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting, ROS scavenging and p-STAT3 activation. Meanwhile, HNSS with increased Aβ affinity greatly inhibited Aβ oligomerization/fibrillation, and interrupted Aβ interaction with neuron/microglia by reducing neuronal mitochondrial Aβ deposition and promoting microglial phagocytosis of Aβ. In 3 × Tg-AD transgenic mice, HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance. This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification, providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.
研究领域:
神经科学
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药理学
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生物技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2023
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IF 14
Bohong Yu,Yubo Liu,Yingxi Zhang,Linyi Xu,Kai Jin,Andi Sun,Xiuli Zhao,Yongjun Wang,Hongzhuo Liu
Mitochondrial dysfunction plays a major role in driving acute kidney injury (AKI) via alteration in energy and oxygen supply, which creates further ROS and inflammatory responses. However, mitochondrial targeting medicine in recovering AKI is challenging. Herein, we conjugated SS31, a mitochondria-targeted antioxidant tetrapeptide connecting a cleavable linker to rapamycin (Rapa), which provided specific interaction with FK506-binding protein (FKBP) in the RBCs . Once entering the bloodstream, SS31-Rapa could be directed to the intracellular space of RBCs, allowing the slow diffusion of the conjugate to tissues via the concentration gradient . The new RBC hitchhiking strategy enables the encapsulation of conjugate into RBC via a less traumatic and more natural and permissive manner, resulting in prolonging the t 1/2 of SS31 by 6.9 folds. SS31-Rapa underwent the direct cellular uptake, instead of the lysosomal pathway, released SS31 in response to activated caspase-3 stimulation in apoptotic cells, favoring the mitochondrial accumulation of SS31. Combined with autophagy induction associated with Rapa, a single dose of SS31-Rapa can effectively reverse cisplatin and ischemia reperfusion-induced AKI. This work thus highlights a simple and effective RBC hitchhiking strategy and a clinically translatable platform technology to improve the outcome of other mitochondrial dysfunctional related diseases.
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产品关联
DOI
PubMed
高影响因子
Nature Communications
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2023
·Vol. 14
·期 1
·1-14
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IF 16.6
Liu Di,Song Yanling,Chen Hui,You Yuchan,Zhu Luwen,Zhang Jucong,Xu Xinyi,Hu Jiahao,Huang Xiajie,Wu Xiaochuan,Xu Xiaoling,Jiang Saiping,Du Yongzhong
Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab′) 2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab′) 2 ) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab′) 2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab′) 2 -SS31, comprising the anti-VEGFR2 F(ab′) 2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab′) 2 . These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.
研究领域:
药理学
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肾病学
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糖尿病
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2023
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IF 9.5
Juan Cen,Xiaoying Dai,Han Zhao,Xiaohan Li,Xiaojiao Hu,Jing Wu,Shaofeng Duan
The blood–brain barrier (BBB) continues to be one of the main clinical obstacles in the treatment of glioma. Current chemotherapies always bring many different side effects, some even permanent. To date, nanomaterial-based vehicles have shown great potential in treating glioma. Herein, we developed a dual targeting liposomal delivery vector loaded with the anticancer drug doxorubicin (DOX) to treat glioma. SS31, a small peptide, has shown dual targeting effects of penetrating the BBB and specifically targeting mitochondria. In this study, a new liposomal delivery system, LS-DOX, was prepared by modifying DOX-loaded liposomes with SS31 for the treatment of in situ glioma. The liposomes demonstrated a high drug encapsulation rate and drug-loading capacity, satisfactory biocompatibility, high glioma accumulation ability, and good stability in vitro. Experimental results showed that the liposomes could effectively cross the BBB and target gliomas, and mitochondria-targeting of SS31 enhances cell uptake. In addition, the liposomes showed a good therapeutic effect on nude mice with glioma in situ with no obvious toxicity and side effects. Therefore, the present research will provide a novel alternative and reference for the effective treatment of glioma.
研究领域:
药学
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神经科学
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纳米技术
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肿瘤学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2021
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IF 8.947
Jiejie Sun,Jingzhou Liu,Chunhong Gao,Jinpeng Zheng,Jinbang Zhang,Yaning Ding,Wei Gong,Meiyan Yang,Zhiping Li,Yuli Wang,Yang Yang,Chunsheng Gao
Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co-modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. Statement of Significance TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane-coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo .
研究领域:
神经科学
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药学
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纳米技术
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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