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Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Thomas J. Anchordoquy, Yechezkel Barenholz, Diana Boraschi, Michael Chorny, Paolo Decuzzi, Marina A. Dobrovolskaia, Z. Shadi Farhangrazi, Dorothy Farrell, Alberto Gabizon, Hamidreza Ghandehari, Biana Godin, Ninh M. La-Beck, Julia Ljubimova, S. Moein Moghimi, Len Pagliaro, Ji-Ho Park, Dan Peer, Erkki Ruoslahti, Natalie J. Serkova, Dmitri Simberg
Several strategies to improve tumor penetration of compounds have been discussed. An approach to boost tumor permeability by tumor-penetrating peptides was presented. These peptides bind to a primary receptor specific for tumor blood vessels, tumor cells, and stroma, then undergo proteolytic cleavage and shift their affinity from the primary receptor to neuropilin-1. Binding to neuropilin-1 subsequently activates an endocytic/exocytic trans-tissue transport pathway, leading to a transient increase in tumor penetration of nanoparticles and small-molecule drugs [15]. This mechanism works especially well in starved tumors due to dependence of the transport process on metabolism.
Human T lymphotropic virus type 1 (HTLV-1)
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
HTLV-1 is a retrovirus in the genus Deltaretrovirus, subfamily Orthoretrovirinae. Risk of transmission increases with number of exposures and depends on the route of transmission, infectivity of the donor, and susceptibility of the recipient. Routes of exposure and their risk of transmission include: Non-leukocyte depleted blood transfusion (8.6%–64%), sharing needles and syringes (presumed high), breastfeeding (22%), transplacental exposure (3%–5%) and unprotected sexual intercourse (1% per year) [7]. Cell-free blood product transmission risk is negligible, and therefore direct cell-to-cell contact is a presumed requirement for virus transmission. The virologic synapse that enables cell to cell transmission between HTLV-1 infected and uninfected cells is likely mediated by the glucose transporter 1 (GLUT-1), heparin sulfate proteoglycans (HSPG), and neuropilin 1 (NRP-1). Investigations continue in fully characterizing viral transmission [10,11].
Antiangiogenic Therapy for Lung Cancer: Small-Molecule Inhibitors
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
VEGF levels are also influenced by proto-oncogenes such as ras and met. Mutant ras can increase VEGF levels in tumors (7). Similarly, stimulation of met and erbB-2 pathways can enhance production of VEGF. It has been shown that blocking the receptor tyrosine kinases (RTKs) in these pathways (e.g., met and erbB-2) or blocking the proteins encoded (e.g., Ras farnesyl transferase inhibitors) can decrease VEGF levels, thereby showing that these therapies can be both antiproliferative and antiangiogenic (8,9). VEGF regulates several endothelial cell functions, including proliferation, differentiation, permeability, vascular tone, and the production of vasoactive molecules. VEGF ligands act through specific binding to three different cell membrane receptors: VEGFR-1 (Flt-1), VEGFR-2 (Flk/KDR), and VEGFR-3 (Flt-4) (10). These receptors consist of an extracellular domain that binds specific VEGF ligands, a transmembrane domain, and an intracellular region that contains a tyrosine kinase domain. In addition, neuropilin 1 (NRP-1) and NRP-2 are coreceptors for specific isoforms of VEGF family members and increase the binding affinity of these ligands to their respective receptors (11).
Advances in molecular therapies for targeting pathophysiology in spinal cord injury
Published in Expert Opinion on Therapeutic Targets, 2023
Ha Neui Kim, Madeline R. McCrea, Shuxin Li
Neuropilin-1, a membrane-bound coreceptor to a tyrosine kinase receptor for VEGF and semaphorin, might contribute to the pruning of neuronal collaterals for motor recovery after partial SCI. Neuropilin-1 knockdown or deletion by local AAV vectors suppressed the recovery of skilled movement 3 and 4 weeks after hemisection SCI in mice [170]. An interesting study reported a synthetic synaptic organizer called CPTX which combined structural elements from cerebellin-1 and neuronal pentraxin-1 [171]. CPTX could interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induce the formation of excitatory synaptic links across the synaptic gap, thus restoring neuronal reconnections. They reported that local CPTX could rapidly induce the formation of excitatory synapses and functionally restore neuronal circuits for functional recovery in several mouse models, including SCI, ataxia, and Alzheimer’s disease.
Ganoderma lucidum polysaccharides ameliorate lipopolysaccharide-induced acute pneumonia via inhibiting NRP1-mediated inflammation
Published in Pharmaceutical Biology, 2022
Xuelian Zhang, Daoshun Wu, Yu Tian, Xiangdong Chen, Jin Lan, Fei Wei, Ye Li, Yun Luo, Xiaobo Sun
Neuropilin-1 (NRP1), an encoded transmembrane protein, is expressed in many human tissues, notably in the lung (Saiz et al. 2021). In addition, NRP1 is a surface receptor found on cancer cells, immune cells and many other cell types (Chuckran et al. 2020; Liu et al. 2020). Mainly, it has been reported that NRP1 was found to be effective in diverse immune cells, including macrophages, dendritic cells and T cell subpopulations, which indicated the vital effect of NRP1 on the regulation of immune response as well as respiratory diseases (Tordjman et al. 2002; Roy et al. 2017; Wilson Ariel et al. 2018). Notably, it has been reported that SARS-CoV-2 Spike protein can bind to the b1b2 domain of NRP1, and NRP1 is an essential mediator to assist the entry of SARS-CoV-2 into normal cells and lead to cell infectivity (Cantuti-Castelvetri et al. 2020; Daly James et al. 2020). At present, the inhibition of NRP1 expression is considered an effective strategy for blocking viral infectivity and spreading (Kolarič et al. 2022).
VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy
Published in Annals of Medicine, 2022
Alessandro Arrigo, Emanuela Aragona, Francesco Bandello
With respect to the neovascular complication, the increased production and release of VEGF activates endothelial cell proliferation and migration, thus promoting neoangiogenesis [53]. Indeed, VEGF molecules activate two tyrosine kinase receptors, namely VEGFR-1 and VEGFR-2, stimulating endothelial proliferation, migration, and survival, thus promoting the progression to PDR [54]. Also in this case, VEGF acts as a major cause of DR-related neovascular process, although being just a part of a more complex pathogenic pathway. Indeed, it was demonstrated that angiopoietin system, over than regulating vascular integrity, it can promote and enhance the effect of VEGF neovascular stimulus [55]. Furthermore, neuropilin-1 (NRP1) was found to act as an isoform-specific receptor for VEGF165 and as a co-receptor of VEGF receptor 2 [56]. In addition, another system implicated on DR pathogenesis and on the enhancement of the neovascular stimulus provided by VEGF is the renin/angiotensin system. Indeed, the severity of DR, expressed both as the rate of progression of NPDR or the progression to PDR, were found strictly related to the activity of the renin/angiotensin system [57].