scholarly journals Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities

2021 ◽  
Vol 9 ◽  
Author(s):  
Bethany Claridge ◽  
Jonathan Lozano ◽  
Qi Hui Poh ◽  
David W. Greening
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Great Promise ◽  
Paracrine Signaling ◽  
Therapeutic Modalities ◽  
Modify Surface ◽  
Quantitative Analyses ◽  
Bio Engineering

Extracellular vesicles (EVs) hold great promise as therapeutic modalities due to their endogenous characteristics, however, further bioengineering refinement is required to address clinical and commercial limitations. Clinical applications of EV-based therapeutics are being trialed in immunomodulation, tissue regeneration and recovery, and as delivery vectors for combination therapies. Native/biological EVs possess diverse endogenous properties that offer stability and facilitate crossing of biological barriers for delivery of molecular cargo to cells, acting as a form of intercellular communication to regulate function and phenotype. Moreover, EVs are important components of paracrine signaling in stem/progenitor cell-based therapies, are employed as standalone therapies, and can be used as a drug delivery system. Despite remarkable utility of native/biological EVs, they can be improved using bio/engineering approaches to further therapeutic potential. EVs can be engineered to harbor specific pharmaceutical content, enhance their stability, and modify surface epitopes for improved tropism and targeting to cells and tissues in vivo. Limitations currently challenging the full realization of their therapeutic utility include scalability and standardization of generation, molecular characterization for design and regulation, therapeutic potency assessment, and targeted delivery. The fields’ utilization of advanced technologies (imaging, quantitative analyses, multi-omics, labeling/live-cell reporters), and utility of biocompatible natural sources for producing EVs (plants, bacteria, milk) will play an important role in overcoming these limitations. Advancements in EV engineering methodologies and design will facilitate the development of EV-based therapeutics, revolutionizing the current pharmaceutical landscape.

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.

Abstract 129: Embryonic Stem Cell Derived Exosomes Revive Endogenous Repair Mechanisms In Failing Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Mohsin Khan ◽  
Suresh K Verma ◽  
Alexander R Mackie ◽  
Erin Vaughan ◽  
Srikanth Garikipati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Cardiac Regeneration ◽  
Great Promise ◽  
Target Cells ◽  
Free System ◽  
Teratoma Formation

Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to ethical concerns, lack of autologous donors and teratoma formation. Recently, it has been observed that beneficial effects of stem cells are mediated by exosomes secreted out under various physiological conditions. ESCs have the ability to produce exosomes however their effect in the context of the heart is unknown. Objective: Determine the effect of ESC derived exosomes for cardiac repair and modulation of CPCs functions in the heart following myocardial infarction. Methods and Results: Exosomes were isolated from murine ESCs (mES Ex) or embryonic fibroblasts (MEFs) by ultracentrifugation and verified by Flotillin-1 immunoblot analysis. Induction of pluripotent markers, survival and in vitro tube formation was enhanced in target cells receiving ESC exosomes indicating therapeutic potential of mES Ex. mES Ex administration resulted in enhanced neovascularization, cardiomyocyte survival and reduced fibrosis post infarction consistent with resurgence of cardiac proliferative response. Importantly, mES Ex mediated considerable enhancement of cardiac progenitor cell (CPC) survival, proliferation and cardiac commitment concurrent with increased c-kit+ CPCs in vivo 4 weeks after mES Ex transfer. miRNA Array analysis of ESC and MEF exosomes revealed significantly high expression of miR290-295 cluster in the ESC exosomes compared to MEF exosomes. The underlying beneficial effect of mES Ex was tied to delivery of ESC miR-294 to the heart and in particular CPCs thereby promoting CPC survival and proliferation as analyzed by FACS based cell death analysis and CyQuant assay respectively. Interestingly, enhanced G1/S transition was observed in CPCs treated with miR-294 in conjunction with significant reduction of G1 phase. Conclusion: In conclusion, mES Ex provide a novel cell free system for cardiac regeneration with the ability to modulate both cardiomyocyte and CPC based repair programs in the heart thereby avoiding the risk of teratoma formation associated with ESCs.

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.

scholarly journals Role of microRNAs in antiviral responses to dengue infection

2020 ◽  
Vol 27 (1) ◽  
Author(s):  
Rui Rui Wong ◽  
Noraini Abd-Aziz ◽  
Sarah Affendi ◽  
Chit Laa Poh
Keyword(s):  
Therapeutic Potential ◽  
Dengue Infection ◽  
Antiviral Agent ◽  
Delivery Systems ◽  
Severe Dengue ◽  
Great Promise ◽  
Hepatitis C Infection ◽  
Cellular Mirnas ◽  
Antiviral Responses

AbstractDengue virus (DENV) is the etiological agent of dengue fever. Severe dengue could be fatal and there is currently no effective antiviral agent or vaccine. The only licensed vaccine, Dengvaxia, has low efficacy against serotypes 1 and 2. Cellular miRNAs are post-transcriptional regulators that could play a role in direct regulation of viral genes. Host miRNA expressions could either promote or repress viral replications. Induction of some cellular miRNAs could help the virus to evade the host immune response by suppressing the IFN-α/β signaling pathway while others could upregulate IFN-α/β production and inhibit the viral infection. Understanding miRNA expressions and functions during dengue infections would provide insights into the development of miRNA-based therapeutics which could be strategized to act either as miRNA antagonists or miRNA mimics. The known mechanisms of how miRNAs impact DENV replication are diverse. They could suppress DENV multiplication by directly binding to the viral genome, resulting in translational repression. Other miRNA actions include modulation of host factors. In addition, miRNAs that could modulate immunopathogenesis are discussed. Major hurdles lie in the development of chemical modifications and delivery systems for in vivo delivery. Nevertheless, advancement in miRNA formulations and delivery systems hold great promise for the therapeutic potential of miRNA-based therapy, as supported by Miravirsen for treatment of Hepatitis C infection which has successfully completed phase II clinical trial.

scholarly journals Pinocembrin Ameliorates Skin Fibrosis via Inhibiting TGF-β1 Signaling Pathway

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1240
Author(s):  
Xiaohe Li ◽  
Yunqian Zhai ◽  
Buri Xi ◽  
Wei Ma ◽  
Jianwei Zhang ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Potential Effect ◽  
Dermal Fibroblasts ◽  
Skin Fibrosis ◽  
In Vivo Studies ◽  
Migration And Invasion ◽  
Therapeutic Modalities ◽  
Tgf Β1

Skin fibrotic diseases, such as keloids, are mainly caused by pathologic scarring of wounds during healing and characterized by benign cutaneous overgrowths of dermal fibroblasts. Current surgical and therapeutic modalities of skin fibrosis are unsatisfactory. Pinocembrin, a natural flavonoid, has been shown to possess a vast range of pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and anti-tumor activities. In this study we explored the potential effect and mechanisms of pinocembrin on skin fibrosis in vitro and in vivo. In vitro studies indicated that pinocembrin dose-dependently suppressed proliferation, migration, and invasion of keloid fibroblasts and mouse primary dermal fibroblasts. The in vivo studies showed that pinocembrin could effectively alleviate bleomycin (BLM)-induced skin fibrosis and reduce the gross weight and fibrosis-related protein expression of keloid tissues in xenograft mice. Further mechanism studies indicated that pinocembrin could suppress TGF-β1/Smad signaling and attenuate TGF-β1-induced activation of skin fibroblasts. In conclusion, our results demonstrate the therapeutic potential of pinocembrin for skin fibrosis.

scholarly journals A novel method for producing functionalized vesicles that efficiently deliver oligonucleotides in vitro and in vivo in mice

2021 ◽  
Author(s):  
Pragati Jain ◽  
Arthur G. Roberts
Keyword(s):  
Immune Response ◽  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Component Mixture ◽  
Vesicle Size ◽  
Insertion Method ◽  
Dialysis Method ◽  
Stability Issues

AbstractNano-based delivery systems have greatly enhanced our ability to administer and target drugs and macromolecules to their therapeutic targets. Oligonucleotide drugs have great therapeutic potential but have off-target effects and stability issues, so they are often encapsulated in functionalized vesicles with targeting ligands such as antibodies (Ab). Herein, we describe a novel, scalable and straightforward approach to produce functionalized vesicles called the “Functionalized Lipid Insertion Method.” This method differs significantly from an older approach referred to as the “Detergent-Dialysis Method.” The older method requires excess detergent and extensive dialysis over many hours to produce the functionalized vesicles. With the “Functionalized Lipid Insertion Method,” only the functionalized lipid is detergent-solubilized during the formation of the functionalized vesicle. The approach reduces the dialysis time, keeps the vesicle intact, and orients the functionalized lipid to improve targeting compared to the older method. The dynamic light scattering (DLS) technique demonstrated that vesicle size is sensitive to the initial detergent-solubilized component mixture by the older method. In contrast, functionalized vesicle size increases are consistent with functionalized lipid insertion into the vesicle. In vitro, functionalized vesicles using our approach are able to deliver oligonucleotides selectively and can functionally affect liver cancer HepG2 cells. Functionalized vesicles produced by this method can also achieve targeted delivery of oligonucleotides in mice without inducing a significant immune response through cytokine production or showing physical signs of an immune response. The industrial and therapeutic significance and implications of functionalized vesicles produced by our method are also discussed.

scholarly journals Paclitaxel-Loaded and Folic Acid Modified PLGA Nanomedicine with Glutathione-Response for the Treatment of Lung Cancer

2020 ◽  
Author(s):  
Zhanxia Zhang ◽  
Wang Yao ◽  
Jialiang Yao ◽  
Fangfang Qian ◽  
Zujun Que ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Folic Acid ◽  
Side Effects ◽  
Targeted Delivery ◽  
Great Promise ◽  
Stimuli Responsive ◽  
Biologically Relevant ◽  
Chemotherapy Agents

Abstract Targeted delivery and smart response of nanomedicine hold great promise to improve the therapeutic efficacy and alleviate the side effects of chemotherapy agents in cancer treatment. While a few research systems about organic nanomedicines with these properties have limited the development prospect of nanomedicines. In the present study, folic acid (FA) targeted delivery and GSH (glutathione) smart responsive nanomedicine was rationally designed for paclitaxel (PTX) delivery in the treatment of lung cancer. Compared with other stimuli responsive nanomedicines, this nano-carrier was not only sensitive to biologically relevant GSH for on demand drug release but also biodegradable into biocompatible by products after fulfilling its delivering task. The nanomedicine can firstly enter into tumor cells via FA and its receptor mediated endocytosis. After lysosomes escape, the PLGA (poly(lactic-co-glycolic acid) nanomedicine was triggered by the higher level of GSH and released its cargo in tumor microenvironment. In vitro and in vivo results revealed that the PLGA nanomedicine not only can inhibit the proliferation and promote the apoptosis of lung cancer cells greatly, but also possesses less toxic side effects when compared with free PTX. Therefore, the proposed drug delivery system demonstrates the encouraging potential for multifunctional nano-platform applicable to enhance the bioavailability and reduce the side effects of chemotherapy agents.

MiR490's diagnostic capacity was demonstrated in various cancer kinds and diseases, adding to its clinical value

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Molecular Therapy ◽  
Molecular Diagnostic ◽  
Diagnostic Tools ◽  
Clinical Value ◽  
Cancer Types ◽  
Diagnostic Capacity

This miR‐490 review first illustrates its association with various clinical malignancies and other diseases. Although in various malignancies miR‐490's activities, regulatory mechanisms and targets were revealed, its significance to other illnesses is beginning to be studied. Note that miR‐490 levels are regulated at different levels by transcription factors, epigenetic factors, and ncRNAs, revealing complicated interplay between these components. A system approach that incorporates miR‐490 and its regulatory components will surely help detect critical miR‐490 hub connections that might affect tumor initiation/progression. Furthermore, a number of pharmacological and environmental variables known to cause disease have also been shown to alter miR‐490 levels, showing miR‐490's significant pathogenesis involvement. The fact that miR‐490 levels are strictly regulated and abnormal miR‐490 levels are reported in many cancer types and diseases highlights miR‐490's significance in controlling cell homeostasis.Due to their increased stability, miRNAs are developed as diagnostic agents. MiR‐490's diagnostic capacity was demonstrated in various cancer kinds and diseases, adding to its clinical value. The potential of miR‐490 as a non-invasive biomarker might possibly be studied by measuring patient serum/saliva/urine levels in tissues or body fluids. Furthermore, miR‐490's demonstrated ability to stratify healthy tissue tumor samples may aid establishing molecular diagnostic tools. In most circumstances, miR‐490's association with improved prognosis is also fascinating. This extra clinical importance makes miR‐490 appropriate for molecular therapy. In most cancer types where miR‐490 has been functionally identified, miR‐490 has been found to be a miRNA tumor suppressor that inhibits several cancer hallmarks by directly controlling oncogenic targets and pathways. In practical practice, a therapy regime using miR‐490 tissue alteration based on rapidly evolving targeted delivery methods may be on the horizon. Nevertheless, further in vivo investigations must be conducted using genetically changed mice models. Although miR‐490 was not yet clinically examined for its therapeutic potential, in vitro and in vivo preclinical experiments revealed enormous promise in translating miR‐490 as a novel therapeutic target. miR‐490 appears as a novel candidate miRNA with significant cancer diagnosis and therapy with its prognostic and diagnostic capabilities. Therefore, miR‐490 might serve as a novel weapon in the current anti-cancer treatment arsenal.

Abstract 111: A Kidney Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Cisplatin-induced Nephrotoxicity

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
John D Imig ◽  
Md A Khan ◽  
Adeniyi M Adebesin ◽  
John R Falck
Keyword(s):  
Folic Acid ◽  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Kidney Tissue ◽  
Renal Tissue ◽  
Epoxyeicosatrienoic Acid ◽  
High Concentration ◽  
Lower Effective Dose

Epoxyeicosatrienoic acid (EET) analogs have exceptional therapeutic potential to combat cardiovascular and kidney diseases. EET analogs combat damage in acute and chronic kidney disease models. Biological actions attributed to EET analogs such as vasodilation, anti-inflammation, anti-apoptosis, and anti-fibrosis are ideally suited to treat kidney diseases. Although EET analogs have performed well in several in vivo models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect in the kidney and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated an EET analog to folic acid because there is a high concentration of folate receptors in renal tissue. The EET analog was conjugated to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. (10mg/kg/hr) for 6 hours via the rat jugular vein. Plasma and kidney tissue were collected and EET-A or EET-F01 measured by LC-MS-MS. EET-A plasma level was 1.6 ng/mL, but EET-A was undetectable in the kidney. On the other hand, EET-F01 was 6.5 ng/mL in plasma and 26.7 ng/mL in kidney tissue. These data demonstrate that EET-F01 targets the kidney. Experiments were conducted to compare EET-F01 and EET-A to decrease cisplatin-induced nephrotoxicity. A single injection of cisplatin (7 mg/kg ip) was administered to WKY rats treated with vehicle, EET-A (10 mg/kg ip) or EET-F01 (20 mg/kg or 2 mg/kg ip) for five days. Cisplatin increased BUN (125 ± 11 mg/dL) and NAG (12 ± 4 IU/L) compared to control (36 ± 9 mg/dL and 4 ± 1 IU/L). EET-F01 was as effective as EET-A in decreasing BUN, NAG, and renal histological injury five days following cisplatin administration. Despite it almost 2x-greater molecular weight compared with EET-A, EET-F01 was effective in lowering BUN and NAG at 20 mg/kg/d and at a 10-fold lower dose of 2 mg/kg/d. These data clearly demonstrate that EET-F01 targets the kidney and allows for a lower effective dose. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

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