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Innovative Target-to-Treat Nanostrategies for Rheumatoid Arthritis
Published in Ana Rute Neves, Salette Reis, Nanoparticles in Life Sciences and Biomedicine, 2018
Virginia Moura Gouveia, Cláudia Nunes, Salette Reis
Synovial vascularization and prominent angiogenesis are crucial for enduring synovitis and progressive joint destruction [20]. Likewise, the VEGF and its receptor found in the synovium are essential elements for neovascularization [20]. In this regard, in addition to HA’s synovial-targeting ability, Lee and coworkers developed a HA-conjugated tocilizumab (TCZ) gold NP, used simultaneously for a targeting and biologic therapeutic approach. TCZ is a monoclonal therapeutic IL-6 antibody against IL-6 signaling by binding to the interleukin-6 receptor (IL-6R) [73]. IL-6 present in the synovium actively contributes to the RA pathogenesis by stimulating synoviocyte cell proliferation and osteoclast activation, plus the production of MMPs, hence promoting cartilage destruction. Additionally, this pro-inflammatory cytokine influences the VEGF expression for the vascularization of inflamed synovial tissue. Therefore, IL-6 is an interesting cytokine target used for RA treatment [17]. Remarkably, the HA-gold NP TCZ complex administered intravenously in a CIA mouse model, aside from being able to target synovial tissues and accumulate within the synovium, also reveals TCZ ability to target angiogenic blood vessels [72, 73]. The observed reduction of VEGF and IL-6 expression in the synovium suggests that treatment with the HA-gold NP TCZ complex had an anti-inflammatory and antiangiogenic effect in arthritic mouse models [72].
Aptamers as Tools for Targeted Drug Delivery
Published in Rakesh N. Veedu, Aptamers, 2017
An approach that combines cell internalization SELEX and high throughput sequencing coupled with bioinformatics analysis to select and identify cell-internalizing RNA aptamers was reported [82]. The authors suggest that apart from the classification based on sequence similarity, structural classification of the aptamers is also important for identification of the functional properties. The authors report the development of predictive tools that is valuable in target sequence identification during aptamer selection. During the experimental process, they were able to identify several RNA aptamers that targeted vascular smooth muscle cells [82]. In vitro selection and characterization of RNA aptamers that target human interleukin-6 receptor (IL-6R) were reported and developed as a potential tool for therapeutic use in different diseases, including cancer and inflammatory diseases [56]. The developed aptamer AIR-3A was only 19 nucleotides in length and retained all the necessary features required for targeting specificity. The AIR-3A aptamer could additionally serve as a delivery vehicle to transport therapeutic molecules to the cells harboring IL-6Rs [56]. Jagat R. Kanwar et al. [41] have reviewed the aptamers that are available for ocular diseases and discussed various modifications that can increase the efficiency of aptamers [41].
Carriers for Nucleic Acid Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Sequence-defined oligoaminoamide oligomers were used for receptor-mediated delivery of siRNA [101] and pDNA [102] into glioma in vivo after systemic injection. For siRNA delivery, an untargeted lipo-oligomer was mixed with a PEGylated oligomer containing an angiopep-2 ligand targeting the LRP-1 receptor, which is overexpressed both on the surface of BCECs and glioma cells [101]. A similar cascade-targeting strategy was used for the delivery of therapeutic pDNA. Here, a nontargeted oligomer was mixed with a PEGylated oligomer containing the heptapeptide I6P7, which binds the interleukin 6 receptor (IL6R). IL6R expression was detected both on the tumour BBB and in various brain tumours such as glioblastoma (Fig. 9.3). Targeted delivery of pDNA encoding inhibitor of growth 4 (pING4) significantly prolonged the survival time of orthotopic U87 glioma-bearing mice [102]. Reporter gene expression was found in the brains of U87 glioblastoma-bearing mice after intracranial injection of pDNA polyplexes formed with bioreducibly linked (cRGDyK)-PEG-ss-PEI. The Arg-Gly-Asp (RGD) sequence binds integrin receptors which are highly expressed in glioma cells, while the cyclic RGD peptide cRGDyK is known to increase the affinity and selectivity of the receptor by providing conformational restraint [32, 103]. PEGPEI polyplexes carrying the therapeutic gene pORF-hTRAIL were targeted with a protease-resistant retro-enantio C-end rule (CendR) peptide-binding neuropilin-1, which plays an important role in tumour angiogenesis, growth and metastasis [104]. Intravenous injection of the polyplexes significantly prolonged the survival time of intracranial U87 glioma-bearing mice from 25 to 30 days. Epidermal growth factor receptor (EGFR)-targeted intratumoural delivery of the synthetic antiproliferative double-stranded RNA polyinosine-cytosine (poly IC) formulated with PEI-PEG-EGF [105–107] induced the complete regression of intracranial tumours in mice, with no obvious adverse toxic effects on normal brain tissue [105]. Several preclinical studies explore the delivery of siRNAs to target genes involved in gliomagenesis, tumour progression and therapy resistance of glial tumours [99]. Tumour growth inhibition and prolonged survival of animals was found after both local application [108–114] and systemic injection [115–120] of siRNA nanoparticles (Table 9.1). Another potentially promising target for glioma-directed delivery of therapeutics is the proangiogenic apelin receptor (APLNR) and its cognate ligand apelin, which play a central role in controlling glioblastoma vascularisation [121]. Apelin and APLNR were found to be dramatically upregulated in glioblastoma-associated microvascular proliferations, but not in the healthy brain [122].
Risk modelling further implicates the angiogenesis pathway in anterior cruciate ligament ruptures
Published in European Journal of Sport Science, 2022
Masouda Rahim, Miguel Lacerda, Malcolm Collins, Michael Posthumus, Alison V. September
Interleukin-1, is involved in a variety of cellular activities, including cell proliferation and differentiation, angiogenesis and apoptosis. In particular, IL-1β, encoded by the IL1B gene, is a pro-inflammatory cytokine responsible for activating numerous downstream signalling cascades (Thampatty et al., 2007; Yang et al., 2005). IL-6, encoded by IL6, is a pleiotropic cytokine with both pro-inflammatory and anti-inflammatory effects. It acts on a wide range of tissues with roles in apoptosis, cell growth and differentiation, as well as angiogenesis. Elevated IL-6 expression was reported in tissues that undergo angiogenesis and IL-6 was also shown to induce VEGF levels to a similar degree as has been observed in hypoxic states (Cohen et al., 1996). IL-6 exerts its biological effects by binding and forming a complex with the interleukin-6 receptor (IL6R) and therefore the receptor may also play a necessary role in IL-6 induced angiogenesis.
Mortality in mechanically ventilated patients with COVID-19: a systematic review
Published in Expert Review of Medical Devices, 2021
Maria Tsikala Vafea, Raina Zhang, Markos Kalligeros, Evangelia K. Mylona, Fadi Shehadeh, Eleftherios Mylonakis
Tocilizumab. Hyperinflammation is believed to contribute to respiratory failure and ARDS [101]. With this rationale, tocilizumab, an interleukin-6 receptor antagonist, has been proposed for use in severe COVID-19. There were 12 studies reporting outcomes in patients with IMV with COVID-19 receiving tocilizumab [12, 36, 56, 61, 74, 75, 83, 86, 89, 94, 101, 104]. Among them, 3 studies reported mortality outcomes in 7, 14 and 28 days after tocilizumab administration and they ranged from 5.5% to 45.7%, with the highest mortality rate of the range reported in 28 days of follow up [61, 75, 104].