Peptide-mediated delivery of therapeutic mRNA in ovarian cancer

Brand, Dirk van den; Gorris, Mark A.J.; Asbeck, Alexander H. van; Palmen, Emma; Ebisch, I.M.W.; Dolstra, Harry; Hällbrink, Mattias; Massuger, Leon F.A.G.; Brock, Roland

doi:10.1016/j.ejpb.2019.05.014

Cited by 72 publications

(63 citation statements)

References 58 publications

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“…Peptide-based delivery systems, both alone and in combination with other materials such as polymers, have been reported in the literature. In a study concerning ovarian cancer therapy, the commercially available cell-penetrating peptide (CPP) PepFect14 was complexed with eGFP mRNA via attractive electrostatic interactions [164]. This nanoparticulate formulation was more efficient in transfecting eGFP mRNA into cells associated with ovarian cancer than commercially available lipofectamine MessengerMAX.…”

Section: Peptide-based Vectorsmentioning

confidence: 99%

“…Similarly, the CPP RALA has been used to effectively deliver both eGFP and OVA mRNA and has been demonstrated to outperform the cationic lipid DOTAP and the fusogenic lipid DOPE [165]. However, current limitations include targeted cell delivery [164] and short circulation half-life due to the low stability in serum-containing medium [166].…”

Section: Peptide-based Vectorsmentioning

confidence: 99%

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Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

et al. 2020

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In the past few years, there has been increasing focus on the use of messenger RNA (mRNA) as a new therapeutic modality. Current clinical efforts encompassing mRNA-based drugs are directed toward infectious disease vaccines, cancer immunotherapies, therapeutic protein replacement therapies, and treatment of genetic diseases. However, challenges that impede the successful translation of these molecules into drugs are that (i) mRNA is a very large molecule, (ii) it is intrinsically unstable and prone to degradation by nucleases, and (iii) it activates the immune system. Although some of these challenges have been partially solved by means of chemical modification of the mRNA, intracellular delivery of mRNA still represents a major hurdle. The clinical translation of mRNA-based therapeutics requires delivery technologies that can ensure stabilization of mRNA under physiological conditions. Here, we (i) review opportunities and challenges in the delivery of mRNA-based therapeutics with a focus on non-viral delivery systems, (ii) present the clinical status of mRNA vaccines, and (iii) highlight perspectives on the future of this promising new type of medicine.

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Section: Peptide-based Vectorsmentioning

confidence: 99%

Section: Peptide-based Vectorsmentioning

confidence: 99%

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

et al. 2020

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“…One peptide that has been shown to yield effective cellular delivery for a variety of oligonucleotides in vitro and in vivo is PepFect 14 (PF14) [ 12 , 13 ]. Recently, we employed PF14 to deliver mRNA in several cellular models of ovarian cancer and also in a peritoneal model of ovarian cancer in vivo in mice [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Protein Expression Correlates Linearly with mRNA Dose over Up to Five Orders of Magnitude In Vitro and In Vivo

et al. 2021

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Messenger RNA is rapidly gaining significance as a therapeutic modality. Here, we address the dependence of dose–response functions on the type of delivery vehicle, cell line, and incubation time. Knowledge of these characteristics is crucial for the application of mRNA. As delivery vehicles, a lipid-based formulation and the cell-penetrating peptide Pepfect14 (PF14) were employed. As cell lines, we included a glomerular endothelial cell line (mGEnC) as a model for differentiated cells, HeLa cells, and SKOV-3 ovarian carcinoma cells. Uptake and expression were detected by flow cytometry, using a Cy5-labelled mRNA coding for enhanced green fluorescent protein (EGFP). There was a linear correlation of dose, uptake, and expression, and this correlation was maintained for over up to 72 h. Through application of a multistep kinetic model, we show that differences in expression levels can already be explained by the number of mRNAs packaged per delivery vehicle. Using luciferase as a reporter protein, linearity of expression was observed over 5 orders of magnitude in vitro and 3 orders of magnitude in vivo. Overall, the results demonstrate that mRNA provides excellent quantitative control over protein expression, also over extended periods of time.

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“…Thus, for CPPmediated transport, transition from bench to bedside, still remains complicated, unless topical delivery is used where less complex protein corona forms around nanoparticles. 11,96,97 Materials and Methods PF14 (see sequences and characteristics of used CPPs and nucleic acids in Table 1), C22-PF14 and NF55 were purchased from Pepmic (China). Splicing correcting oligonucleotides with 2'OMe modification and phosphorothioate backbone, and labelled with Cy5 or biotin were from Microsynth (Switzerland), or Metabion (Germany), and pGL3 plasmid was from Promega, (4.7 kbp, USA).…”

Section: Discussionmentioning

confidence: 99%

Internalisation and biological activity of nucleic acids delivering cell-penetrating peptide nanoparticles is controlled by the biomolecular corona

Lorents¹,

Maloverjan

Padari³

et al. 2021

Preprint

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Nucleic acid molecules can be transferred into cells to alter gene expression and, thus, alleviate certain pathological conditions. Cell-penetrating peptides (CPPs) are vectors that can be used for transfecting nucleic acids as well as many other compounds. CPPs associate nucleic acids non-covalently, forming stable nanoparticles and providing efficient transfection of cells in vitro. However, in vivo, expected efficiency is achieved only in rare cases. One of the reasons for this discrepancy is formation of protein corona around nanoparticles, once they are exposed to a biological environment, e.g. blood stream. In this study, we compared CPP-nucleic acid nanoparticles formed in the presence of bovine, murine and human serum. We used Western blot and mass-spectrometry to identify the major constituents of protein corona forming around nanoparticles, showing that proteins involved in transport, haemostasis and complement system are its major components. We investigated physical features of nanoparticles, and measured their biological efficiency in splice-correction assay. We showed that protein corona constituents might alter the fate of nanoparticles in vivo, e.g. by subjecting them to phagocytosis. We demonstrated that composition of protein corona of nanoparticles is species-specific that leads to dissimilar transfection efficiency and should be taken into account while developing delivery systems for nucleic acids.

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Peptide-mediated delivery of therapeutic mRNA in ovarian cancer

Cited by 72 publications

References 58 publications

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

Protein Expression Correlates Linearly with mRNA Dose over Up to Five Orders of Magnitude In Vitro and In Vivo

Internalisation and biological activity of nucleic acids delivering cell-penetrating peptide nanoparticles is controlled by the biomolecular corona

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