Novel immunotherapeutic approaches to skin cancer treatments using protein transduction technology

Shibagaki, Naotaka; Okamoto, Takashi; Mitsui, Hiroshi; Inozume, Takashi; Kanzaki, Mirei; Shimada, Shinji

doi:10.1016/j.jdermsci.2010.12.003

Cited by 9 publications

(4 citation statements)

References 59 publications

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“…CPPs are short peptide sequences (usually built of fewer than 30 residues) that have a proven capacity to penetrate the cell membrane . This class of peptides is efficient, and numerous studies confirm that, among all arginine-containing CPPs, those with eight or nine consecutive arginine residues are the most effective and least cytotoxic. − The translocation of arginine (as polyarginine or included into other peptide sequences) through a bilayer was addressed theoretically as well and the energy barriers were estimated, − confirming the importance of the presence of this amino acid. The attachment of small molecules like fluorophores or the addition of hydrophobic components can significantly influence not only the cellular uptake and distribution of CPPs, but also the overall toxicity.…”

Section: Introductionmentioning

confidence: 92%

Molecular Structure and Pronounced Conformational Flexibility of Doxorubicin in Free and Conjugated State within a Drug–Peptide Compound

et al. 2015

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The search for targeted drug delivery systems requires the design of drug-carrier complexes, which could both reach the malignant cells and preserve the therapeutic substance activity. A promising strategy aimed at enhancing the uptake and reducing the systemic toxicity is to bind covalently the drug to a cell-penetrating peptide. To understand the structure-activity relationship in such preparations, the chemotherapeutic drug doxorubicin was investigated by unrestrained molecular dynamics simulations, supported by NMR, which yielded its molecular geometry in aqueous environment. Furthermore, the structure and dynamics of a conjugate of the drug with a cell-penetrating peptide was obtained from molecular dynamics simulations in aqueous solution. The geometries of the unbound compounds were characterized at different temperatures, as well as the extent to which they change after covalent binding and whether/how they influence each other in the drug-peptide conjugate. The main structural fragments that affect the conformational ensemble of every molecule were found. The results show that the transitions between different substructures of the three compounds require a modest amount of energy. At increased temperature, either more conformations become populated as a result of the thermal fluctuations or the relative shares of the various conformers equalize at the nanosecond scale. These frequent structural interconversions suggest expressed conformational freedom of the molecules. Conjugation into the drug-peptide compound partially immobilizes the molecules of the parent compounds. Nevertheless, flexibility still exists, as well as an effective intra- and intermolecular hydrogen bonding that stabilizes the structures. We observe compact packing of the drug within the peptide that is also based on stacking interactions. All this outlines the drug-peptide conjugate as a prospective building block of a more complex drug-carrier system.

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Section: Introductionmentioning

confidence: 92%

Molecular Structure and Pronounced Conformational Flexibility of Doxorubicin in Free and Conjugated State within a Drug–Peptide Compound

et al. 2015

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“…As in an article by Shibagaki et al. 2010, protein transduction domains technology (PTD) 54 is the short cationic amino acids that help peptides enter multiple cell types. The molecules can be proteins, oligonucleotides, peptides, nucleic acid, etc.…”

Section: Protein Transduction Technology As a Novel Approach To Skin ...mentioning

confidence: 99%

Protein therapeutics as an emerging strategy to deal with skin cancer: A short review

Kulshrestha,

Goel

2023

Experimental Dermatology

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Cancer has turned into a global menace with an exponential increase in the rate of death every year. Amongst all forms of cancers, skin cancer is the one becoming more common day by day because of the increased exposure to ultraviolet rays, chemicals, pollutants, etc. Skin cancer is of three types namely basal cell, squamous cell and melanoma which is one of the most aggressive forms of cancer with a low survival rate and easy relapse. Melanoma is also notorious for being multi‐drug resistant which accounts for its low survival rates in it. Many kinds of therapeutics are been practiced in the contemporary world, but among them, protein therapeutics is been emerging as a promising field with multiple molecular pathway targets that have revolutionized the science of oncology. Proteins acts as small‐molecule targets for cancer cells by binding to the cell surface receptors. Proteins including bromodomain and extra‐terminal domain (BET) and some toxin proteins are been tried on for dealing with melanoma targeting the major pathways including MAPK, NF‐κB and PI3K/AKT. The protein therapeutics also targets the tumour microenvironment including myofibrils, lymphatic vessels etc., thus inducing tumour cell death. In the review, several kinds of proteins and their function toward cell death will be highlighted in the context of skin cancer. In addition to this, the review will look into the inhibition of the function of other inflammatory pathways by inflammasomes and cytokines, both of which have a role in preventing cancer.

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“…Growing interest in CPPs is attributed to the simplicity of use, diversity and potential ability to target cellular subtypes within the skin. Several CPPs, including the well-known TAT [5, 10–11, 13, 15], polyarginines [7, 9, 12], penetratin [8–9, 16], RALA [6, 9] and TD-1 [17] are known to penetrate across the SC. Some of the CPPs also have the ability to translocate themselves and cargo-molecules within viable epidermis [11, 18–19].…”

Section: Introductionmentioning

confidence: 99%

31P solid-state NMR based monitoring of permeation of cell penetrating peptides into skin

Desai¹,

Cormier²,

Shah³

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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The main objective of the current study was to investigate penetration of cell penetrating peptides (CPPs: TAT, R8, R11 and YKA) through skin intercellular lipids using 31P magic angle spinning (MAS) solid-state NMR. In vitro skin permeation studies were performed on rat skin, sections (0–60, 61–120 and 121–180 µm) were collected and analyzed for 31P NMR signal. The concentration dependent shift of 0, 25, 50, 100 and 200 mg/ml of TAT on skin layers, diffusion of TAT, R8, R11 and YKA in the skin and time dependent permeation of R11 was measured on various skin sections using 31P solid-state NMR. Further, CPPs and CPP-tagged fluorescent dye encapsulate liposomes (FLip) in skin layers were tagged using confocal microscopy. The change in 31P NMR chemical shift was found to depend monotonically on the amount of CPP applied on skin, with saturation behavior above 100 mg/ml CPP concentration. R11 and TAT caused more shift in solid-state NMR peaks compared to other peptides. Furthermore, NMR spectra showed R11 penetration up to 180 µm within 30 min. The results of the solid-state NMR study were in agreement with confocal microscopy studies. Thus, 31P solid-state NMR can be used to track CPP penetration into different skin layers.

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Novel immunotherapeutic approaches to skin cancer treatments using protein transduction technology

Cited by 9 publications

References 59 publications

Molecular Structure and Pronounced Conformational Flexibility of Doxorubicin in Free and Conjugated State within a Drug–Peptide Compound

Molecular Structure and Pronounced Conformational Flexibility of Doxorubicin in Free and Conjugated State within a Drug–Peptide Compound

Protein therapeutics as an emerging strategy to deal with skin cancer: A short review

31P solid-state NMR based monitoring of permeation of cell penetrating peptides into skin

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