SPA: a peptide antagonist that acts as a cell-penetrating peptide for drug delivery.
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ABSTRACT:
SUBMITTER: Song J
PROVIDER: S-EPMC6968712 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSmall interfering RNAs (siRNAs) are powerful tools to control gene expression. However, due to their poor cellular permeability and stability, their therapeutic development requires a specific delivery system. Among them, cell-penetrating peptides (CPP) have been shown to transfer efficiently siRNA inside the cells. Recently we developed amphipathic peptides able to self-assemble with siRNAs as peptide-based nanoparticles and to transfect them into cells. However, despite the great potential of these drug delivery systems, most of them display a low resistance to proteases.ResultsHere, we report the development and characterization of a new CPP named RICK corresponding to the retro-inverso form of the CADY-K peptide. We show that RICK conserves the main biophysical features of its L-parental homologue and keeps the ability to associate with siRNA in stable peptide-based nanoparticles. Moreover the RICK:siRNA self-assembly prevents siRNA degradation and induces inhibition of gene expression.ConclusionsThis new approach consists in a promising strategy for future in vivo application, especially for targeted anticancer treatment (e.g. knock-down of cell cycle proteins). Graphical abstract RICK-based nanoparticles: RICK peptides and siRNA self-assemble in peptide-based nanoparticles to penetrate into the cells and to induce target protein knock-down.
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Project description:The unique structure and physiology of a tumor microenvironment impede intra-tumoral penetration of chemotherapeutic agents. A novel iRGD peptide that exploits the tumor microenvironment can activate integrin-dependent binding to tumor vasculatures and neuropilin-1 (NRP-1)-dependent transport to tumor tissues. Recent studies have focused on its dual-targeting ability to achieve enhanced penetration of chemotherapeutics for the efficient eradication of cancer cells. Both the covalent conjugation and the co-administration of iRGD with chemotherapeutic agents and engineered delivery vehicles have been explored. Interestingly, the iRGD-mediated drug delivery also enhances penetration through the blood-brain barrier (BBB). Recent studies have shown its synergistic effect with BBB disruptive techniques. The efficacy of immunotherapy involving immune checkpoint blockades has also been amplified by using iRGD as a targeting moiety. In this review, we presented the recent advances in iRGD technology, focusing on cancer treatment modalities, including the current clinical trials using iRGD. The iRGD-mediated nano-carrier system could serve as a promising strategy in drug delivery to the deeper tumor regions, and be combined with various therapeutic interventions due to its novel targeting ability.
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Project description:The current study investigated the use of two cationic peptides, Xentry-KALA (XK) and Xentry-Protamine (XP), for intracellular delivery of Connexin43 antisense oligonucleotides (Cx43AsODN). The charge and size of Cx43AsODN:XK and Cx43AsODN:XP complexes was determined by Zetasizer analysis. The earliest positive zeta potential reading was obtained at a 1:2 and 1:1.2 charge ratio of Cx43AsODN:XK and Cx43AsODN:XP respectively, with Cx43AsODN:XK resulting in overall larger complexes than Cx43AsODN:XP. Gel shift mobility assays revealed complete complex formation at a 1:2.5 and 1:2.2 charge ratio of Cx43AsODN:XK and Cx43AsODN:XP, respectively. Cellular uptake studies were carried out in ARPE-19 cells. While both complexes were able to enter the cells, Cx43AsODN:XK uptake appeared punctate and circular indicative of endosomal containment. Cx43AsODN:XP uptake, in contrast, resulted in diffuse appearance inside the cell suggesting endosomal escape of the cargo. Finally, western blot analysis confirmed that Cx43AsODN:XP was able to knockdown Cx43 expression in these cells under normal and hypoxic conditions.
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Project description:One of the main obstacles to most medication administrations (such as the vaccine constructs) is the cellular membrane's inadequate permeability, which reduces their efficiency. Cell-penetrating peptides (CPPs) or protein transduction domains (PTDs) are well-known as potent biological nanocarriers to overcome this natural barrier, and to deliver membrane-impermeable substances into cells. The physicochemical properties of CPPs, the attached cargo, concentration, and cell type substantially influence the internalization mechanism. Although the exact mechanism of cellular uptake and the following processing of CPPs are still uncertain; but however, they can facilitate intracellular transfer through both endocytic and non-endocytic pathways. Improved endosomal escape efficiency, selective cell targeting, and improved uptake, processing, and presentation of antigen by antigen-presenting cells (APCs) have been reported by CPPs. Different in vitro and in vivo investigations using CPP conjugates show their potential as therapeutic agents in various medical areas such as infectious and non-infectious disorders. Effective treatments for a variety of diseases may be provided by vaccines that can cooperatively stimulate T cell-mediated immunity (T helper cell activity or cytotoxic T cell function), and immunologic memory. Delivery of antigen epitopes to APCs, and generation of a potent immune response is essential for an efficacious vaccine that can be facilitated by CPPs. The current review describes the delivery of numerous vaccine components by various CPPs and their immunostimulatory properties.
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Project description:Highly efficient gene delivery vehicles are pursued to progress gene therapy. In this study, we developed the cell-penetrating peptide-labelled and degradable gene carriers for efficient external gene transfection. The cationic carriers were prepared by coupling low-molecular-weight polyethylenimine (PEI800) with 4'4-dithiodibutyric acid (DA), and HIV-1 Trans-Activator of Transcription (TAT) was conjugated to the carriers as a penetrating peptide. The resulted PEI-DA-TAT was able to condense plasmid DNA (pDNA) into a complex with a hydrodynamic size of around 150 nm under a neutral condition. PEI-DA-TAT showed negligible cytotoxicity to both Hela and HEK 293 cells with the cell viability of more than 80% beyond the carrier concentration of 50 μg/mL. This new carrier displayed better performance in regard to DNA transfection efficiency in comparison with the carriers of non-TAT labelled PEI-DA, commercial PEI25K and low-molecular-weight PEI (PEI800). The transfection efficiency of PEI-DA-TAT was increased by 8% compared with PEI-DA and PEI25K. The experimental findings suggested that the developed PEI-DA-TAT is a promising carrier for efficient DNA delivery with low cytotoxicity for gene therapy.
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Project description:On account of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, amphiphilic block copolymer-based micelles have been widely utilized for chemotherapy drug delivery. In order to further improve the antitumor ability and to also reduce undesired side effects of drugs, cell-penetrating peptides have been used to functionalize the surface of polymer micelles endowed with the ability to target tumor tissues. Herein, we first synthesized functional polyethylene glycol-polylactic acid (PEG-PLA) tethered with maleimide at the PEG section of the block polymer, which was further conjugated with a specific peptide, the transactivating transcriptional activator (TAT), with an approved capacity of aiding translocation across the plasma membrane. Then, TAT-conjugated, paclitaxel-loaded nanoparticles were self-assembled into stable nanoparticles with a favorable size of 20 nm, and displayed a significantly increased cytotoxicity, due to their enhanced accumulation via peptide-mediated cellular association in human breast cancer cells (MCF-7) in vitro. But when further used in vivo, TAT-NP-PTX showed an acceleration of the drug's plasma clearance rate compared with NP-PTX, and therefore weakened its antitumor activities in the mice model, because of its positive charge, its elimination by the endoplasmic reticulum system more quickly, and its targeting effect on normal cells leading towards being more toxic. So further modification of TAT-NP-PTX to shield TAT peptide's positive charges may be a hot topic to overcome the present dilemma.
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Project description:Skin, being the largest organ of the body, is an important site for drug administration. However, most of the drugs have poor permeability and thus drug delivery through the skin is very challenging. In this study, we examined the transdermal delivery capability of IMT-P8, a novel cell-penetrating peptide. We generated IMT-P8-GFP and IMT-P8-KLA fusion constructs and evaluated their internalization into mouse skin after topical application. Our results demonstrate that IMT-P8 is capable of transporting green fluorescent protein (GFP) and proapoptotic peptide, KLA into the skin and also in different cell lines. Interestingly, uptake of IMT-P8-GFP was considerably higher than TAT-GFP in HeLa cells. After internalization, IMT-P8-KLA got localized to the mitochondria and caused significant cell death in HeLa cells signifying an intact biological activity. Further in vivo skin penetration experiments revealed that after topical application, IMT-P8 penetrated the stratum corneum, entered into the viable epidermis and accumulated inside the hair follicles. In addition, both IMT-P8-KLA and IMT-P8-GFP internalized into the hair follicles and dermal tissue of the skin following topical application. These results suggested that IMT-P8 could be a potential candidate to be used as a topical delivery vehicle for various cosmetic and skin disease applications.
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Project description:Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18ΔE, which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol-Michael addition to form novel PDCs. Our results indicate that sC18ΔE could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development.
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Project description:In this study, we have identified a novel cell-penetrating sequence, termed hAP10, from the C-terminus of the human protein Acinus. hAP10 was able to efficiently enter various normal and cancerous cells, likely through an endocytosis pathway, and to deliver an EGFP cargo to the cell interior. Cell penetration of a peptide, hAP10DR, derived from hAP10 by mutation of an aspartic acid residue to an arginine was dramatically increased. Interestingly, a peptide containing a portion of the heptad leucine repeat region domain of the survival protein AAC-11 (residues 377-399) fused to either hAP10 or hAP10DR was able to induce tumor cells, but not normal cells, death both ex vivo on Sézary patients' circulating cells and to inhibit tumor growth in vivo in a sub-cutaneous xenograft mouse model for the Sézary syndrome. Combined, our results indicate that hAP10 and hAP10DR may represent promising vehicles for the in vitro or in vivo delivery of bioactive cargos, with potential use in clinical settings.
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Project description:Cell-penetrating peptides (CPPs), developed for more than 30 years, are still being extensively studied due to their excellent delivery performance. Compared with other delivery vehicles, CPPs hold promise for delivering different types of drugs. Here, we review the development process of CPPs and summarize the composition and classification of the CPP-based delivery systems, cellular uptake mechanisms, influencing factors, and biological barriers. We also summarize the optimization routes of CPP-based macromolecular drug delivery from stability and targeting perspectives. Strategies for enhanced endosomal escape, which prolong its half-life in blood, improved targeting efficiency and stimuli-responsive design are comprehensively summarized for CPP-based macromolecule delivery. Finally, after concluding the clinical trials of CPP-based drug delivery systems, we extracted the necessary conditions for a successful CPP-based delivery system. This review provides the latest framework for the CPP-based delivery of macromolecular drugs and summarizes the optimized strategies to improve delivery efficiency.
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