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Cancers Jun 2023Glioblastoma multiforme (GB) and high-risk neuroblastoma (NB) are known to have poor therapeutic outcomes. As for most cancers, chemotherapy and radiotherapy are the... (Review)
Review
Glioblastoma multiforme (GB) and high-risk neuroblastoma (NB) are known to have poor therapeutic outcomes. As for most cancers, chemotherapy and radiotherapy are the current mainstay treatments for GB and NB. However, the known limitations of systemic toxicity, drug resistance, poor targeted delivery, and inability to access the blood-brain barrier (BBB), make these treatments less satisfactory. Other treatment options have been investigated in many studies in the literature, especially nutraceutical and naturopathic products, most of which have also been reported to be poorly effective against these cancer types. This necessitates the development of treatment strategies with the potential to cross the BBB and specifically target cancer cells. Compounds that target the endopeptidase, matrix metalloproteinase 2 (MMP-2), have been reported to offer therapeutic insights for GB and NB since MMP-2 is known to be over-expressed in these cancers and plays significant roles in such physiological processes as angiogenesis, metastasis, and cellular invasion. Chlorotoxin (CTX) is a promising 36-amino acid peptide isolated from the venom of the deathstalker scorpion, , demonstrating high selectivity and binding affinity to a broad-spectrum of cancers, especially GB and NB through specific molecular targets, including MMP-2. The favorable characteristics of nanoparticles (NPs) such as their small sizes, large surface area for active targeting, BBB permeability, etc. make CTX-functionalized NPs (CTX-NPs) promising diagnostic and therapeutic applications for addressing the many challenges associated with these cancers. CTX-NPs may function by improving diffusion through the BBB, enabling increased localization of chemotherapeutic and genotherapeutic drugs to diseased cells specifically, enhancing imaging modalities such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), optical imaging techniques, image-guided surgery, as well as improving the sensitization of radio-resistant cells to radiotherapy treatment. This review discusses the characteristics of GB and NB cancers, related treatment challenges as well as the potential of CTX and its functionalized NP formulations as targeting systems for diagnostic, therapeutic, and theranostic purposes. It also provides insights into the potential mechanisms through which CTX crosses the BBB to bind cancer cells and provides suggestions for the development and application of novel CTX-based formulations for the diagnosis and treatment of GB and NB in the future.
PubMed: 37444498
DOI: 10.3390/cancers15133388 -
Toxins Mar 2015Chlorotoxin is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool... (Review)
Review
Chlorotoxin is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool to characterize chloride channels. While studying glioma-specific chloride currents, it was soon discovered that chlorotoxin possesses targeting properties towards cancer cells including glioma, melanoma, small cell lung carcinoma, neuroblastoma and medulloblastoma. The investigation of the mechanism of action of chlorotoxin has been challenging because its cell surface receptor target remains under questioning since two other receptors have been claimed besides chloride channels. Efforts on chlorotoxin-based applications focused on producing analogues helpful for glioma diagnosis, imaging and treatment. These efforts are welcome since gliomas are very aggressive brain cancers, close to impossible to cure with the current therapeutic arsenal. Among all the chlorotoxin-based strategies, the most promising one to enhance patient mean survival time appears to be the use of chlorotoxin as a targeting agent for the delivery of anti-tumor agents. Finally, the discovery of chlorotoxin has led to the screening of other scorpion venoms to identify chlorotoxin-like peptides. So far several new candidates have been identified. Only detailed research and clinical investigations will tell us if they share the same anti-tumor potential as chlorotoxin.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Neurotoxins; Peptides; Scorpion Venoms; Scorpions
PubMed: 25826056
DOI: 10.3390/toxins7041079 -
Pharmaceutics Nov 2022In the generational evolution of nano-based drug delivery carriers, active targeting has been a major milestone for improved and selective drug accumulation in tissues...
In the generational evolution of nano-based drug delivery carriers, active targeting has been a major milestone for improved and selective drug accumulation in tissues and cell types beyond the existing passive targeting capabilities. Among the various active targeting moieties, chlorotoxin, a peptide extracted from scorpions, demonstrated promising tumor cell accumulation and selection. With lung cancer being among the leading diagnoses of cancer-related deaths in both men and women, novel therapeutic methodologies utilizing nanotechnology for drug delivery emerged. Given chlorotoxin's promising biological activity, we explore its potential against lung cancer and its utilization for active targeting against this cancer's tumor cells. Our analysis indicates that despite the extensive chlorotoxin's research against glioblastoma, lung cancer research with the molecule has been limited, despite some promising early results.
PubMed: 36559106
DOI: 10.3390/pharmaceutics14122613 -
Toxins Nov 2018Chlorotoxin (CTX) is a 36-amino-acid disulfide-containing peptide derived from the venom of the scorpion . CTX alters physiology in numerous ways. It interacts with... (Review)
Review
Chlorotoxin (CTX) is a 36-amino-acid disulfide-containing peptide derived from the venom of the scorpion . CTX alters physiology in numerous ways. It interacts with voltage gated chloride channels, Annexin-2, and matrix metalloproteinase-2 (MMP-2). CTX-based bioconjugates have been widely subjected to phase I/II clinical trials and have shown substantial promise. Many studies have demonstrated that CTX preferentially binds to neuroectodermal tumors, such as glioblastoma, without cross-reactivity to normal brain cells. With its ability to penetrate the blood-brain-barrier (BBB) and its tyrosine residue allows covalent conjugation with functional moieties, CTX is an attractive platform to explore development of diagnostic and therapeutic agents for gliomas. In this review, we outline CTX structure and its molecular targets, summarize molecular variations of CTX developed for glioma imaging, and discuss future trends and perspectives for CTX conjugates as a theranostic agent.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Molecular Imaging; Multimodal Imaging; Scorpion Venoms
PubMed: 30486274
DOI: 10.3390/toxins10120496 -
Current Pharmaceutical Design Dec 2011Surgical resection remains the primary component of cancer therapy. The precision required to successfully separate cancer tissue from normal tissue relies heavily on... (Review)
Review
Surgical resection remains the primary component of cancer therapy. The precision required to successfully separate cancer tissue from normal tissue relies heavily on the surgeon's ability to delineate the tumor margins. Despite recent advances in surgical guidance and monitoring systems, intra-operative identification of these margins remains imprecise and directly influences patient prognosis. If the surgeon had improved tools to distinguish these margins, tumor progression and unacceptable morbidity could be avoided. In this article, we review the history of chlorotoxin and its tumor specificity and discuss the research currently being generated to target optical imaging agents to cancer tissue.
Topics: Amino Acid Sequence; Animals; Brain Neoplasms; Contrast Media; Diagnostic Imaging; Fluorescent Dyes; Humans; Intraoperative Care; Models, Molecular; Molecular Sequence Data; Nanoparticles; Protein Binding; Scorpion Venoms; Spectrometry, Fluorescence
PubMed: 22204434
DOI: 10.2174/138161211798999375 -
Advanced Pharmaceutical Bulletin Oct 2019Chlorotoxin (CTX) is a minute 4 kDa protein made up of 36 amino acid residues, commonly known for its binding affinity to chloride channels and matrix... (Review)
Review
Chlorotoxin (CTX) is a minute 4 kDa protein made up of 36 amino acid residues, commonly known for its binding affinity to chloride channels and matrix metalloproteinase-2 (MMP-2) of glioma tumors of the spine and brain. This property and the possibility of conjugating this peptide to nanoparticles have enabled its diverse use in various biotechnological and biomedical applications for cancer treatment, such as in tumor imaging and radiotherapy. Because of the fascinating biological properties CTX possesses, elucidating its mechanism of action may hold promise for the development of new and effective therapeutic drugs, as well as more sensitive and highly specific cancer-screening kits. This article therefore reviews the currently known applications of CTX and suggests diverse ways in which it can be applied for the design of improved drugs and diagnostic tools for cancer.
PubMed: 31857956
DOI: 10.15171/apb.2019.061 -
Contrast Media & Molecular Imaging 2018Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of...
PURPOSES
Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of [F]-fluoropropionyl-chlorotoxin ([F]-FP-chlorotoxin) as a novel PET tracer was investigated, and biodistribution in vivo and PET imaging were performed in the C6 glioma model.
PROCEDURES
[F]-FP-chlorotoxin was prepared from the reaction of chlorotoxin with [F]-NFB (4-nitrophenyl 2-[F]-fluoropropionate), which was synthesized from multistep reactions. Biodistribution was determined in 20 normal Kunming mice. Small-animal PET imaging with [F]-FP-chlorotoxin was performed on the same rats bearing orthotopic C6 glioma at different time points (60 min, 90 min, and 120 min) after injection and compared with 2-deoxy-2-[F] fluoro-D-glucose ([F]-FDG).
RESULTS
[F]-FP-Chlorotoxin was successfully synthesized in the radiochemical yield of 41% and the radiochemical purity of more than 98%. Among all the organs, the brain had the lowest and stable uptake of [F]-FP-chlorotoxin, while the kidney showed the highest uptake. Compared with [F]-FDG, a low uptake of [F]-FP-chlorotoxin was detected in normal brain parenchyma and a high accumulation of [F]-FP-chlorotoxin was found in the gliomas tissue. The glioma to normal brain uptake ratio of [F]-FP-chlorotoxin was higher than that of [F]-FDG. Furthermore, the uptake of [F]-FP-chlorotoxin at 90 min after injection was better than that at 60 min after injection.
CONCLUSIONS
Compared with [F]-FDG, [F]-FP-chlorotoxin has a low and stable uptake in normal brain parenchyma. [F]-FP-Chlorotoxin seems to be a potential PET tracer with a good performance in diagnosis of the glioma.
Topics: Animals; Cell Line, Tumor; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Glioma; Mice; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Scorpion Venoms; Tissue Distribution; Transplantation, Heterologous
PubMed: 30670934
DOI: 10.1155/2018/8439162 -
Cytotechnology Oct 2020Glioblastoma multiforme is the most common primary central nervous system malignancy, accounting for half of all intracranial primary tumors. In this study we...
Glioblastoma multiforme is the most common primary central nervous system malignancy, accounting for half of all intracranial primary tumors. In this study we constructed a multifunctional chlorotoxin fusion protein E-CHP that combines enhanced green fluorescent protein (E), glioma-targeting peptide chlorotoxin (C), destabilizing lipid membrane peptide riHA2 (H), and C-terminal and mouse double minute domains of p53 (P). E-CHP was expressed in Escherichia coli and purified by His affinity chromatography. Fluorescence microscopy observation showed that E-CHP could effectively target glioma cells; real-time quantitative PCR revealed that E-CHP increased miR-374a expression; and the dual luciferase reporter assay showed that tumor necrosis factor alpha-induced protein (TNFAIP)8 is a direct target of miR-374a. E-CHP and miR-374a inhibited the proliferation and migration of glioma cells, and Western blot analysis indicated that they suppressed TNFAIP8 expression in glioma cells and promoted the expression of caspase-3 and -8. Finally, E-CHP and miR-374a stimulated the apoptosis of glioma cells, as determined by flow cytometry analysis. These results suggest that miR-374a is a new candidate target for glioma therapy, whereas E-CHP fusion protein has the potential to be developed as a multifunctional carrier for targeted drug delivery and therapy.
PubMed: 32685991
DOI: 10.1007/s10616-020-00411-w