Cell-penetrating peptides in oncologic pharmacotherapy: A review

Vale, Nuno; Duarte, Diana; Silva, Sara; Correia, Ana Salomé; Costa, Bárbara; Gouveia, Maria João; Ferreira, Abigail

doi:10.1016/j.phrs.2020.105231

Cited by 33 publications

(29 citation statements)

References 292 publications

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“…It can therefore be postulated that LP covered with mRNA and LAH4-L1 accumulate more in DC 2.4 than in HeLa cells (due to DC2.4 cells' high capacity for engulfing particles), thus increasing cytotoxicity in DC 2.4 cells. As toxicity of cellpenetrating peptides has already been highlighted in several articles [19,47], a preliminary study was conducted in this article to reduce the effects of LAH4-L1 on DC 2.4 cells. By decreasing the mRNA/LAH4-L1 w/w ratio in the pLbL formulation from 1:20 to 1:5, cytotoxicity was divided by a factor larger than 3 without altering the transfection efficiency.…”

Section: Discussionmentioning

confidence: 99%

LipoParticles: Lipid-Coated PLA Nanoparticles Enhanced In Vitro mRNA Transfection Compared to Liposomes

et al. 2021

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The approval of two mRNA vaccines as urgent prophylactic treatments against Covid-19 made them a realistic alternative to conventional vaccination methods. However, naked mRNA is rapidly degraded by the body and cannot effectively penetrate cells. Vectors capable of addressing these issues while allowing endosomal escape are therefore needed. To date, the most widely used vectors for this purpose have been lipid-based vectors. Thus, we have designed an innovative vector called LipoParticles (LP) consisting of poly(lactic) acid (PLA) nanoparticles coated with a 15/85 mol/mol DSPC/DOTAP lipid membrane. An in vitro investigation was carried out to examine whether the incorporation of a solid core offered added value compared to liposomes alone. To that end, a formulation strategy that we have named particulate layer-by-layer (pLbL) was used. This method permitted the adsorption of nucleic acids on the surface of LP (mainly by means of electrostatic interactions through the addition of LAH4-L1 peptide), allowing both cellular penetration and endosomal escape. After a thorough characterization of size, size distribution, and surface charge— and a complexation assessment of each vector—their transfection capacity and cytotoxicity (on antigenic presenting cells, namely DC2.4, and epithelial HeLa cells) were compared. LP have been shown to be significantly better transfecting agents than liposomes through pLbL formulation on both HeLa and DC 2.4 cells. These data illustrate the added value of a solid particulate core inside a lipid membrane, which is expected to rigidify the final assemblies and makes them less prone to early loss of mRNA. In addition, this assembly promoted not only efficient delivery of mRNA, but also of plasmid DNA, making it a versatile nucleic acid carrier that could be used for various vaccine applications. Finally, if the addition of the LAH4-L1 peptide systematically leads to toxicity of the pLbL formulation on DC 2.4 cells, the optimization of the nucleic acid/LAH4-L1 peptide mass ratio becomes an interesting strategy—essentially reducing the peptide intake to limit its cytotoxicity while maintaining a relevant transfection efficiency.

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Section: Discussionmentioning

confidence: 99%

LipoParticles: Lipid-Coated PLA Nanoparticles Enhanced In Vitro mRNA Transfection Compared to Liposomes

et al. 2021

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“…Refs. [ 222 , 223 ]), a subfamily of cell-penetrating peptides [ 224 , 225 ], have in fact been used to deliver drugs to mitochondria, at least in vitro . For example, Kelley's group coupled chlorambucil to a peptide consisting of three repeated doublets of cyclohexylphenylalanine and d -arginine.…”

Section: Modulation Of Cancer Cell Fate By Peptides Targeting Mitochondrial Ion Channel Interactionsmentioning

confidence: 99%

Targeting mitochondrial ion channels for cancer therapy

2021

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Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.

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“…Psoralenic Species (nmol/g Tissue) Psoralenic Species (% of Injected Dose) 15 23 ± 3 20 ± 3 30 17 ± 2 16 ± 1 The total amount of An2-PAPTP and its metabolites, summarized in Table 3, is comprehensive of all the species having the characteristic psoralenic UV spectrum obtained by the overall extraction procedure (i.e., from organic solvent extraction and basic hydrolysis of the remaining pellet), and represents and underestimation of the real concentration in the tissue (see Section 4.7.3). This is because no recovery yield correction was applied, since it was impossible to identify most of the species extracted, and because PAPTPL extracted after high-pH hydrolysis of the pellet could come either from An2-PAPTP or from metabolites.…”

Section: Time Of Treatment (Min)mentioning

confidence: 99%

“…Some cell-penetrating peptides are reported to function as trans-BBB "ferries" of this type [25][26][27][28][29][30]. The first, possibly best-known and one of the most efficient [31,32] of these is TAT, a segment of the transactivator of transcription of human immunodeficiency virus (HIV) [33,34].…”

Section: Introductionmentioning

confidence: 99%

An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors

et al. 2021

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A developing family of chemotherapeutics—derived from 5-(4-phenoxybutoxy)psoralen (PAP-1)—target mitochondrial potassium channel mtKv1.3 to selectively induce oxidative stress and death of diseased cells. The key to their effectiveness is the presence of a positively charged triphenylphosphonium group which drives their accumulation in the organelles. These compounds have proven their preclinical worth in murine models of cancers such as melanoma and pancreatic adenocarcinoma. In in vitro experiments they also efficiently killed glioblastoma cells, but in vivo they were powerless against orthotopic glioma because they were completely unable to overcome the blood-brain barrier. In an effort to improve brain delivery we have now coupled one of these promising compounds, PAPTP, to well-known cell-penetrating and brain-targeting peptides TAT48–61 and Angiopep-2. Coupling has been obtained by linking one of the phenyl groups of the triphenylphosphonium to the first amino acid of the peptide via a reversible carbamate ester bond. Both TAT48–61 and Angiopep-2 allowed the delivery of 0.3–0.4 nmoles of construct per gram of brain tissue upon intravenous (i.v.) injection of 5 µmoles/kg bw to mice. This is the first evidence of PAPTP delivery to the brain; the chemical strategy described here opens the possibility to conjugate PAPTP to small peptides in order to fine-tune tissue distribution of this interesting compound.

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Cell-penetrating peptides in oncologic pharmacotherapy: A review

Cited by 33 publications

References 292 publications

LipoParticles: Lipid-Coated PLA Nanoparticles Enhanced In Vitro mRNA Transfection Compared to Liposomes

LipoParticles: Lipid-Coated PLA Nanoparticles Enhanced In Vitro mRNA Transfection Compared to Liposomes

Targeting mitochondrial ion channels for cancer therapy

An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors

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