Cell-penetrating peptide (CPP)

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Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system

Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system

Abstract: As a potent therapeutic agent, small interfering RNA (siRNA) has been exploited to silence critical genes involved in tumor initiation and progression. However, development of a desirable delivery system is required to overcome the unfavorable properties of siRNA such as its high degradability, molecular size, and negative charge to help increase its accumulation in tumor tissues and promote efficient cellular uptake and endosomal/lysosomal escape of the nucleic acids. In this study, we developed a new activatable cell-penetrating peptide (ACPP) that is responsive to an acidic tumor microenvironment, which was then used to modify the surfaces of siRNA-loaded liposomes. The ACPP is composed of a cell-penetrating peptide (CPP), an acid-labile linker (hydrazone), and a polyanionic domain, including glutamic acid and histidine. In the systemic circulation (pH 7.4), the surface polycationic moieties of the CPP (polyarginine) are “shielded” by the intramolecular electrostatic interaction of the inhibitory domain. When exposed to a lower pH, a common property of solid tumors, the ACPP undergoes acid-catalyzed breakage at the hydrazone site, and the consequent protonation of histidine residues promotes detachment of the inhibitory peptide. Subsequently, the unshielded CPP would facilitate the cellular membrane penetration and efficient endosomal/lysosomal evasion of liposomal siRNA. A series of investigations demonstrated that once exposed to an acidic pH, the ACPP-modified liposomes showed elevated cellular uptake, downregulated expression of polo-like kinase 1, and augmented cell apoptosis. In addition, favorable siRNA avoidance of the endosome/lysosome was observed in both MCF-7 and A549 cells, followed by effective cytoplasmic release. In view of its acid sensitivity and therapeutic potency, this newly developed pH-responsive and ACPP-mediated liposome system represents a potential platform for siRNA-based cancer treatment.
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PEGylated enhanced cell penetrating peptide nanoparticles for lung gene therapy

PEGylated enhanced cell penetrating peptide nanoparticles for lung gene therapy

Developing successful airway gene therapy is complex as gene transfer agents must penetrate lung mucus and reach the airway epi- thelium prior to removal from the lung by mucociliary clearance (MCC) [12]. This navigation is even more challenging in CF lungs due to pa- thological alteration of mucus properties that makes this barrier even harder to penetrate [13]. CF sputum is a highly dense meshwork composed of mucin fibres, possessing negatively charged and hydro- phobic domains, and other adhesive macromolecules such as DNA fragments released from bacteria and endogenous cells [14]. As a consequence, particle diffusion is largely impeded within the mucus gel by steric obstruction and/or mucoadhesive interactions with sputum components. In particular, conventional non-viral gene vectors for- mulated with cationic materials possess positively charged surfaces and thus are readily trapped by negatively charged mucus via electrostatic interactions [15]. Furthermore, charged particles rapidly aggregate in physiological ionic environments, leading to entrapment within the mucus gel via steric obstruction [16]. It has previously been demon- strated that the modi fi cation of particle surfaces with a dense layer of poly(ethylene glycol) (PEG) inhibits particle aggregation as well as mucoadhesion, thereby leading to efficient mucus penetration of na- noparticles (NPs) [17, 18]. Importantly, due to their ability to penetrate airway mucus, PEGylated DNA NPs have been shown to provide widespread airway distribution, prolonged lung retention and ulti- mately a high-level transgene expression following inhalation [19 – 21]. The work presented here is based on novel modified cell penetrating peptide (CPP)-based gene vectors. Glycosaminoglycan (GAG)-binding enhanced transduction (GET) peptides are multi-domain sequences comprising of a heparan sulfate (HS) cell targeting sequence fused to a CPP for improved membrane association and synergistically enhanced intracellular delivery of therapeutic cargoes [22]. We have previously described GET peptides for improved delivery of a self-reporting cargo (monomeric red fluorescent protein; mRFP) in difficult-to-transduce cell types including mesenchymal stem cells (MSCs), human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). The GET-system has been utilised for a wide variety of applications from the spatio-temporal control of cell programming in hydrogel matrices to the delivery of runt-related transcription factor 2 (RUNX2) for osteogenesis of MSCs [23, 24]. Furthermore, GET-mRFP proteins have retained activity when encapsulated into poly(DL-lactic acid-co- glycolic acid) (PLGA) microparticles for controlled release and sus- tained delivery to cells over extended periods of time [25].
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In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

Abstract: In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX)-loaded novel cell-penetrating peptide (CPP)-modified pH-sensitive liposomes (CPPL) (referred to as CPPL(DOX)) with an opti- mal CPP density of 4%. In CPPL, a polyethylene glycol (PEG) derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate) was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p,0.01) and resulted in more cell apoptosis as a result of DNA disruption as well as a relatively lower tumor growth ratio (T/C%). Histological examination did not show any signs of necrosis or inflammation in normal tissues, but large cell dissolving areas were found in tumors following the treatment of animals with CPPL(DOX). Our findings provide important and detailed information regarding the distribution of CPPL(DOX) in vivo and reveal their abilities of tumor penetration and potential for the treatment of breast cancer. Keywords: tumor targeting, TUNEL stain, hemolysis, therapy for breast cancer, pharmaco- kinetics
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Cell-penetrating peptide conjugates of gambogic acid enhance the antitumor effect on human bladder cancer EJ cells through ROS-mediated apoptosis

Cell-penetrating peptide conjugates of gambogic acid enhance the antitumor effect on human bladder cancer EJ cells through ROS-mediated apoptosis

Purpose: The object of this study was to synthesize peptide-drug conjugates in which the cell- penetrating peptide TAT (trans-activator of transcription) was conjugated to GA and evaluated the anti-cancer activity of this GA-CPP conjugate (GA-TAT) in EJ bladder cancer cells. Methods: GA is built onto the TAT, and the GA-TAT conjugates are cleaved from the solid support and purified via HPLC. The equilibrium solubility of GA-TAT was measured using the shake-flask method. The effects of GA-TAT on EJ cell viability and proliferation were determined by MTT assay, Edu assay and colony formation assay, respectively. After treated with 1.0 μM GA-TAT for 24 h, the apoptosis rate of EJ cells were detected by Acridine orange/ ethidium bromide (AO/EB) assay and flow cytometry assay. The proteins of caspase-3 (pro- cessing), caspase-9 (processing), Bcl-2 and Bax were analyzed by Western blotting, and the intracellular reactive oxygen species (ROS) production was evaluated by a reactive oxygen species assay.
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Enhancing cellular uptake of activable cell-penetrating peptide–doxorubicin conjugate by enzymatic cleavage

Enhancing cellular uptake of activable cell-penetrating peptide–doxorubicin conjugate by enzymatic cleavage

Abstract: The use of activable cell-penetrating peptides (ACPPs) as molecular imaging probes is a promising new approach for the visualization of enzymes. The cell-penetrating function of a polycationic cell-penetrating peptide (CPP) is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a proteinase-sensitive substrate present between the CPP and polyanionic peptide affords dissociation of both domains and enables the activated CPP to enter cells. This ACPP strategy could also be used to modify antitumor agents for tumor-targeting therapy. Here, we aimed to develop a conjugate of ACPP with antitumor drug doxorubicin (DOX) sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for tumor-targeting therapy purposes. The ACPP-DOX conjugate was successfully synthesized. Enzymatic cleavage of ACPP-DOX conjugate by matrix metalloproteinase (MMP)-2/9 indicated that the activation of ACPP-DOX occurred in an enzyme concentration–dependent manner. Flow cytometry and laser confocal microscope studies revealed that the cellular uptake of ACPP-DOX was enhanced after enzymatic-triggered activation and was higher in HT-1080 cells (overexpressed MMPs) than in MCF-7 cells (under-expressed MMPs). The antiproliferative assay showed that ACPP had little toxicity and that ACPP-DOX effectively inhibited HT-1080 cell proliferation. These experiments revealed that the ACPP-DOX conjugate could be triggered by MMP-2/9, which enabled the activated CPP-DOX to enter cells. ACPP-DOX conjugate may be a potential prodrug delivery system used to carry antitumor drugs for MMP-related tumor therapy.
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A novel CAV derived cell-penetrating peptide efficiently delivers exogenous molecules through caveolae-mediated endocytosis

A novel CAV derived cell-penetrating peptide efficiently delivers exogenous molecules through caveolae-mediated endocytosis

Cell-penetrating peptide (CPP) is a promising cargo for delivering bioactive molecules. In this study, the N terminus of VP1 from chicken anemia virus, designated as CVP1, was found to carry enriched arginine residues with α-helix. By confocal imaging, flow cytometry and MTT assay, we identified CVP1 as a novel, safe and efficient CPP. CVP1-FITC peptide could entry different types of cells tested with dose dependence, but without cytotoxic effects. Compared with TAT-FITC peptide, the CVP1-FITC peptide showed much higher cell-penetrating activity. Moreover, CVP1 could successfully deliver β-glycosidase, poly (I:C) and plasmid into HCT116 cells. Inhibitors and temperature sensitivity analysis further indicated that the cell-penetrating activity of CVP1 was based on ATP-dependent and caveolae-medi- ated endocytosis. All these data demonstrate that CVP1 has efficient cell-penetrating activity and great potential for developing a novel delivery vector.
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Investigation of Cell-Penetrating Peptide Transformation in Two Regenerable Tissue Culture Systems

Investigation of Cell-Penetrating Peptide Transformation in Two Regenerable Tissue Culture Systems

With the availability of fully sequenced plant genomes there is more opportunity than ever to realize the potential of plant trait genetic modification. Traits important to agronomic growth, maturation, crop yield, and flowering can now be identified and manipulated (Bolger et al. 2014). Current plant transformation techniques can be used quite successfully in certain systems. However, the efficiency of said techniques differs across species, genotypes, and tissues (De Cleene and De Ley 1976, De Cleene 1985, Cheng et al. 2004). Novel plant transformation techniques are being developed to increase the efficiency of plant transformation, as well as the range of plants and tissues that can be transformed. Cell-penetrating peptide transformation is one such proposed technique. In animal systems, CPP transformation is quite developed, and has a wide demonstrated range of applicability (Sawant et al. 2006, Yang et al. 2014). The hope is to achieve the same level of success for CPP transformation in plants.
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pH Responsive Triblock Copolymeric Micelles Decorated with a Cell Penetrating Peptide Provide Efficient Doxorubicin Delivery

pH Responsive Triblock Copolymeric Micelles Decorated with a Cell Penetrating Peptide Provide Efficient Doxorubicin Delivery

Polyethyleneimine (PEI) is a synthetic cationic polymer with a high amine density that is employed in gene delivery because it promotes transfection [13]. PEI facili- tates drug release from the endosomal compartment and protects it from enzymatic degradation. The cytotoxic effect of low molecular-weight PEI can be reduced by conjugating it with biocompatible polymers or hydro- phobic moieties [13, 14]. Despite its common use in gene transfection, PEI can also be used in pH-responsive drug delivery systems. The amine groups in PEI will undergo protonation in acidic environments and the repulsive force between protonated amine groups will then result in a swollen micellar structure. This phenomenon will destabilize the micellar structure and eventually increase the release rates of loaded drugs [15]. The cationic peptide, poly- L -arginine (pArg), is a cell- penetrating peptide that translocates through cell mem- branes and facilitates cellular uptake. pArg has therefore been utilized in gene therapy [16], protein/vaccine delivery [17], and cancer treatment [18]. Recent studies reported that poly(amino acid)-based nanoparticles could also effectively translocate through cell membranes [19–22].
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Intracellular delivery of cell-penetrating peptide-transcriptional factor fusion protein and its role in selective osteogenesis

Intracellular delivery of cell-penetrating peptide-transcriptional factor fusion protein and its role in selective osteogenesis

Abstract: Protein-transduction technology has been attempted to deliver macromolecular materials, including protein, nucleic acids, and polymeric drugs, for either diagnosis or thera- peutic purposes. Herein, fusion protein composed of an arginine-rich cell-penetrating peptide, termed low-molecular-weight protamine (LMWP), and a transcriptional coactivator with a PDZ-binding motif (TAZ) protein was prepared and applied in combination with biomaterials to increase bone-forming capacity. TAZ has been recently identified as a specific osteogenic stimulating transcriptional coactivator in human mesenchymal stem cell (hMSC) differentia- tion, while simultaneously blocking adipogenic differentiation. However, TAZ by itself cannot penetrate the cells, and thus needs a transfection tool for translocalization. The LMWP-TAZ fusion proteins were efficiently translocalized into the cytosol of hMSCs. The hMSCs treated with cell-penetrating LMWP-TAZ exhibited increased expression of osteoblastic genes and protein, producing significantly higher quantities of mineralized matrix compared to free TAZ. In contrast, adipogenic differentiation of the hMSCs was blocked by treatment of LMWP-TAZ fusion protein, as reflected by reduced marker-protein expression, adipocyte fatty acid-binding protein 2, and peroxisome proliferator-activated receptor-γ messenger ribonucleic acid levels. LMWP-TAZ was applied in alginate gel for the purpose of localization and controlled release. The LMWP-TAZ fusion protein-loaded alginate gel matrix significantly increased bone formation in rabbit calvarial defects compared with alginate gel matrix mixed with free TAZ protein. The protein transduction of TAZ fused with cell-penetrating LMWP peptide was able selectively to stimulate osteogenesis in vitro and in vivo. Taken together, this fusion protein-transduction technology for osteogenic protein can thus be applied in combination with bio materials for tissue regeneration and controlled release for tissue-engineering purposes.
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Synthesis, DNA-Binding and Antibacterial Activity of the Cell-Penetrating Peptide HIV-1 Tat (49-57)

Synthesis, DNA-Binding and Antibacterial Activity of the Cell-Penetrating Peptide HIV-1 Tat (49-57)

The interaction of cell-penetrating peptide human immunodeficiency virus transacting activator of transcription, peptide Tat (49-57), which is the minimal transduction domain of human immunodeficiency virus Tat protein, with calf thymus DNA was investigated with UV/Vis spectroscopy, fluorescence spectroscopy, circular dichroism, and viscometry. Peptide Tat (49-57) could interact with DNA via the groove binding mode, which is accompanied with electrostatic interaction. The fluorescence experiments revealed that the binding constant was 2.63×10 5 l×mol −1 . The UV/Vis spectroscopy and
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The effect of dexamethasone/cell-penetrating peptide nanoparticles on gene delivery for inner ear therapy

The effect of dexamethasone/cell-penetrating peptide nanoparticles on gene delivery for inner ear therapy

Abstract: Dexamethasone (Dex)-loaded PHEA-g-C18-Arg8 (PCA) nanoparticles (PCA/Dex) were developed for the delivery of genes to determine the synergistic effect of Dex on gene expression. The cationic PCA nanoparticles were self-assembled to create cationic micelles containing an octadecylamine (C18) core with Dex and an arginine 8 (Arg8) peptide shell for electrostatic complexation with nucleic acids (connexin 26 [Cx26] siRNA, green fluorescent protein [GFP] DNA or brain-derived neurotrophic factor [BDNF] pDNA). The PCA/Dex nanoparticles conjugated with Arg8, a cell-penetrating peptide that enhances permeability through a round window membrane in the inner ear for gene delivery, exhibited high uptake efficiency in HEI-OC1 cells. This potential carrier co-delivering Dex and the gene into inner ear cells has a diameter of 120–140 nm and a zeta potential of 20–25 mV. Different types of genes were complexed with the Dex-loaded PCA nanoparticle (PCA/Dex/gene) for gene expression to induce additional anti-inflammatory effects. PCA/Dex showed mildly increased expression of GFP and lower mRNA expression of inflammatory cytokines (IL1b, IL12, and INFr) than did Dex-free PCA nanoparticles and Lipofectamine ® reagent in HEI-OC1 cells. In
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The Telomerase-Derived Anticancer Peptide Vaccine GV1001 as an Extracellular Heat Shock Protein-Mediated Cell-Penetrating Peptide

The Telomerase-Derived Anticancer Peptide Vaccine GV1001 as an Extracellular Heat Shock Protein-Mediated Cell-Penetrating Peptide

Abstract: Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered macromolecules. GV1001, a peptide derived from a reverse-transcriptase subunit of telomerase (hTERT) and developed as a vaccine against various cancers, reportedly has unexpected CPP properties. Unlike typical CPPs, such as the HIV-1 TAT peptide, GV1001 enabled the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes. The eHSP-GV1001 interaction may have biological effects in addition to its cytosolic delivery function. GV1001 was originally designed as a MHC class II-binding cancer epitope, but its CPP properties may contribute to its strong anti-cancer immune response relative to other telomerase peptide-based vaccines. Cell signaling via eHSP-GV1001 binding may lead to unexpected biological effects, such as direct anticancer or antiviral effects. In this review, we focus on the CPP effects of GV1001 bound to eHSP90 and ehsp70.
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Designing and enhancing the antifungal activity of corneal specific cell penetrating peptide using gelatin hydrogel delivery system

Designing and enhancing the antifungal activity of corneal specific cell penetrating peptide using gelatin hydrogel delivery system

We downloaded the entire protein dataset of Fusarium solani from the FTP site of NCBI database to design CPP which can penetrate both corneal epithelium and F. solani. This served as our dataset 6. Further comparisons of dataset 4 (731 nonredundant CPPs) vs dataset 6 (F. solani) proteome resulted in the list of 140 CPPs with the abovementioned selec- tion criteria. These 140 CPPs constitute our dataset 7. Finally, to arrive at a CPP which will have the potential to penetrate both corneal epithelium and F. solani, a comparison between dataset 5 vs dataset 7 was done which resulted in 38 CPPs. The 38 CPPs were passed through the criteria of peptide solubility and the cell-penetrating property using Innovagen peptide solubility calculator (https://pepcalc.com/) and CPPpred (http://bioware.ucd.ie/ ~ compass/biowareweb/Server_pages/ cpppred.php), respectively. The CPP score is given within the range of 0–1, wherein the peptides with the score of .0.5 are suggestive of better cell penetration. This procedure resulted in four CPPs. Two peptides, VRF005 and VRF007, were selected on the basis of high CPP score, amphiphilicity, and solubility for modeling and experimental validation.
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<p>Transportan-derived cell-penetrating peptide delivers siRNA to inhibit replication of influenza virus in vivo</p>

<p>Transportan-derived cell-penetrating peptide delivers siRNA to inhibit replication of influenza virus in vivo</p>

when the ratio was .4:1 and the effective binding ratio of siGFP to TP is 16:1. Here, we did not know the bind- ing mechanism of T9(dR) and siRNA. Nevertheless, we hypothesized that it might be related to the charge and size of peptide. As a chimeric peptide, T9(dR) is longer than most of the published CPPs. The structure of CPPs is very complex. Correspondingly, T9(dR) and siNP formulated nanoparticles in large size around 350–600 nm within 1 hour at room temperature. Compared with the published results, the size is larger than the nanoparticles reported by the other researchers. At 15 and 60 minutes, average size of the particles increased from 350 to 650 nm. It indicated that T9(dR) and siRNA dissociated to some degree, but the mechanism is still under investigation. Nanoparticles comprising CPP and siRNA have to be attached to the cell membrane to intrude into cells. Usually, nanoparticle size is a key parameter for internalization pathways. In this study, TP or T9(dR) and siRNA complex may penetrate cellular membrane by caveolae-mediated internalization, which is the predominant entry route for 500-nm particles. 47 Other-
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A Cell Penetrating Peptide for Inhibiting MAPKAP Kinase 2 Mediated Inflammatory Cytokine Release Following Glial  Cell Activation

A Cell Penetrating Peptide for Inhibiting MAPKAP Kinase 2 Mediated Inflammatory Cytokine Release Following Glial Cell Activation

Protein kinase regulation can be accomplished through the use of substrate-based inhibiting peptides [27]. The peptide sequence, KKKALNRQLGVAA, was identified as a substrate-based inhibitor of MK2 in vitro [28]. Cell-penetrating peptides (CPPs) have also been studied as a mechanism for delivering MK2-inhibiting peptide sequences into cells. Lopes et al. (2009) demonstrated that the CPP, WLRRIKAWLRRI conjugated to KALNRQLGVAA, inhibited MK2 activity as determined by reduced HSP27 phosphorylation [29]. This CPP competes with substrates, such as heterogeneous nuclear ribonucleoprotein A0 (hnRNPA0) [30] and tristetrapro- lin (TTP) [31], at the MK2 active site, resulting in a reduction in substrate phosphorylation. Ward et al. (2009) found the peptide sequence, YARAAARQARAKALARQLGVAA (MK2i), to be a non-toxic and more specific inhibitor of MK2 [32] [33]. Therefore, it is hypothesized that MK2i will reduce the expression of inflammatory cytokines from activated microglia, resulting in less secondary damage to the cortical environment. This report provides in vitro evidence of MK2i’s ability to lower inflammatory cytokine production, decrease cortical cell death, and reduce glial cell activation following TNF-α and lipopolysaccharide (LPS) treatment within a mixed primary cortical cell culture.
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A branched TAT cell-penetrating peptide as a novel delivery carrier for the efficient gene transfection

A branched TAT cell-penetrating peptide as a novel delivery carrier for the efficient gene transfection

Although natural CPPs can penetrate into the cells without toxicity, transfection efficiency is too low to achieve expected therapeutic effects due to their low- molecular-weight, unstable linear structure and weak gene condensation capability. To overcome these draw- backs, various CPP modifications have been studied by conjugating with different chemical moieties. The branched structures are more advantageous than linear molecules to deliver biomolecules into cells [25]. To construct a branched structure, linear molecules must be linked with each other. As one method for linking, the disulfide bond is a simple and useful bridge for pep- tide modification because disulfide bridge can be easily linked by an oxidation method. In addition, the disulfide link is sensitively cleaved by reducing agents such as glutathione (GSH) which is overproduced in cytoplasm of cancer cells compared with normal cells [26]. There- fore, the branched peptide linked by a disulfide bond with each other would be degraded in cancer cells under reducing conditions.
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Effect of cell-penetrating peptide-coated nanostructured lipid carriers on the oral absorption of tripterine

Effect of cell-penetrating peptide-coated nanostructured lipid carriers on the oral absorption of tripterine

result indicated that the NLCs clearly enhanced the absorp- tion of tripterine in the intestine, and this effect was especially improved when the particles were coated with the CPP. The low absorption of tripterine may be attributable to its poor water solubility, and the physicochemical barrier formed by the GIT and intestinal epithelium. Therefore, the improved absorption of tripterine in the T-NLCs and CT-NLCs could be explained as follows: a smaller particle size enables per- meation of the drug across the cell membranes, and/or an affinity exists between the lipid material used here and the cell membrane. 29 The CT-NLCs showed higher absorption
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Antitumor activity of tripterine via cell-penetrating peptide-coated nanostructured lipid carriers in a prostate cancer model

Antitumor activity of tripterine via cell-penetrating peptide-coated nanostructured lipid carriers in a prostate cancer model

NLC, would be maintained at a constant concentration for a relatively long period in vivo, thereby having consistent antitumor efficacy. Further, Ste-R 6 L 2 (a type of CPP com- posed mainly of arginine and leucine) could confer a posi- tive charge to the nanoparticles. Taken together, the major mechanism accounting for the superiority of CT-NLC over T-NLC and free tripterine may involve the positive charge density of CT-NLC having high electrostatic interaction with the negatively charged tumor cell surface and CPP mediating intracellular nanoparticle delivery via both endocytic and nonendocytic pathways.
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Strategies for ocular siRNA delivery: Potential and limitations of non-viral nanocarriers

Strategies for ocular siRNA delivery: Potential and limitations of non-viral nanocarriers

Protein-based siRNA delivery involves the formation of ‘proticles, ’ where proteins are conjugated (electrostatically or covalently) to siRNA for delivery. For example, albumin- protamine-oligonucleotide forms nanocarrier complexes (230–320 nm diameter), which can be safely delivered to cells [38]. Recently, Johnson et al. have developed a novel cell-penetrating peptide (CPP) for ocular delivery of small and large molecules, including siRNA, fluorescent probes, plasmid DNA and quantum dots to RPE, photoreceptor and ganglion cells in vitro and in vivo [39]. Not only do the authors report >50% transgene silencing after peptide- siRNA delivery in human embryonic retinal cells in vitro, but they also demonstrate that this peptide-based nanocar- rier can transduce approximately 85% of the neural retina within 2 h of intravitreal injection in vivo [39]. The lack of toxicity, biodegradability and serum stability of these nano- carriers makes them particularly advantageous as a delivery vehicle [38]. However, protein-based nanocarriers have been known to localize and degrade within endolysosomes after cellular uptake [40]. This problem will likely require additional nanocarrier design considerations such as endosomal escape strategies for its successful applica- tion in ocular conditions.
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<p>Enhanced Efficacy of Photodynamic Therapy by Coupling a Cell-Penetrating Peptide with Methylene Blue</p>

<p>Enhanced Efficacy of Photodynamic Therapy by Coupling a Cell-Penetrating Peptide with Methylene Blue</p>

Secondly, we measured the efficiency of PDT at different light energies with constant photosensitizer (MB and MB-Pro) concentrations. The cells were incu- bated post-treatment for 2 days (Figure 6A) or 3 days (Figure 6B). The dark control (MB 10 µM, laser light 0 J/cm 2 ) exhibited no significant cell death after treat- ment with 10 µM for MB and MB-Pro compared with the negative control subgroup (MB 0 µM). Increasing either the input energy or the incubation time increased the efficiency of PDT with both MB and MB-Pro. The significant differences of the cytotoxicity between MB- PDT and MB-Pro-PDT in 2 and 3 days are shown in Figure 6. Significant effects of PDT using MB-Pro were also observed after treatment with 60 J/cm 2 as shown in Figure 6B. The cell viability of PDT with MB-Pro was 32.2% at 10 µM following 3 days of incubation and 72.3% by PDT with MB alone when using an irradiation energy of 60 J/cm 2 ; the difference in cell viabilities for MB and MB-Pro was 40% (P<0.001). PDT using MB did not exceed 30% cyto- toxicity; however, PDT with MB-Pro resulted in almost 70% cytotoxicity.
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