scholarly journals Nanocarriers for Protein Delivery to the Cytosol: Assessing the Endosomal Escape of Poly(Lactide-co-Glycolide)-Poly(Ethylene Imine) Nanoparticles

Nanomaterials ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 652 ◽  
Author(s):  
Marianna Galliani ◽  
Chiara Tremolanti ◽  
Giovanni Signore
Keyword(s):  
Protein Delivery ◽  
Therapeutic Proteins ◽  
Endosomal Escape ◽  
Ethylene Imine ◽  
Enzyme Superoxide Dismutase ◽  
Rapid Clearance ◽  
Poly Ethylene ◽  
Enzyme Delivery

Therapeutic proteins and enzymes are a group of interesting candidates for the treatment of numerous diseases, but they often require a carrier to avoid degradation and rapid clearance in vivo. To this end, organic nanoparticles (NPs) represent an excellent choice due to their biocompatibility, and cross-linked enzyme aggregates (CLEAs)-loaded poly (lactide-co-glycolide) (PLGA) NPs have recently attracted attention as versatile tools for targeted enzyme delivery. However, PLGA NPs are taken up by cells via endocytosis and are typically trafficked into lysosomes, while many therapeutic proteins and enzymes should reach the cellular cytosol to perform their activity. Here, we designed a CLEAs-based system implemented with a cationic endosomal escape agent (poly(ethylene imine), PEI) to extend the use of CLEA NPs also to cytosolic enzymes. We demonstrated that our system can deliver protein payloads at cytoplasm level by two different mechanisms: Endosomal escape and direct translocation. Finally, we applied this system to the cytoplasmic delivery of a therapeutically relevant enzyme (superoxide dismutase, SOD) in vitro.

scholarly journals Carboxylated branched poly(β-amino ester) nanoparticles enable robust cytosolic protein delivery and CRISPR-Cas9 gene editing

2019 ◽  
Vol 5 (12) ◽  
pp. eaay3255 ◽  
Author(s):  
Yuan Rui ◽  
David R. Wilson ◽  
John Choi ◽  
Mahita Varanasi ◽  
Katie Sanders ◽  
...  
Keyword(s):  
Protein Delivery ◽  
Gene Editing ◽  
Gene Knockout ◽  
Cell Types ◽  
Endosomal Escape ◽  
Biological Research ◽  
Amino Ester ◽  
Cytosolic Protein

Efficient cytosolic protein delivery is necessary to fully realize the potential of protein therapeutics. Current methods of protein delivery often suffer from low serum tolerance and limited in vivo efficacy. Here, we report the synthesis and validation of a previously unreported class of carboxylated branched poly(β-amino ester)s that can self-assemble into nanoparticles for efficient intracellular delivery of a variety of different proteins. In vitro, nanoparticles enabled rapid cellular uptake, efficient endosomal escape, and functional cytosolic protein release into cells in media containing 10% serum. Moreover, nanoparticles encapsulating CRISPR-Cas9 ribonucleoproteins (RNPs) induced robust levels of gene knock-in (4%) and gene knockout (>75%) in several cell types. A single intracranial administration of nanoparticles delivering a low RNP dose (3.5 pmol) induced robust gene editing in mice bearing engineered orthotopic murine glioma tumors. This self-assembled polymeric nanocarrier system enables a versatile protein delivery and gene editing platform for biological research and therapeutic applications.

scholarly journals Cartilage-targeting Poly(Ethyleneglycol) (PEG)-formononetin (FMN) Nanodrug for Treating Osteoarthritis

2021 ◽  
Author(s):  
Wei Xiong ◽  
Qiumei Lan ◽  
Xiaonan Liang ◽  
Jinmin Zhao ◽  
Hanji Huang ◽  
...  
Keyword(s):  
Average Diameter ◽  
Therapeutic Effects ◽  
Efficient Treatment ◽  
Catabolic Genes ◽  
Systemic Side Effects ◽  
Rapid Clearance ◽  
Targeting Peptide ◽  
Poly Ethylene

Abstract Intra-articular (IA) injection is an efficient treatment for osteoarthritis. Such a treatment will minimize systemic side effects and avoid the inconvenience of frequent injections. However, the joint has poor bioavailability for systemically administered drugs and experiences rapid clearance of therapeutics after intra-articular injection. Delivering system modified through active targeting strategies to facilitate localization within specific joint tissues such as cartilage is hopeful to increase the therapeutic effects. In this study, we designed a nanoscaled amphiphilic and cartilage-targeting polymer-drug delivery system by using formononetin (FMN)-poly(ethylene glycol) (PEG) (denoted as PCFMN), which was prepared by PEGylation of FMN followed by coupling with cartilage-targeting peptide (CollBP). Our results showed that PCFMN was approximately regular spherical with the average diameter about 218 nm. The in vitro test using IL-1β stimulated chondrocytes indicated that PCFMN were biocompatible and upregulated anabolic genes while simultaneously downregulated catabolic genes of the articular cartilage. The therapeutic effects in vivo indicated that PCFMN could effectively attenuate the progression of OA as evidenced by immunohistochemical staining and histological analysis. In addition, PCFMN showed higher intention time in joints and better anti-inflammatory effects than FMN, indicating the efficacy of cartilage targeting nanodrug on OA. This study may provide reference for clinical OA therapy.

scholarly journals Efficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Siyuan Yu ◽  
Han Yang ◽  
Tingdong Li ◽  
Haifeng Pan ◽  
Shuling Ren ◽  
...  
Keyword(s):  
Protein Delivery ◽  
Leucine Zipper ◽  
Endosomal Escape ◽  
Cell Penetrating Peptide ◽  
Macromolecular Drugs ◽  
Cell Penetrating ◽  
In Series ◽  
Factor Α

AbstractProtein delivery with cell-penetrating peptide is opening up the possibility of using targets inside cells for therapeutic or biological applications; however, cell-penetrating peptide-mediated protein delivery commonly suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting in vivo efficacy. Here, we present an intracellular protein delivery system consisting of four modules in series: cell-penetrating peptide, pH-dependent membrane active peptide, endosome-specific protease sites and a leucine zipper. This system exhibits enhanced delivery efficiency and serum tolerance, depending on proteolytic cleavage-facilitated endosomal escape and leucine zipper-based dimerisation. Intravenous injection of protein phosphatase 1B fused with this system successfully suppresses the tumour necrosis factor-α-induced systemic inflammatory response and acetaminophen-induced acute liver failure in a mouse model. We believe that the strategy of using multifunctional chimaeric peptides is valuable for the development of cell-penetrating peptide-based protein delivery systems, and facilitate the development of biological macromolecular drugs for use against intracellular targets.

In vitro and in vivo protein delivery from in situ forming poly(ethylene glycol)–poly(lactide) hydrogels

2007 ◽  
Vol 119 (3) ◽  
pp. 320-327 ◽  
Author(s):  
Christine Hiemstra ◽  
Zhiyuan Zhong ◽  
Sophie R. Van Tomme ◽  
Mies J. van Steenbergen ◽  
John J.L. Jacobs ◽  
...  
Keyword(s):  
Ethylene Glycol ◽  
Protein Delivery ◽  
Poly Ethylene Glycol ◽  
In Situ Forming ◽  
Poly Ethylene

Crosslinked nanocarriers based upon poly(ethylene imine) for systemic plasmid delivery: In vitro characterization and in vivo studies in mice

2007 ◽  
Vol 118 (3) ◽  
pp. 370-380 ◽  
Author(s):  
Michael Neu ◽  
Oliver Germershaus ◽  
Shirui Mao ◽  
Karl-Heinz Voigt ◽  
Martin Behe ◽  
...  
Keyword(s):  
In Vivo Studies ◽  
Ethylene Imine ◽  
In Vitro Characterization ◽  
Poly Ethylene ◽  
Plasmid Delivery

scholarly journals Protein-avoidant ionic liquid (PAIL)–coated nanoparticles to increase bloodstream circulation and drive biodistribution

2020 ◽  
Vol 6 (48) ◽  
pp. eabd7563
Author(s):  
Christine M. Hamadani ◽  
Morgan J. Goetz ◽  
Samir Mitragotri ◽  
Eden E. L. Tanner
Keyword(s):  
Ionic Liquid ◽  
Ionic Liquids ◽  
Biomedical Applications ◽  
Serum Proteins ◽  
Poly Ethylene Glycol ◽  
Coated Nanoparticles ◽  
Rapid Clearance ◽  
Poly Ethylene

The rapid clearance of intravenously administered nanoparticles (NPs) from the bloodstream is a major unsolved problem in nanomedicine. Here, we describe the first use of biocompatible protein-avoidant ionic liquids (PAILs) as NP surface modifiers to reduce opsonization. An ionic liquid choline hexenoate, selected for its aversion to serum proteins, was used to stably coat the surface of poly(lactic-co-glycolic acid) (PLGA) NPs. Compared with bare PLGA and poly(ethylene glycol)–coated PLGA particles, the PAIL-PLGA NPs showed resistance to protein adsorption in vitro and greater retention in blood of mice at 24 hours. Choline hexenoate redirected biodistribution of NPs, with preferential accumulation in the lungs with 50% of the administered dose accumulating in the lungs and <5% in the liver. Lung accumulation was attributed to spontaneous attachment of the PAIL-coated NPs on red blood cells in vivo. Overall, ionic liquids are a promising class of materials for NP modification for biomedical applications.

Bifunctional and Bioreducible Dendrimer Bearing a Fluoroalkyl Tail for Efficient Protein Delivery Both In Vitro and In Vivo

Nano Letters ◽  
2020 ◽  
Vol 20 (12) ◽  
pp. 8600-8607 ◽  
Author(s):  
Jia Lv ◽  
Changping Wang ◽  
Hongru Li ◽  
Zhan Li ◽  
Qianqian Fan ◽  
...  
Keyword(s):  
Protein Delivery

scholarly journals Photo-Crosslinked Polymeric Matrix with Antimicrobial Functions for Excisional Wound Healing in Mice

Nanomaterials ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. 791 ◽  
Author(s):  
Ming-Hsiang Chang ◽  
Yu-Ping Hsiao ◽  
Chia-Yen Hsu ◽  
Ping-Shan Lai
Keyword(s):  
Wound Healing ◽  
Wound Infection ◽  
Polymer Solution ◽  
Wound Dressing ◽  
Glycol Diacrylate ◽  
Excisional Wound ◽  
Poly Ethylene ◽  
Systemic Infections

Wound infection extends the duration of wound healing and also causes systemic infections such as sepsis, and, in severe cases, may lead to death. Early prevention of wound infection and its appropriate treatment are important. A photoreactive modified gelatin (GE-BTHE) was synthesized by gelatin and a conjugate formed from the 3,3′,4,4′-benzophenone tetracarboxylic dianhydride (BTDA) and the 2-hydroxyethyl methacrylate (HEMA). Herein, we investigated the photocurable polymer solution (GE-BTHE mixture) containing GE-BTHE, poly(ethylene glycol) diacrylate (PEGDA), chitosan, and methylene blue (MB), with antimicrobial functions and photodynamic antimicrobial chemotherapy for wound dressing. This photocurable polymer solution was found to have fast film-forming property attributed to the photochemical reaction between GE-BTHE and PEGDA, as well as the antibacterial activity in vitro attributed to the ingredients of chitosan and MB. Our in vivo results also demonstrated that untreated wounds after 3 days had the same scab level as the GE-BTHE mixture-treated wounds after 20 s of irradiation, which indicates that the irradiated GE-BTHE mixture can be quickly transferred into artificial scabs to protect wounds from an infection that can serve as a convenient excisional wound dressing with antibacterial efficacy. Therefore, it has the potential to treat nonhealing wounds, deep burns, diabetic ulcers and a variety of mucosal wounds.

scholarly journals Local Toxicity of Topically Administrated Thermoresponsive Systems: In Vitro Studies with In Vivo Correlation

2018 ◽  
Vol 47 (3) ◽  
pp. 426-432 ◽  
Author(s):  
Sivan Yogev ◽  
Ayelet Shabtay-Orbach ◽  
Abraham Nyska ◽  
Boaz Mizrahi
Keyword(s):  
Block Copolymer ◽  
Ethylene Glycol ◽  
Medical Devices ◽  
Poly Lactic Acid ◽  
Poly Ethylene Glycol ◽  
Thermoresponsive Polymers ◽  
Wide Range ◽  
Poly Ethylene

Thermoresponsive materials have the ability to respond to a small change in temperature—a property that makes them useful in a wide range of applications and medical devices. Although very promising, there is only little conclusive data about the cytotoxicity and tissue toxicity of these materials. This work studied the biocompatibility of three Food and Drug Administration approved thermoresponsive polymers: poly( N-isopropyl acrylamide), poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) tri-block copolymer, and poly(lactic acid-co-glycolic acid) and poly(ethylene glycol) tri-block copolymer. Fibroblast NIH 3T3 and HaCaT keratinocyte cells were used for the cytotoxicity testing and a mouse model for the in vivo evaluation. In vivo results generally showed similar trends as the results seen in vitro, with all tested materials presenting a satisfactory biocompatibility in vivo. pNIPAM, however, showed the highest toxicity both in vitro and in vivo, which was explained by the release of harmful monomers and impurities. More data focusing on the biocompatibility of novel thermoresponsive biomaterials will facilitate the use of existing and future medical devices.

In vivo and in vitro degradation of poly(ether ester) block copolymers based on poly(ethylene glycol) and poly(butylene terephthalate)

Biomaterials ◽  
2004 ◽  
Vol 25 (2) ◽  
pp. 247-258 ◽  
Author(s):  
A.A. Deschamps ◽  
A.A. van Apeldoorn ◽  
H. Hayen ◽  
J.D. de Bruijn ◽  
U. Karst ◽  
...  
Keyword(s):  
Block Copolymers ◽  
Ethylene Glycol ◽  
Poly Ethylene Glycol ◽  
In Vitro Degradation ◽  
Butylene Terephthalate ◽  
Poly Ethylene ◽  
Ether Ester
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