Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases

Rufino-Ramos, David; Albuquerque, Patrícia R. de; Carmona, Vítor; Perfeito, Rita; Nobre, Rui Jorge; Almeida, Luís Pereira de

doi:10.1016/j.jconrel.2017.07.001

Cited by 315 publications

(243 citation statements)

References 169 publications

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“…Interestingly, cell penetration sequences similar to those incorporated in a number of the peptides listed in Table 1 have shown facility for crossing the blood brain barrier [51,66]. Use of drug delivery vehicles including exosomal vectors may also assist in this key task [67]. Further challenges are afforded by the complexities associated with the tumor microenvironment, cellular heterogeneity and evolving evidence that TMZ resistance is mediated by multiple molecular pathways unrelated to the expression of MGMT.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

Grek

Sheng

Naus

et al. 2018

Current Opinion in Pharmacology

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Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells. Carboxyl-terminal Cx43 peptidomimetics show therapeutic promise in overcoming TMZ resistance via mechanisms that may include modulating junctional activity between tumor cells and peritumoral cells and/or downstream molecular signaling events mediated by Cx43 protein binding. High levels of intra-tumor and inter-tumor heterogeneity make it difficult to clearly define specific populations for Cx43-targeted therapy; hence, development of in vitro models that better mimic the microenvironment of malignant glioma, and the incorporation of patient-derived stem cells, could provide opportunities for patient-specific drug screening. This review summarizes recent advances in understanding the roles of Cx43 in malignant glioma, with a special focus on tumor microenvironment, TMZ resistance, and therapeutic opportunity offered by Cx43 peptidomimetics.

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Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

Grek

Sheng

Naus

et al. 2018

Current Opinion in Pharmacology

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“…The release of EVs is now recognized as an important modulator of crosstalk between many cells types, and in disease states. (60) Recently, McBride and colleagues (61) demonstrated that bone marrow mesenchymal stem cell-derived exosomes transport WNT3a and enhance dermal fibroblast proliferation and angiogenesis in vitro.…”

Section: Mitochondrial Biogenesismentioning

confidence: 99%

Crosstalk Between MLO‐Y4 Osteocytes and C2C12 Muscle Cells Is Mediated by the Wnt/β‐Catenin Pathway

et al. 2017

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We examined the effects of osteocyte secreted factors on myogenesis and muscle function. MLO-Y4 osteocyte-like cell conditioned media (CM) (10%) increased ex vivo soleus muscle contractile force by ~25%. MLO-Y4 and primary osteocyte CM (1–10%) stimulated myogenic differentiation of C2C12 myoblasts, but 10% osteoblast CMs did not enhance C2C12 cell differentiation. Since WNT3a and WNT1 are secreted by osteocytes, and the expression level of Wnt3a is increased in MLO-Y4 cells by fluid flow shear stress, both were compared, showing WNT3a more potent than WNT1 in inducing myogenesis. Treatment of C2C12 myoblasts with WNT3a at concentrations as low as 0.5ng/mL mirrored the effects of both primary osteocyte and MLO-Y4 CM by inducing nuclear translocation of β-catenin with myogenic differentiation, suggesting that Wnts might be potential factors secreted by osteocytes that signal to muscle cells. Knocking down Wnt3a in MLO-Y4 osteocytes inhibited the effect of CM on C2C12 myogenic differentiation. Sclerostin (100ng/mL) inhibited both the effects of MLO-Y4 CM and WNT3a on C2C12 cell differentiation. RT-PCR array results supported the activation of the Wnt/β-catenin pathway by MLO-Y4 CM and WNT3a. These results were confirmed by qPCR showing up-regulation of myogenic markers and two Wnt/β-catenin downstream genes, Numb and Flh1. We postulated that MLO-Y4 CM/WNT3a could modulate intracellular calcium homeostasis as the trigger mechanism for the enhanced myogenesis and contractile force. MLO-Y4 CM and WNT3a increased caffeine-induced Ca2+ release from the sarcoplasmic reticulum (SR) of C2C12 myotubes and the expression of genes directly associated with intracellular Ca2+ signaling and homeostasis. Together, these data show that in vitro and ex vivo, osteocytes can stimulate myogenesis and enhance muscle contractile function and suggest that Wnts could be mediators of bone to muscle signaling, likely via modulation of intracellular Ca2+ signaling and the Wnt/β-Catenin pathway.

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“…The reasons turned out to be that (1) an anatomical barrier exists within tumor; (2) the targeted ligands are unstable and inactive on the membrane surface; and (3) the ligand is insufficient to trigger the binding of the target (Nogueira et al, 2015;Juliano, 2016). Fortunately, EVs have great potential for natural drug delivery, because they can penetrate through anatomical barriers (Rufino-Ramos et al, 2017;Das et al, 2019), keep stability (Zhang et al, 2018a), and maintain sufficient binding effects . Although EVs' merits make them ideal for drug delivery, EV-based drug delivery remains challenging, such as short of standardized isolation methods, low drug loading efficiency, and restricted clinical grade production.…”

Section: Introductionmentioning

confidence: 99%

Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source

et al. 2020

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Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are nanosized membrane vesicles derived from most cell types. Carrying diverse biomolecules from their parent cells, EVs are important mediators of intercellular communication and thus play significant roles in physiological and pathological processes. Owing to their natural biogenesis process, EVs are generated with high biocompatibility, enhanced stability, and limited immunogenicity, which provide multiple advantages as drug delivery systems (DDSs) over traditional synthetic delivery vehicles. EVs have been reported to be used for the delivery of siRNAs, miRNAs, protein, small molecule drugs, nanoparticles, and CRISPR/Cas9 in the treatment of various diseases. As a natural drug delivery vectors, EVs can penetrate into the tissues and be bioengineered to enhance the targetability. Although EVs' characteristics make them ideal for drug delivery, EV-based drug delivery remains challenging, due to lack of standardized isolation and purification methods, limited drug loading efficiency, and insufficient clinical grade production. In this review, we summarized the current knowledge on the application of EVs as DDS from the perspective of different cell origin and weighted the advantages and bottlenecks of EV-based DDS. ARTICLE HISTORY

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Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases

Cited by 315 publications

References 169 publications

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

Crosstalk Between MLO‐Y4 Osteocytes and C2C12 Muscle Cells Is Mediated by the Wnt/β‐Catenin Pathway

Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source

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