Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

Wang, Meiyan; Yang, Xiaomei; Zhang, Peng; Yang, Xiaobo; Chen, You‐Wei; Jing, Yuanya; Kong, Jilie; Yang, Xiaowei; Sun, Fang-Lin

doi:10.1002/advs.201500393

Cited by 27 publications

(21 citation statements)

References 60 publications

(87 reference statements)

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“…Since insulin was commercially marketed in 1982, an increasing number of proteins and peptides, with greater than 200 products 1 in the past 3 decades, have been approved for treatment of diverse diseases including cancer, infection, diabetes, and inflammatory disease 2 , 3 . Undoubtedly, protein therapeutics, such as protein replacement therapies and human antibodies 4 , 5 , play an essential role in treatment of human diseases. Moreover, protein-based therapy is considered safer than gene therapy due to the absence of random or permanent genetic alterations.…”

Section: Introductionmentioning

confidence: 99%

Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo-lysosomal route

Xin¹,

Teng²,

Lv³

et al. 2018

Theranostics

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Protein therapeutics is playing an increasingly critical role in treatment of human diseases. However, current vectors are captured by the digestive endo-lysosomal system, which results in an extremely low fraction (<2%) of protein being released in the cytoplasm. This paper reports a drug-delivering-drug platform (HA-PNPplex, 200 nm) for potent intracellular delivery of protein and combined treatment of cancer.Methods: The platform was prepared by loading functional protein on pure drug nanoparticles (PNPs) followed by hyaluronic acid coating and was characterized by dynamic light scattering, transmission electron microscopy, and gel electrophoresis. In vitro, cellular uptake, trafficking, and cytotoxicity were evaluated by flow cytometry and confocal laser microscopy. Protein expression was assayed by western blot. In vivo, blood circulation and biodistribution were studied using a fluorescence imaging system, antitumor efficacy was assessed in a caspase 3-deficient tumor model, and biocompatibility was determined by comparison of hemolytic activity and proinflammatory cytokines and tissue histology.Results: HA-PNPplex delivered the functional protein, caspase 3, to cells via bypassing endo-lysosomes and raised the caspase-3 level 6.5-fold in caspase 3-deficient cells. Promoted tumor accumulation (1.5-fold) and penetration were exhibited, demonstrating a high tumor-targeting ability of HA-PNPplex. HA-PNPplex rendered a 7-fold increase in caspase 3 in tumor and allowed for a 100% tumor growth inhibition and >60% apoptosis, implying significant antitumor activities.Conclusions: This platform gains cellular entry without entrapment in the endo-lysosomes and enables efficient intracellular protein delivery and resultant profound cancer treatment. This platform, with extremely high drug-loading, is a valuable platform for combined cancer therapy with small-molecule drugs and proteins. More importantly, this work offers a robust and safe approach for protein therapeutics and intracellular delivery of other functional peptides, as well as gene-based therapy.

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Section: Introductionmentioning

confidence: 99%

Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo-lysosomal route

Xin¹,

Teng²,

Lv³

et al. 2018

Theranostics

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“…Monitoring the synthesis of glycosaminoglycans by periodic acid-Schiff showed that the increasing number of positive cells in the GF-PEI-MSN complex group. In the presence of this nanoparticle, mouse embryonic stem cells acquire a potency to give rise to endodermal lineage and hepatocyte-like phenotype after transplantation into the injured liver in the mouse model [145]. In conclusion, nanomaterials possess advantages for tissue regeneration.…”

Section: Hepatic Differentiation Via the Combination Of Cell Source Amentioning

confidence: 92%

Current progress in hepatic tissue regeneration by tissue engineering

et al. 2019

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Background: Liver, as a vital organ, is responsible for a wide range of biological functions to maintain homeostasis and any type of damages to hepatic tissue contributes to disease progression and death. Viral infection, trauma, carcinoma, alcohol misuse and inborn errors of metabolism are common causes of liver diseases are a severe known reason for leading to end-stage liver disease or liver failure. In either way, liver transplantation is the only treatment option which is, however, hampered by the increasing scarcity of organ donor. Over the past years, considerable efforts have been directed toward liver regeneration aiming at developing new approaches and methodologies to enhance the transplantation process. These approaches include producing decellularized scaffolds from the liver organ, 3D bio-printing system, and nano-based 3D scaffolds to simulate the native liver microenvironment. The application of small molecules and micro-RNAs and genetic manipulation in favor of hepatic differentiation of distinct stem cells could also be exploited. All of these strategies will help to facilitate the application of stem cells in human medicine. This article reviews the most recent strategies to generate a high amount of mature hepatocyte-like cells and updates current knowledge on liver regenerative medicine.

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“…This strategy ensures an 80-90% hepatocyte yield. Recently, Wang et al established a polymer-modified nanoparticle-based sustained delivery system for growth factors to direct stem cell differentiation into hepatocytes [47]. Their approach can help to overcome the limitations linked with current models and make sure efficient delivery of growth factors to improve ESC differentiation toward a hepatocyte-like lineage.…”

Section: Embryonic Stem Cells and Hepatocyte Generationmentioning

confidence: 99%

“…HSCs and MSCs can be advantageous cell sources for liver regeneration as compared to hepatocytes since they can be obtained relatively easily from blood and bone marrow of live donors. Since BMSCs are immune-modulators, a reduced chance of graft rejection is an additional property of these stem cells [47,51]. In clinical trials, patients with autologous BMSC (CD34 + cell) transplantation had no procedure-related complications and showed improved quality of life [30].…”

Section: Bone Marrow Stem Cells (Bmscs)mentioning

confidence: 99%

Regenerative Medicine in Liver Cirrhosis: Promises and Pitfalls

Tayyeb¹,

Azam²,

Nisar³

et al. 2017

Liver Cirrhosis - Update and Current Challenges

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Liver cirrhosis is irreversible and mostly ends up with complete loss of liver function/ end-stage liver failure, and the only proven treatment is liver transplantation. Scarcity of donor, high cost, lifelong immunosuppression, and surgical complications are the major issues associated with liver transplantation and these urge to look for alternate therapeutic approaches. Advancements in the field of regenerative medicine are arising hope for the treatment of liver cirrhosis. This chapter deals with the scope of liver regenerative medicine in the treatment of liver cirrhosis. Review of the literature showed that liver regenerative medicine no doubt holds great promises and added a lot of hope to the cure of liver diseases. Primarily, cell-based therapies had shown great potential to treat liver cirrhosis. Successful clinical human trials further strengthen their significance in the field. However, recent trends in liver regenerative medicine are focusing on the development of tissue engineering leading to generation of the whole organ. Despite advantages, liver regenerative medicine has several limitations and sometimes been over-optimistically interpreted. In conclusion, the current scenario advocates to conduct more preclinical and clinical trials to effectively replace liver transplantation with liver regenerative medicine to treat liver diseases.

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Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

Cited by 27 publications

References 60 publications

Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo-lysosomal route

Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo-lysosomal route

Current progress in hepatic tissue regeneration by tissue engineering

Regenerative Medicine in Liver Cirrhosis: Promises and Pitfalls

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