NRP1 transport of cancer therapeutics mediated by tumor-penetrating
                        peptides

Leng, Qixin; Woodle, Martin C.; Mixson, A. James

doi:10.1358/dof.2017.042.02.2564106

Cited by 12 publications

(10 citation statements)

References 51 publications

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“…Moreover, high NRP1 expression levels were associated to the survival time of patients with various types of tumors. Therefore, the present data indicated a pro-carcinogenic effect of NRP1 in tumors, which was also supported by previous studies ( 10 , 33 ).…”

Section: Discussionsupporting

confidence: 93%

Effects of NRP1 on angiogenesis and vascular maturity in�endothelial cells are dependent on the expression of SEMA4D

et al. 2020

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Angiogenesis and vascular maturation play important roles in tumorigenesis and tumor development. The expression of neuropilin 1 (NRP1) is closely associated with angiogenesis in tumors; however, the molecular mechanisms of action in angiogenesis and tumor maturation, as well as the potential clinical value of NRP1 remain unclear. The importance of NRP1 expression in tumor progression was determined using The Cancer Genome Atlas (TCGA) database analysis. Gain- and loss-of-function experiments of NRP1 were performed in vascular endothelial cells (ECs) to investigate the functions in angiogenesis. CCK-8, flow cytometry, Transwell experiments and a series of in vitro experiments were used to detect cell functions. A combination of angiogenesis antibody arrays and RNA-Seq analyses were performed to reveal the proangiogenic mechanisms of action. The function of semaphorin 4D (SEMA4D) was also investigated separately. NRP1 mRNA levels were significantly increased in primary tumors compared with normal tissues based on TCGA data (P<0.01) and were associated with tumor development in patients. Gain- and loss-of-function experiments highlighted the function of NRP1 in promoting EC proliferation, motility and capillary-like tube formation and in reducing apoptosis. NRP1 overexpression led to significantly decreased EC markers (PECAM-1, angiogenin, PIGF and MMP-9) expression levels and reduced the vascular maturity. MAPK7, TPM1, RRBP1, PTPRK, HSP90A, PRKD2, PFKFB3, RGS4 and SPARC were revealed to play important roles in this process. SEMA4D was revealed to be a key protein associated with NRP1 in ECs. These data indicated that NRP1-promoted angiogenesis may be induced at the cost of reducing maturity of the ECs. NRP1 may also be a therapeutic target for antiangiogenic strategies and a candidate prognostic marker for tumors.

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Section: Discussionsupporting

confidence: 93%

Effects of NRP1 on angiogenesis and vascular maturity in�endothelial cells are dependent on the expression of SEMA4D

et al. 2020

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“…The NRP1-binding motif has been harnessed to generated peptides that are directed to and penetrate into the tumor. Such NRP1-specific tumor targeting peptides effectively enhance the uptake of various therapeutic agents [377]. These peptides follow the C-end rule (CendR) with the consensus sequence R/KXXR/K, which shows optimum binding affinity when two non-basic amino acids are between the flanking R/K [40,378].…”

Section: Nrp As a Therapeutic Targetmentioning

confidence: 99%

“…The risk that tumor-penetrating peptides might also promote the spread of metastases by inducing increased vascular permeability at the tumor site, in addition to improved drug permeation, appears to be limited, as they not only not increased metastasis but also reduced them [377,395,396]. Moreover, there is no evidence that systemically administered tumor-penetrating peptides affect the vasculature of normal tissues [377].…”

Section: Nrp As a Therapeutic Targetmentioning

confidence: 99%

Neuropilins in the Context of Tumor Vasculature

Niland

Eble

2019

IJMS

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Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, they critically modulate the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. This review highlights the diverse neuropilin ligands and interacting partners on endothelial cells, which are relevant in the context of the tumor vasculature and the tumor microenvironment. In addition to tumor cells, the latter contains cancer-associated fibroblasts, immune cells, and endothelial cells. Based on the prevalent neuropilin-mediated interactions, the suitability of various neuropilin-targeted substances for influencing tumor angiogenesis as a possible building block of a tumor therapy is discussed.

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“…A potential target for achieving the specificity is the neuropilin-1 (NRP-1) transport system. NRP-1 is expressed in most tissues; however, it is upregulated in angiogenic tumor blood vessels (including brain endothelial cells) and usually in tumor cells. , Furthermore, it was reported that NRP-1 is overexpressed in gliomas and NRP-1 expression is increased with the elevation of glioma grade . NRP-1 is a transmembrane glycoprotein with multiple domains.…”

Section: Introductionmentioning

confidence: 99%

Cellular Internalization and Inhibition Capacity of New Anti-Glioma Peptide Conjugates: Physicochemical Characterization and Evaluation on Various Monolayer- and 3D-Spheroid-Based in Vitro Platforms

et al. 2021

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Most therapeutic agents used for treating brain malignancies face hindered transport through the blood−brain barrier (BBB) and poor tissue penetration. To overcome these problems, we developed peptide conjugates of conventional and experimental anticancer agents. SynB3 cell-penetrating peptide derivatives were applied that can cross the BBB. Tuftsin derivatives were used to target the neuropilin-1 transport system for selectivity and better tumor penetration. Moreover, SynB3-tuftsin tandem compounds were synthesized to combine the beneficial properties of these peptides. Most of the conjugates showed high and selective efficacy against glioblastoma cells. SynB3 and tandem derivatives demonstrated superior cellular internalization. The penetration profile of the conjugates was determined on a lipid monolayer and Transwell co-culture system with noncontact HUVEC-U87 monolayers as simple ex vivo and in vitro BBB models. Importantly, in 3D spheroids, daunomycin-peptide conjugates possessed a better tumor penetration ability than daunomycin. These conjugates are promising tools for the delivery systems with tunable features.

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NRP1 transport of cancer therapeutics mediated by tumor-penetrating peptides

Cited by 12 publications

References 51 publications

Effects of NRP1 on angiogenesis and vascular maturity in�endothelial cells are dependent on the expression of SEMA4D

Effects of NRP1 on angiogenesis and vascular maturity in�endothelial cells are dependent on the expression of SEMA4D

Neuropilins in the Context of Tumor Vasculature

Cellular Internalization and Inhibition Capacity of New Anti-Glioma Peptide Conjugates: Physicochemical Characterization and Evaluation on Various Monolayer- and 3D-Spheroid-Based in Vitro Platforms

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