scholarly journals Biodistribution of Exosomes and Engineering Strategies for Targeted Delivery of Therapeutic Exosomes

2021 ◽  
Author(s):  
Hojun Choi ◽  
Yoorim Choi ◽  
Hwa Young Yim ◽  
Amin Mirzaaghasi ◽  
Jae-Kwang Yoo ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Surface Engineering ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Protein Composition ◽  
Covalent Bonds ◽  
Systemic Injection ◽  
Recent Advances

AbstractExosomes are cell-secreted nano-sized vesicles which deliver diverse biological molecules for intercellular communication. Due to their therapeutic potential, exosomes have been engineered in numerous ways for efficient delivery of active pharmaceutical ingredients to various target organs, tissues, and cells. In vivo administered exosomes are normally delivered to the liver, spleen, kidney, lung, and gastrointestinal tract and show rapid clearance from the blood circulation after systemic injection. The biodistribution and pharmacokinetics (PK) of exosomes can be modulated by engineering various factors such as cellular origin and membrane protein composition of exosomes. Recent advances accentuate the potential of targeted delivery of engineered exosomes even to the most challenging organs including the central nervous system. Major breakthroughs have been made related to various imaging techniques for monitoring in vivo biodistribution and PK of exosomes, as well as exosomal surface engineering technologies for inducing targetability. For inducing targeted delivery, therapeutic exosomes can be engineered to express various targeting moieties via direct modification methods such as chemically modifying exosomal surfaces with covalent/non-covalent bonds, or via indirect modification methods by genetically engineering exosome-producing cells. In this review, we describe the current knowledge of biodistribution and PK of exosomes, factors determining the targetability and organotropism of exosomes, and imaging technologies to monitor in vivo administered exosomes. In addition, we highlight recent advances in strategies for inducing targeted delivery of exosomes to specific organs and cells.

scholarly journals Gold Nanoparticle-Based Fluorescent Theranostics for Real-Time Image-Guided Assessment of DNA Damage and Repair

2019 ◽  
Vol 20 (3) ◽  
pp. 471 ◽  
Author(s):  
Shriya S. Srinivasan ◽  
Rajesh Seenivasan ◽  
Allison Condie ◽  
Stanton L. Gerson ◽  
Yanming Wang ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Real Time ◽  
Targeted Delivery ◽  
Specific Binding ◽  
Imaging Techniques ◽  
Cancer Cell Line ◽  
Molecular Probe ◽  
Biodistribution Studies

Chemotherapeutic dosing, is largely based on the tolerance levels of toxicity today. Molecular imaging strategies can be leveraged to quantify DNA cytotoxicity and thereby serve as a theranostic tool to improve the efficacy of treatments. Methoxyamine-modified cyanine-7 (Cy7MX) is a molecular probe which binds to apurinic/apyrimidinic (AP)-sites, inhibiting DNA-repair mechanisms implicated by cytotoxic chemotherapies. Herein, we loaded (Cy7MX) onto polyethylene glycol-coated gold nanoparticles (AuNP) to selectively and stably deliver the molecular probe intravenously to tumors. We optimized the properties of Cy7MX-loaded AuNPs using optical spectroscopy and tested the delivery mechanism and binding affinity using the DLD1 colon cancer cell line in vitro. A 10:1 ratio of Cy7MX-AuNPs demonstrated a strong AP site-specific binding and the cumulative release profile demonstrated 97% release within 12 min from a polar to a nonpolar environment. We further demonstrated targeted delivery using imaging and biodistribution studies in vivo in an xenografted mouse model. This work lays a foundation for the development of real-time molecular imaging techniques that are poised to yield quantitative measures of the efficacy and temporal profile of cytotoxic chemotherapies.

scholarly journals Targeted Delivery of Mesenchymal Stem Cell-Derived Nanovesicles for Spinal Cord Injury Treatment

2020 ◽  
Vol 21 (11) ◽  
pp. 4185
Author(s):  
Ju-Ro Lee ◽  
Jae Won Kyung ◽  
Hemant Kumar ◽  
Sung Pil Kwon ◽  
Seuk Young Song ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Clinical Application ◽  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Systemic Injection ◽  
Cord Injury ◽  
Macrophage Membrane

Due to the safety issues and poor engraftment of mesenchymal stem cell (MSC) implantation, MSC-derived exosomes have been spotlighted as an alternative therapy for spinal cord injury (SCI). However, insufficient productivity of exosomes limits their therapeutic potential for clinical application. Moreover, low targeting ability of unmodified exosomes is a critical obstacle for their further applications as a therapeutic agent. In the present study, we fabricated macrophage membrane-fused exosome-mimetic nanovesicles (MF-NVs) from macrophage membrane-fused umbilical cord blood-derived MSCs (MF-MSCs) and confirmed their therapeutic potential in a clinically relevant mouse SCI model (controlled mechanical compression injury model). MF-NVs contained larger quantity of ischemic region-targeting molecules compared to normal MSC-derived nanovesicles (N-NVs). The targeting molecules in MF-NVs, which were derived from macrophage membranes, increased the accumulation of MF-NVs in the injured spinal cord after the in vivo systemic injection. Increased accumulation of MF-NVs attenuated apoptosis and inflammation, prevented axonal loss, enhanced blood vessel formation, decreased fibrosis, and consequently, improved spinal cord function. Synthetically, we developed targeting efficiency-potentiated exosome-mimetic nanovesicles and present their possibility of clinical application for SCI.

scholarly journals The Role of PPARγin the Transcriptional Control by Agonists and Antagonists

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Tamotsu Tsukahara
Keyword(s):  
Transcriptional Repression ◽  
Transcriptional Control ◽  
Thyroid Hormone Receptor ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cyclic Phosphatidic Acid

In recent years, peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to be a target for the treatment of type II diabetes. Furthermore, it has received attention for its therapeutic potential in many other human diseases, including atherosclerosis, obesity, and cancers. Recent studies have provided evidence that the endogenously produced PPARγ antagonist, 2,3-cyclic phosphatidic acid (cPA), which is similar in structure to lysophosphatidic acid (LPA), inhibits cancer cell invasion and metastasisin vitroandin vivo. We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the corepressor protein, silencing mediator of retinoic acid and thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARγ target gene transcription. We then analyzed the molecular mechanism of cPA's action on PPARγ. In this paper, we summarize the current knowledge on the mechanism of PPARγ-mediated transcriptional activity and transcriptional repression in response to novel lipid-derived ligands, such as cPA.

scholarly journals Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

2020 ◽  
Author(s):  
Mariana Conceição ◽  
Laura Forcina ◽  
Oscar P. B. Wiklander ◽  
Dhanu Gupta ◽  
Joel Z. Nordin ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Signalling Pathway ◽  
Peptide Sequence ◽  
Target Cells ◽  
Dimerization Domain ◽  
Decoy Receptor ◽  
Stat3 Phosphorylation

AbstractThe cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.

scholarly journals Nanotechnology Approaches for Chloroplast Biotechnology Advancements

2021 ◽  
Vol 12 ◽  
Author(s):  
Gregory M. Newkirk ◽  
Pedro de Allende ◽  
Robert E. Jinkerson ◽  
Juan Pablo Giraldo
Keyword(s):  
Synthetic Biology ◽  
Plant Species ◽  
Targeted Delivery ◽  
Current Knowledge ◽  
Ex Vivo ◽  
Future Research ◽  
Agricultural Field ◽  
Diverse Plant Species ◽  
Diverse Plant

Photosynthetic organisms are sources of sustainable foods, renewable biofuels, novel biopharmaceuticals, and next-generation biomaterials essential for modern society. Efforts to improve the yield, variety, and sustainability of products dependent on chloroplasts are limited by the need for biotechnological approaches for high-throughput chloroplast transformation, monitoring chloroplast function, and engineering photosynthesis across diverse plant species. The use of nanotechnology has emerged as a novel approach to overcome some of these limitations. Nanotechnology is enabling advances in the targeted delivery of chemicals and genetic elements to chloroplasts, nanosensors for chloroplast biomolecules, and nanotherapeutics for enhancing chloroplast performance. Nanotechnology-mediated delivery of DNA to the chloroplast has the potential to revolutionize chloroplast synthetic biology by allowing transgenes, or even synthesized DNA libraries, to be delivered to a variety of photosynthetic species. Crop yield improvements could be enabled by nanomaterials that enhance photosynthesis, increase tolerance to stresses, and act as nanosensors for biomolecules associated with chloroplast function. Engineering isolated chloroplasts through nanotechnology and synthetic biology approaches are leading to a new generation of plant-based biomaterials able to self-repair using abundant CO2 and water sources and are powered by renewable sunlight energy. Current knowledge gaps of nanotechnology-enabled approaches for chloroplast biotechnology include precise mechanisms for entry into plant cells and organelles, limited understanding about nanoparticle-based chloroplast transformations, and the translation of lab-based nanotechnology tools to the agricultural field with crop plants. Future research in chloroplast biotechnology mediated by the merging of synthetic biology and nanotechnology approaches can yield tools for precise control and monitoring of chloroplast function in vivo and ex vivo across diverse plant species, allowing increased plant productivity and turning plants into widely available sustainable technologies.

scholarly journals Phage Therapy as a Focused Management Strategy in Aquaculture

2021 ◽  
Vol 22 (19) ◽  
pp. 10436
Author(s):  
José Ramos-Vivas ◽  
Joshua Superio ◽  
Jorge Galindo-Villegas ◽  
Félix Acosta
Keyword(s):  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Control Strategies ◽  
Bacterial Species ◽  
Lytic Enzymes ◽  
Wide Range ◽  
Cultured Fish

Therapeutic bacteriophages, commonly called as phages, are a promising potential alternative to antibiotics in the management of bacterial infections of a wide range of organisms including cultured fish. Their natural immunogenicity often induces the modulation of a variated collection of immune responses within several types of immunocytes while promoting specific mechanisms of bacterial clearance. However, to achieve standardized treatments at the practical level and avoid possible side effects in cultivated fish, several improvements in the understanding of their biology and the associated genomes are required. Interestingly, a particular feature with therapeutic potential among all phages is the production of lytic enzymes. The use of such enzymes against human and livestock pathogens has already provided in vitro and in vivo promissory results. So far, the best-understood phages utilized to fight against either Gram-negative or Gram-positive bacterial species in fish culture are mainly restricted to the Myoviridae and Podoviridae, and the Siphoviridae, respectively. However, the current functional use of phages against bacterial pathogens of cultured fish is still in its infancy. Based on the available data, in this review, we summarize the current knowledge about phage, identify gaps, and provide insights into the possible bacterial control strategies they might represent for managing aquaculture-related bacterial diseases.

scholarly journals DARPin_9-29-Targeted Gold Nanorods Selectively Suppress HER2-Positive Tumor Growth in Mice

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5235
Author(s):  
Galina M. Proshkina ◽  
Elena I. Shramova ◽  
Marya V. Shilova ◽  
Ivan V. Zelepukin ◽  
Victoria O. Shipunova ◽  
...  
Keyword(s):  
Gold Nanorods ◽  
Targeted Delivery ◽  
Photothermal Therapy ◽  
Near Infrared ◽  
Therapeutic Potential ◽  
Infrared Light ◽  
Strong Reduction ◽  
Her2 Positive ◽  
Excellent Stability

Near-infrared phototherapy has great therapeutic potential for cancer treatment. However, for efficient application, in vivo photothermal agents should demonstrate excellent stability in blood and targeted delivery to pathological tissue. Here, we demonstrated that stable bovine serum albumin-coated gold mini nanorods conjugated to a HER2-specific designed ankyrin repeat protein, DARPin_9-29, selectively accumulate in HER2-positive xenograft tumors in mice and lead to a strong reduction in the tumor size when being illuminated with near-infrared light. The results pave the way for the development of novel DARPin-based targeted photothermal therapy of cancer.

Oral Targeted Delivery by Nanoparticles Enhances Efficacy of an Hsp90 Inhibitor by Reducing Systemic Exposure in Murine Models of Colitis and Colitis-Associated Cancer

2019 ◽  
Vol 14 (1) ◽  
pp. 130-141 ◽  
Author(s):  
Mei Yang ◽  
Fang Zhang ◽  
Chunhua Yang ◽  
Lixin Wang ◽  
Junsik Sung ◽  
...  
Keyword(s):  
Delivery System ◽  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Systemic Exposure ◽  
Hsp90 Inhibitor ◽  
Systemic Administration ◽  
Raw 264.7 Cells ◽  
In Vivo Models ◽  
Promising Therapeutic Approach

AbstractBackground and AimsHeat shock protein 90 [Hsp90]-targeted therapy has been proposed as a promising strategy for the treatment of ulcerative colitis [UC] and colitis-associated cancer [CAC]. Systemic administration of the Hsp90 inhibitor, 17-AAG, was found to be profoundly protective in preclinical mouse models of inflammatory bowel disease [IBD]. However, the therapeutic potential of 17-AAG is limited by potential side effects associated with its systemic exposure and the modest bioavailability afforded by its oral administration.MethodsTo address these issues, we used a versatile single-step surface-functionalizing technique to prepare a 17-AAG oral delivery system using PLGA/PLA-PEG-FA nanoparticles [NP-PEG-FA/17-AAG].ResultsNP-PEG-FA could be efficiently taken up by mouse Colon-26 cells and activated Raw 264.7 cells in vitro and by inflamed mouse colitis tissues in vivo. The therapeutic efficacy of orally administrated NP-PEG-FA/17-AAG was evaluated in in vivo models using dextran sulphate sodium [DSS]-induced UC and azoxymethane [AOM]/DSS-induced CAC, and the results indicated that NP-PEG-FA/17-AAG significantly alleviated the symptoms of UC and CAC. More importantly, our inflamed colitis-targeted 17-AAG nano-formulation reduced systemic exposure and provided a degree of therapeutic response similar to that obtained by systemic administration [intraperitoneal] of 17-AAG, but at a ten-fold lower dose.ConclusionsWe describe a convenient, orally administrated 17-AAG delivery system that exhibits enhanced efficacy in UC and CAC therapy while reducing systemic exposure. This system may represent a promising therapeutic approach for treating UC and CAC.

Porous silicon nanomaterials: recent advances in surface engineering for controlled drug-delivery applications

Nanomedicine ◽  
2019 ◽  
Vol 14 (24) ◽  
pp. 3213-3230 ◽  
Author(s):  
De-Xiang Zhang ◽  
Lars Esser ◽  
Roshan B Vasani ◽  
Helmut Thissen ◽  
Nicolas H Voelcker
Keyword(s):  
Drug Delivery ◽  
Surface Modification ◽  
Porous Silicon ◽  
Surface Engineering ◽  
Controlled Drug Delivery ◽  
Current Status ◽  
Polymer Grafting ◽  
Recent Advances ◽  
Drug Delivery Applications

Porous silicon (pSi) nanomaterials are increasingly attractive for biomedical applications due to their promising properties such as simple and feasible fabrication procedures, tunable morphology, versatile surface modification routes, biocompatibility and biodegradability. This review focuses on recent advances in surface modification of pSi for controlled drug delivery applications. A range of functionalization strategies and fabrication methods for pSi-polymer hybrids are summarized. Surface engineering solutions such as stimuli-responsive polymer grafting, stealth coatings and active targeting modifications are highlighted as examples to demonstrate what can be achieved. Finally, the current status of engineered pSi nanomaterials for in vivo applications is reviewed and future prospects and challenges in drug-delivery applications are discussed.

scholarly journals Neutrophil Reverse Migration Becomes Transparent with Zebrafish

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Taylor W. Starnes ◽  
Anna Huttenlocher
Keyword(s):  
Immune Responses ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
The Novel ◽  
Imaging Studies ◽  
Advanced Imaging ◽  
Precise Control ◽  
Reverse Migration ◽  
A Site

The precise control of neutrophil-mediated inflammation is critical for both host defense and the prevention of immunopathology. In vivo imaging studies in zebrafish, and more recently in mice, have made the novel observation that neutrophils leave a site of inflammation through a process called neutrophil reverse migration. The application of advanced imaging techniques to the genetically tractable, optically transparent zebrafish larvae was critical for these advances. Still, the mechanisms underlying neutrophil reverse migration and its effects on the resolution or priming of immune responses remain unclear. Here, we review the current knowledge of neutrophil reverse migration, its potential roles in host immunity, and the live imaging tools that make zebrafish a valuable model for increasing our knowledge of neutrophil behavior in vivo.

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