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Cell-penetrating peptides

Yuping Wei, Liang Ma, Liang Zhang, Xia Xu
An effective drug delivery system requires efficient drug uptake and release inside cancer cells. Here, we report a novel drug delivery system, in which paclitaxel (PTX) interacts with a novel cell penetrating peptide (CPP) through noncovalent interaction designed based on molecular simulations. This CPP/PTX complex confers high efficiency in delivering PTX into cancer cells not by endocytosis but by an energy-independent pathway. Once inside cells, the noncovalent interaction between PTX and the CPP may allow fast release of PTX within cells due to the direct translocation of CPP/PTX...
2017: International Journal of Nanomedicine
Shu Peng, Andrea Barba-Bon, Yu-Chen Pan, Werner M Nau, Dong-Sheng Guo, Andreas Hennig
Phosphorylation and dephosphorylation of peptides by kinases and phosphatases is essential for signal transduction in biological systems and many diseases involve abnormal activities of these enzymes. Herein, we introduce amphiphilic calixarenes as key components for supramolecular, phosphorylation-responsive membrane transport systems. Dye efflux experiments with liposomes demonstrated that calixarenes are highly active counterion activators for established cell-penetrating peptides with EC50 values in the low nanomolar range...
October 11, 2017: Angewandte Chemie
Yin Ren, Jessica E Sagers, Lukas D Landegger, Sangeeta N Bhatia, Konstantina M Stankovic
Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-based or small molecule therapeutics. Tumor-targeted delivery of small interfering RNA (siRNA) therapeutics provides a direct and effective means to interrogate targets while minimizing off-target effects. To establish a preclinical model for therapeutic inhibition of putative targets in VS, archived tumor specimens, fresh tumor cells derived from patients with sporadic VS, and an established schwannoma cell line were screened...
October 10, 2017: Scientific Reports
Héctor de Lucio, Ana María Gamo, Marta Ruiz-Santaquiteria, Sonia de Castro, Pedro A Sánchez-Murcia, Miguel A Toro, Kilian Jesús Gutiérrez, Federico Gago, Antonio Jiménez-Ruiz, María-José Camarasa, Sonsoles Velázquez
The objective of the current study was to enhance the proteolytic stability of peptide-based inhibitors that target critical protein-protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR) using a backbone modification strategy. To achieve this goal we carried out the synthesis, proteolytic stability studies and biological evaluation of a small library of α/β(3)-peptide foldamers of different length (from 9-mers to 13-mers) and different α→β substitution patterns related to prototype linear α-peptides...
September 21, 2017: European Journal of Medicinal Chemistry
Jinming Zhang, Yifeng Zheng, Xi Xie, Lan Wang, Ziren Su, Yitao Wang, Kam W Leong, Meiwan Chen
Although tumor-targeting nanovehicles for hepatocellular carcinoma (HCC) chemotherapy have attracted great research and clinic interest, the poor cancer penetration, inefficient cellular uptake, and slow intracellular drug release greatly compromise their therapeutic outcomes. In this work, a multifunctional mixed micellar system, consisting of glycyrrhetinic acid (GA) for specific liver-targeting, trans-activator of transcription (TAT) peptide for potent cell penetration, and pH-sensitive poly(β-amino ester) polymers for acidic-triggered drug release, was developed to provide HCC-targeting delivery and pH-triggered release of doxorubicin (DOX)...
October 10, 2017: Molecular Pharmaceutics
Jacques Lux, Alexander M Vezeridis, Kenneth Hoyt, Stephen Roy Adams, Amanda M Armstrong, Shashank R Sirsi, Robert Mattrey
Acute deep vein thrombosis (DVT) is the formation of a blood clot in the deep veins of the body that can lead to fatal pulmonary embolism. Acute DVT is difficult to distinguish from chronic DVT by ultrasound (US), the imaging modality of choice, and is therefore treated aggressively with anticoagulants, which can lead to internal bleeding. Here we demonstrate that conjugating perfluorobutane (PFB)-filled microbubbles (MBs) with thrombin-sensitive activatable cell-penetrating peptides (ACPP) could lead to the development of contrast agents that detect acute thrombosis with US imaging...
October 10, 2017: ACS Applied Materials & Interfaces
Yuqian Zhang, Weijun Xiu, Yiting Sun, Di Zhu, Qi Zhang, Lihui Yuwen, Lixing Weng, Zhaogang Teng, Lianhui Wang
The fast-developing field of nanotechnology provides unprecedented opportunities for the increasing demands of biomedicine, especially for cancer diagnostics and treatment. Here, novel multifunctional zero-dimensional-two-dimensional (0D-2D) RGD-QD-MoS2 nanosheets (NSs) with excellent fluorescence, photothermal conversion, and cancer-targeting properties were successfully prepared by functionalizing single-layer MoS2 NSs with fluorescent quantum dots (QDs) and arginine-glycine-aspartic (RGD) containing peptides...
October 10, 2017: Nanoscale
Sanne van Lith, Dirk van den Brand, Rike Wallbrecher, Sander van Duijnhoven, Roland Brock, William Leenders
Overexpression of (mutated) receptor tyrosine kinases is a characteristic of many aggressive tumors and induction of receptor uptake has long been recognized as a therapeutic modality. A conjugate of a synthetically produced cell penetrating peptide, corresponding to amino acids 38-59 of human lactoferrin, and the recombinant llama single-domain antibody (VHH) 7D12 that binds the human epidermal growth factor receptor (EGFR), was generated via sortase A-mediated transpeptidation. The conjugate blocks EGF-mediated EGFR activation with higher efficacy than both modalities alone, a phenomenon that is caused by both effective receptor blockade and internalization...
October 10, 2017: Chembiochem: a European Journal of Chemical Biology
Rok Razpotnik, Neža Novak, Vladka Čurin Šerbec, Uros Rajcevic
Antibodies have been shown to be a potent therapeutic tool. However, their use for targeting brain diseases, including neurodegenerative diseases and brain cancers, has been limited, particularly because the blood-brain barrier (BBB) makes brain tissue hard to access by conventional antibody-targeting strategies. In this review, we summarize new antibody therapeutic approaches to target brain tumors, especially malignant gliomas, as well as their potential drawbacks. Many different brain delivery platforms for antibodies have been studied such as liposomes, nanoparticle-based systems, cell-penetrating peptides (CPPs), and cell-based approaches...
2017: Frontiers in Immunology
Colin Fadzen, Justin Wolfe, Choi-Fong Cho, E Antonio Chiocca, Sean Lawler, Bradley L Pentelute
Here we describe the utility of peptide macrocyclization through perfluoroaryl-cysteine SNAr chemistry in facilitating crossing the blood-brain barrier. Multiple macrocyclic analogues of the peptide transportan-10 were investigated that displayed increased uptake in two different cell lines and improved proteolytic stability. One of these analogues (M13) exhibited substantially increased delivery across a cellular spheroid model of the blood-brain barrier. Through in vivo and ex vivo imaging of mouse brains, we demonstrate that this perfluoroarene-based macrocycle of TP10 exhibits increased penetration of the brain parenchyma following intravenous administration in mice...
October 9, 2017: Journal of the American Chemical Society
Kenji Suda, Tatsuya Murakami, Norimoto Gotoh, Ryosuke Fukuda, Yasuhiko Hashida, Mitsuru Hashida, Akitaka Tsujikawa, Nagahisa Yoshimura
Age-related macular degeneration (AMD), in which choroidal neovascularization (CNV) affects the center of the retina (macula), leads to the irreversible visual loss. The intravitreal injection of anti-angiogenesis antibodies improved the prognosis of AMD, but relatively less invasive therapies should be explored. In the present study, we show that a high-density lipoprotein (HDL) mutant is a therapeutically active drug carrier capable of treating a posterior eye disease in mice via instillation. Various HDL mutants were prepared with apoA-I proteins fused with different cell-penetrating peptides (CPPs) and phospholipids with different alkyl chain lengths; their sizes were further controlled in the range of 10-25nm...
October 5, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
Elena Britti, Fabien Delaspre, Anat Feldman, Melissa Osborne, Hagar Greif, Jordi Tamarit, Joaquim Ros
Friedreich ataxia (FA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein. As there is no cure available for this disease, many strategies have been developed to reduce the deleterious effects of such deficiency. One of these approaches is based on delivering frataxin to the tissues by coupling the protein to trans-activator of transcription (TAT) peptides, which enables cell membranes crossing. In this study, we tested the efficiency of TAT-MTScs-FXN fusion protein to decrease neurodegeneration markers on frataxin-depleted neurons obtained from dorsal root ganglia (DRG), one of the most affected tissues...
October 5, 2017: Journal of Cellular and Molecular Medicine
Muhammad Jan Akhunzada, Balasubramanian Chandramouli, Nicholus Bhattacharjee, Sara Macchi, Francesco Cardarelli, Giuseppe Brancato
It is widely accepted that endocytosis mediates the uptake of cationic cell penetrating peptides (CPPs) at relatively low concentrations (i.e. nano- to micromolar), while direct transduction across the plasma membrane comes into play at higher concentrations (i.e. micro- to millimolar). This latter process appears to depend on peptide-driven cellular processes, which in turn may induce local perturbations of plasma-membrane composition and/or integrity, and to be favored by peptide aggregation, especially into dimers...
October 5, 2017: Physical Chemistry Chemical Physics: PCCP
Thekkuttuparambil Ananthanarayanan Ajith
Advances in understanding and manipulating genes have set the stage for scientists to alter a person's genetic material to prevent or treat diseases. Over the past decade, somatic gene therapy has been increasingly applied in clinical trials where the genetic material (DNA and RNA) introduced into a person's cell. Mutation and inactivation of the tumor suppressor genes are the unified concept of the development of tumor in humans. Therefore, researchers have discovered potential of gene therapies in the treatment of cancer...
September 2017: Journal of Experimental Therapeutics & Oncology
Qilin Yu, Bing Zhang, Jianrong Li, Mingchun Li
Graphene oxide (GO) nanosheets grafted with actin targeting and cell penetrating peptides were designed. The nanosheets were able to severely disrupt the organization of the tumor actin cytoskeleton, exhibiting excellent antitumor activity and high tumor specificity. This study implies the favorable potential of cancer therapies targeting the actin cytoskeleton.
October 4, 2017: Chemical Communications: Chem Comm
Prashant Sharma, Hyun Ah Cho, Jae-Won Lee, Woo Seung Ham, Bum Chul Park, Nam-Hyuk Cho, Young Keun Kim
Zinc oxide (ZnO) nanocomposites have been widely applied in biomedical fields due to their multifunctionality and biocompatibility. However, the physicochemical properties of ZnO nanocomposite involved in nano-bio interactions are poorly defined. To assess the potential applicability of ZnO nanowires for intracellular delivery of biomolecules, we examined the dynamics of cellular activity of cells growing on densely packed ZnO nanowire arrays with two different physical conformations, vertical (VNW) or fan-shaped (FNW) nanowires...
October 4, 2017: Nanoscale
Moataz Dowaidar, Maxime Gestin, Carmine Pasquale Cerrato, Mohammed Hakim Jafferali, Helerin Margus, Paula Ann Kivistik, Kariem Ezzat, Einar Hallberg, Margus Pooga, Mattias Hällbrink, Ülo Langel
Cell-penetrating peptides (CPPs) uptake mechanism is still in need of more clarification to have a better understanding of their action in the mediation of oligonucleotide transfection. In this study, the effect on early events (1 h treatment) in transfection by PepFect14 (PF14), with or without oligonucleotide cargo on gene expression, in HeLa cells, have been investigated. The RNA expression profile was characterized by RNA sequencing and confirmed by qPCR analysis. The gene regulations were then related to the biological processes by the study of signaling pathways that showed the induction of autophagy-related genes in early transfection...
October 3, 2017: Scientific Reports
Jiaying Zhao, Fufeng Liu, Chunhui Huang, Jieyi Shentu, Minjun Wang, Chenkai Sun, Liping Chen, Sicheng Yan, Fang Fang, Yuanyuan Wang, Shujun Xu, C Benjamin Naman, Qinwen Wang, Shan He, Wei Cui
The oligomer of β-amyloid (Aβ) is considered the main neurotoxin in Alzheimer's disease (AD). Therefore, the inhibition of the formation of Aβ oligomer could be a target for AD therapy. In this study, with the help of the dot blotting assay and transmission electronic microscopy, it was have discovered that 5-hydroxycyclopenicillone, a cyclopentenone recently isolated from a sponge-associated fungus, effectively reduced the formation of Aβ oligomer from Aβ peptide in vitro. Molecular dynamics simulations suggested hydrophobic interactions between 5-hydroxycyclopenicillone and Aβ peptide, which might prevent the conformational transition and oligomerization of Aβ peptide...
October 1, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Jing Yu, Lei Sun, Jinge Zhou, Lipeng Gao, Lijuan Nan, Shimin Zhao, Ting Peng, Lin Han, Jing Wang, Weiyue Lu, Lin Zhang, Yiting Wang, Zhiqiang Yan, Lei Yu
To enhance the tumor-penetrating ability and targeting therapeutic effect of polymer-drug conjugates (PDCs), tumor-penetrating peptide RGERPPR (RGE) modified and PEGylated poly(l-γ-glutamylglutamine)-paclitaxel (PGG-PTX) nanoparticles (RGE-PEG/PGG-PTX NPs) were prepared by using a so-called "modular" design strategy. In brief, a RGERPPR-conjugated targeting material, DSPE-PEG-RGERPPR, was first synthesized and assembled with PGG-PTX into RGE-PEG/PGG-PTX NPs based on the hydrophobic interaction between the groups of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and PTX...
October 10, 2017: Bioconjugate Chemistry
A M McKeon, J Noonan, M Devocelle, B M Murphy, D M Griffith
Novel Pt(iv) tumour penetrating peptide (TPP) conjugates are reported. They are the first example of metallodrugs to target a membrane bound heat shock protein 70 positive (memHSP70+) phenotype in cancer cells. The conjugates exhibit superior cytotoxicity as compared to oxaliplatin alone in Pt resistant colorectal cancer cells with relatively high memHSP70+ expression. Substitution of TPP in Pt(iv) peptide conjugates with scrambled peptide (ScP) essentially abolishes the observed cytotoxicity.
October 12, 2017: Chemical Communications: Chem Comm
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