Tumour lineage-homing cell-penetrating peptides as anticancer molecular delivery systems

Kondo, Eisaku; Saito, Ken; Tashiro, Yuichi; Kamide, Kaeko; Uno, Shusei; Furuya, Tomoko; Mashita, Masao; Nakajima, Kiichiro; Tsumuraya, Tomoyuki; Kobayashi, Naoya; Nishibori, Masahiro; Tanimoto, Mitsune; Matsushita, Masayuki

doi:10.1038/ncomms1952

Cited by 132 publications

(130 citation statements)

References 25 publications

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“…Tumor targeting peptides represent a promising new class of prognostic tools due to their advantageous biodistribution with fast body clearance and their capacity to effectively penetrate viable cells (1)(2)(3). However, it is essential that such probes exhibit specific binding to tumor cells and exclude normal tissue.…”

Section: Introductionmentioning

confidence: 99%

SelectiveIn VivoImaging of Syngeneic, Spontaneous, and Xenograft Tumors Using a Novel Tumor Cell–Specific Hsp70 Peptide-Based Probe

et al. 2014

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Although in vivo targeting of tumors using fluorescently labeled probes has greatly gained in importance over the last few years, most of the clinically applied reagents lack tumor cell specificity. Our novel tumor cell-penetrating peptide-based probe (TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface of a broad variety of human and mouse tumors and metastases, but not on normal tissues. Because of the rapid turnover rate of membrane Hsp70, fluorescently labeled TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically induced and xenograft tumors following intravenous administration, thereby enabling site-specific labeling of primary tumors and metastases. In contrast with the commercially available nonpeptide small molecule a v b 3 -integrin antagonist IntegriSense, TPP exhibits a significantly higher tumor-to-background contrast and stronger tumor-specific signal intensity in all tested tumor models. Moreover, in contrast with IntegriSense, TPP reliably differentiates between tumor cells and cells of the tumor microenvironment, such as tumor-associated macrophages and fibroblasts, which were found to be membrane-Hsp70 negative. Therefore, TPP provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. TPP might also be a promising platform for tumor-specific drug delivery and other Hsp70-based targeted therapies. Cancer Res; 74(23); 6903-12. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

SelectiveIn VivoImaging of Syngeneic, Spontaneous, and Xenograft Tumors Using a Novel Tumor Cell–Specific Hsp70 Peptide-Based Probe

et al. 2014

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“…We selected two representative peptide spacers (GA and RVRR) as different spacer elements based on the original peptide of P a (Table 1) and verified whether these changes would affect the formulation and transfection efficiency of Q-complexes. In addition, we inhibited the intercellular uptake pathways, mainly including the CD44 mediating and dynamin-dependent pathways that HA and the tumor cell-penetrating peptide (KMPNWTYRFRMT-PRK) specifically depended on, 13 respectively. Q-complexes were hypothesized to achieve intracellular delivery through multifunctional peptide completely wrapping nucleic acids and strongly penetrating specific tumor cell lines.…”

Section: Discussionmentioning

confidence: 94%

“…This result showed that the internalization pathway of these nanocomplexes was mainly dynamin-dependent, thereby reflecting a strong penetrating ability of the peptide component in the nanoparticles. 13 The internalization mechanism of most LPD and HLPD was also partly both clathrin-20 ( Figure 7C) and macropinocytosis-dependent 21 ( Figure 7D) pathways. We further investigated the intracellular paths of Q-complexes observed through confocal microscopy ( Figure 8).…”

mentioning

confidence: 98%

“…The ternary complex was associated with negatively charged HA and formulated quaternary complexes (HLPD, also named as Q-complexes). Specifically, we applied a hepatic tumorspecific cell-penetrating peptide (KRPTMRFRYTWNPMK) 13 to polyarginine 16 (R 16 ) in the absence or presence of spacer to create a multifunctional peptide, which could specifically permeate hepatic tumor cells and tightly condense nucleic acids. The HA coated at the surface of ternary complexes is in charge of shielding the negative charge of the nanoparticle surface, as well as the oriented binding to the tumor tissues and cells because HA actively targets receptors (such as CD44) distributed on the surfaces of the tumor cells.…”

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confidence: 99%

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Effect of inserted spacer in hepatic cell-penetrating multifunctional peptide component on the DNA intracellular delivery of quaternary complexes based on modular design

Zhang¹,

Li²,

Sun³

et al. 2016

IJN

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“…At the molecular level, we elucidated a novel cell-specific function of NFATc1/β isoforms as triggers for the release of BCL6-dependent transcriptional repression. The interplay between NFATc1 and BCL6 defines a novel molecular target for the design of cell-type specific antagonists [44] that control the CCL2/CCR2 axis in chronic inflammations. Inhibitors of interaction between both factors could provide alternatives to the current therapy regimens in transplantation medicine.…”

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confidence: 99%

NFATc1 releases BCL6‐dependent repression of CCR2 agonist expression in peritoneal macrophages from Saccharomyces cerevisiae infected mice

et al. 2016

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The link between the extensive usage of calcineurin (CN) inhibitors cyclosporin A and tacrolimus (FK506) in transplantation medicine and the increasing rate of opportunistic infections within this segment of patients is alarming. Currently, how peritoneal infections are favored by these drugs, which impair the activity of several signaling pathways including the Ca ++ /CN/NFAT, Ca ++ /CN/cofilin, Ca ++ /CN/BAD, and NF-κB networks, is unknown. Here, we show that Saccharomyces cerevisiae infection of peritoneal resident macrophages triggers the transient nuclear translocation of NFATc1β isoforms, resulting in a coordinated, CN-dependent induction of the Ccl2, Ccl7, and Ccl12 genes, all encoding CCR2 agonists. CN inhibitors block the CCR2-dependent recruitment of inflammatory monocytes (IM) to the peritoneal cavities of S. cerevisiae infected mice. In myeloid cells, NFATc1/β proteins represent the most prominent NFATc1 isoforms. NFATc1/β ablation leads to a decrease of CCR2 chemokines, impaired mobilization of IMs, and delayed clearance of infection. We show that, upon binding to a composite NFAT/BCL6 regulatory element within the Ccl2 promoter, NFATc1/β proteins release the BCL6-dependent repression of Ccl2 gene in macrophages. These findings suggest a novel CN-dependent cross-talk between NFAT and BCL6 transcription factors, which may affect the outcome of opportunistic fungal infections in immunocompromised patients.Keywords: BCL6 r CCL2 r CCR2 r Inflammatory monocytes r NFATc1 r Opportunistic infection Additional supporting information may be found in the online version of this article at the publisher's web-site [4,5]. Although ablation of CN-B compromises neutrophil-dependent killing of fungal pathogens ex vivo [6], it is still not completely clear how CsA and FK506 facilitate fungal and other opportunistic infections. We will show here that in peritoneal macrophages CsA and FK506 inhibit the synthesis of chemokines that attract neutrophils and inflammatory monocytes (IMs) to the site of infection.Tissue-specific resident macrophages [7] are key components of the heterogeneous mononuclear phagocyte system, which is defined on the basis of common ontogeny and phagocytic activity [8]. The mononuclear phagocyte system provides the first line of innate immune responses against invading pathogens. In the peritoneal cavity, resident macrophages constitute the largest population of phagocytotic cells. However, the successful clearance of peritoneal infections critically depends on the rapid recruitment of neutrophils and IMs [9] from a specific shortlived CX 3 CR1 lo CCR2 + subset of peripheral blood monocytes [10].Peritoneal infections trigger the release of several CCR2-specific chemokines from peritoneal resident macrophages (prM ), such as CCL2, CCL7, and CCL13. However, significantly reduced numbers of recruited IMs and the inability to control toxoplasmosis in mice deficient for CCL2 or CCR2 suggest a critical nonredundant role for the CCR2/CCL2 axis in the clearance of peritoneal infections [11,12]. Aberrant...

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Tumour lineage-homing cell-penetrating peptides as anticancer molecular delivery systems

Cited by 132 publications

References 25 publications

SelectiveIn VivoImaging of Syngeneic, Spontaneous, and Xenograft Tumors Using a Novel Tumor Cell–Specific Hsp70 Peptide-Based Probe

SelectiveIn VivoImaging of Syngeneic, Spontaneous, and Xenograft Tumors Using a Novel Tumor Cell–Specific Hsp70 Peptide-Based Probe

Effect of inserted spacer in hepatic cell-penetrating multifunctional peptide component on the DNA intracellular delivery of quaternary complexes based on modular design

NFATc1 releases BCL6‐dependent repression of CCR2 agonist expression in peritoneal macrophages from Saccharomyces cerevisiae infected mice

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