Recent Advances in Cell Penetrating Peptide-Based Anticancer Therapies

Habault, Justine; Poyet, Jean-Luc

doi:10.3390/molecules24050927

Cited by 240 publications

(198 citation statements)

References 139 publications

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“…CPPs demonstrated to be highly efficient in cargo delivery in vitro, being able to mediate the uptake of different cargo molecules in a number of cell lines. However, their success as delivery systems in vivo has been limited, mostly due to in vivo stability issues (they are susceptible to proteolytic degradation), immunogenicity or toxicity due to the lack of specificity [7,124,125]. Up to now, a number of in vivo studies have been done, in which CPPs such as TAT or penetratin have been tested for their cytotoxic and immunogenic potential [3].…”

Section: In Vivo Application Of Cppsmentioning

confidence: 99%

Internalization mechanisms of cell-penetrating peptides

Ruseska

Zimmer

2020

Beilstein J. Nanotechnol.

304

264

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In today’s modern era of medicine, macromolecular compounds such as proteins, peptides and nucleic acids are dethroning small molecules as leading therapeutics. Given their immense potential, they are highly sought after. However, their application is limited mostly due to their poor in vivo stability, limited cellular uptake and insufficient target specificity. Cell-penetrating peptides (CPPs) represent a major breakthrough for the transport of macromolecules. They have been shown to successfully deliver proteins, peptides, siRNAs and pDNA in different cell types. In general, CPPs are basic peptides with a positive charge at physiological pH. They are able to translocate membranes and gain entry to the cell interior. Nevertheless, the mechanism they use to enter cells still remains an unsolved piece of the puzzle. Endocytosis and direct penetration have been suggested as the two major mechanisms used for internalization, however, it is not all black and white in the nanoworld. Studies have shown that several CPPs are able to induce and shift between different uptake mechanisms depending on their concentration, cargo or the cell line used. This review will focus on the major internalization pathways CPPs exploit, their characteristics and regulation, as well as some of the factors that influence the cellular uptake mechanism.

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Section: In Vivo Application Of Cppsmentioning

confidence: 99%

Internalization mechanisms of cell-penetrating peptides

Ruseska

Zimmer

2020

Beilstein J. Nanotechnol.

304

264

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“…The latter approach has been successfully employed to improve both the stability and the intestinal absorption of peptide drugs [157][158][159]. In the area of cancer drug delivery, where peptide-based chemotherapeutic agents are routinely required to be delivered to intracellular targets, increasing levels of success are being recorded with the development of innovative techniques like the use of cell-penetrating peptides, viral based-vectors, and nanoparticle-based systems [160][161][162]. It is expected that these new developments can be leveraged upon in delivering peptide-based HbS inhibitors into the intracellular compartment of RBCs.…”

Section: Benefits and Challenges Associated With Peptide-based Drugsmentioning

confidence: 99%

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

2019

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Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12-and 15-mers under consideration in recent years.Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].Despite growing understanding of the polymerization of HbS and its effects on red blood cells (RBCs), until very recently, only two drugs-hydroxyurea and L-glutamine-were approved by the United States (US) Food and Drug Administration (FDA) for the management of SCD [12]. Hydroxyurea is the most widely employed drug treatment of sickle cell anemia in different age groups [13][14][15][16][17][18]. While its clinically observed efficacy has been attributed to different effects at the cellular level [19], the most important mechanism of action relates to its ability to induce the production of fetal hemoglobin (HbF), which does not polymerize, and to increase the total concentration of hemoglobin [20,21]. Hydroxyurea remains a viable treatment option for SCD, and the concern of toxicities associated with its administration has largely been limited to side effects that resolve with medication discontinuation [22][23][24][25][26]. There have, however, been certain reports of associated malignancies [27][28][29][30][31][32], but further investigations are needed to categorically confirm these [33]. L-glutamine is the second approved drug treatment [12,34]. While its mechanism of action is not known, and only suggested to involve a reduction of oxidative stress via elevation of the levels of reduced glutathione [35,36], it is clear that it has no effect on hemo...

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“…Mechanisms of cellular uptake of CPP conjugated to low molecular weight agents or grafted onto nanoparticles has been reviewed in detail elsewhere [7][8][9]16,32,33]. The list of identified CPPs keeps increasing and, synthetic CPPs such as octaarginine (R8) have been designed to enhance cellular uptake of CPP-conjugated materials [16,31,34].…”

Section: Cell Penetrating Peptidesmentioning

confidence: 99%

“…Several CPP-based strategies are under clinical trials (Table 2) (reviewed in [21,22,32]). AM-111 (Auris Medical) is a conjugate of the Janus Kinase inhibitor brimapitide and TAT CPP [100].…”

Section: Clinical Trialsmentioning

confidence: 99%

Stimuli-Sensitive Cell Penetrating Peptide-Modified Nanocarriers

Perche

2019

Processes

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The integration of drugs into nanocarriers favorably altered their pharmacodynamics and pharmacokinetics compared to free drugs, and increased their therapeutic index. However, selective cellular internalization in diseased tissues rather than normal tissues still presents a formidable challenge. In this chapter I will cover solutions involving environment-responsive cell-penetrating peptides (CPPs). I will discuss properties of CPPs as universal cellular uptake enhancers, and the modifications imparted to CPP-modified nanocarriers to confine CPP activation to diseased tissues.

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Recent Advances in Cell Penetrating Peptide-Based Anticancer Therapies

Cited by 240 publications

References 139 publications

Internalization mechanisms of cell-penetrating peptides

Internalization mechanisms of cell-penetrating peptides

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

Stimuli-Sensitive Cell Penetrating Peptide-Modified Nanocarriers

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