Chlorotoxin

CTX, CLTX; the imaging conjugate is tozuleristide (BLZ-100, "Tumor Paint"); the earlier radiotherapeutic was TM-601 / <sup>131</sup>I-TM-601

Oncology & imaging

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Summary

Class: Naturally occurring 36-amino-acid scorpion-venom peptide with four disulfide bonds (a "short-chain scorpion toxin" fold); used as a tumour-targeting ligand rather than as a drug in its own right
Mechanism: Binds selectively to glioma and several other tumour cell surfaces — the target is generally attributed to a matrix metalloproteinase-2 complex and chloride channel components — and carries whatever is attached to it (a fluorescent dye, a radioisotope, a receptor) to the tumour
Routes studied: Intravenous (imaging conjugate, before surgery); intracavitary and intravenous (radioiodinated version)
Half-life: The imaging conjugate clears from blood over hours, with tumour fluorescence detectable intra-operatively for a surgical window the trials describe as several hours to a day after dosing
Storage: Not applicable to this profile — see research context notes
Regulatory status: Not approved anywhere. Investigational in all jurisdictions

Doses are as reported in studies or by the community — never recommendations.

1What it is

Chlorotoxin is a small peptide from the venom of the deathstalker scorpion, Leiurus quinquestriatus, found across North Africa and the Middle East. It was isolated and characterised in the early 1990s by DeBin and Strichartz, who named it for its action on chloride conductance.

It matters not because of what it does to people but because of what it sticks to. In the late 1990s Harald Sontheimer's group found that chlorotoxin binds glioma cells — the most common and most lethal primary brain cancers — far more avidly than it binds normal brain. Gliomas are notoriously difficult to remove completely because the tumour margin blends into functioning brain tissue; a surgeon working by eye and feel cannot see where the tumour ends. A molecule that selectively decorates tumour cells is therefore a surgical tool.

That led to two generations of products. TM-601 was chlorotoxin labelled with iodine-131, developed as a targeted radiotherapy delivered into the resection cavity or intravenously. Tozuleristide (BLZ-100) is chlorotoxin conjugated to indocyanine green, a near-infrared fluorescent dye already in clinical use. Given intravenously before surgery, it is intended to make residual tumour glow under a dedicated imaging camera — hence the informal name "Tumor Paint". Chlorotoxin has more recently been used as the targeting domain of a chimeric antigen receptor for engineered T cells.

An important and frequently garbled point: chlorotoxin is one of the less dangerous components of a dangerous venom. Deathstalker envenomation is potentially fatal, particularly in children, but that toxicity comes mainly from sodium-channel-active toxins in the same venom, not from chlorotoxin. Chlorotoxin's own targets are largely insect and crustacean channels, and it has shown low mammalian toxicity in the doses used clinically. It is a tumour-targeting address label that happens to have been found in venom.

2How it's thought to work

Selective tumour binding. The best-supported account is binding to a complex involving matrix metalloproteinase-2 (MMP-2) on the tumour cell surface, with contributions from chloride channel proteins (ClC-3 has been proposed) and from annexin A2 in some reports. The precise receptor remains contested, which is itself an open question for the field.

Chloride conductance. The original pharmacology — inhibition of small-conductance chloride channels — is thought to contribute to effects on glioma cell shape change and invasion, which require volume regulation. This is a mechanistic observation, not the basis of the imaging use.

Payload delivery. For both the fluorescent and radiolabelled conjugates, chlorotoxin's role is purely to concentrate the payload. The dye provides visible signal; the isotope provides local radiation.

Low molecular weight and crossing into brain. Its small size and stable disulfide-bonded fold allow it to reach tumour tissue behind a partly disrupted blood–brain barrier.

A scorpion peptide that binds selectively to glioma cells. Used less as a channel blocker than as a targeting tag, attached to a dye that makes tumour margins visible during surgery.Schematic — not to scale

3What the research shows

Glioma margin visualisation in adults

A Phase 1 dose-escalation study of intravenous tozuleristide before glioma resection reported that the agent was well tolerated and that intra-operative fluorescence could be detected in tumour tissue, with the signal correlating imperfectly with histology (Patil 2019, Neurosurgery). Small, uncontrolled, dose-finding; it established feasibility and safety, not benefit to patients. [5]

Paediatric central nervous system tumours

A Phase 1 study in children with CNS tumours reported tolerability and fluorescence across several tumour types (ClinicalTrials.gov NCT02462629). A subsequent larger paediatric study was undertaken; an expanded access protocol was later opened (NCT04343274), which in practice indicates that routine licensed supply was not available. As of this review no regulatory approval exists and the programme's status is best described as stalled †.

Graded B/D

Other tumour types

Chlorotoxin binding has been reported across a wide range of tumours of neuroectodermal origin and some others — medulloblastoma, melanoma, neuroblastoma, prostate and breast carcinoma — mostly in cell and animal work, with some human imaging in skin and breast tumours.

Radioiodinated chlorotoxin therapy

<sup>131</sup>I-TM-601 was taken into Phase 1 and early Phase 2 studies in recurrent glioma, delivered intracavitary or intravenously, with reports of tolerability and tumour localisation (Mamelak 2006, J Clin Oncol). Development did not continue to approval. [4]

Graded C/D

Chlorotoxin-directed CAR T cells

Using chlorotoxin instead of an antibody fragment as the tumour-recognition domain of a CAR, T cells showed activity against glioblastoma in mouse models (Wang 2020, Science Translational Medicine). Preclinical; early-phase human study has been pursued †. [6]

4Reported side effects and interactions

Literature-reported

Literature (conjugate, clinical trials). the Phase 1 imaging studies reported the agent to be generally well tolerated. Indocyanine green conjugates carry a recognised risk of hypersensitivity reactions, and infusion reactions have been described with this class of agent. Because the trials were small, uncommon adverse effects would not have been detected.

Literature (envenomation). this is the relevant human exposure route for the parent venom, not for chlorotoxin itself. Deathstalker stings cause severe local pain, autonomic storm, pulmonary oedema and myocardial injury, and can be fatal in children; treatment is supportive with antivenom where available. These effects are attributed to other venom components.

Community-reported

Community use: essentially none documented. Self-administration would be pointless — the molecule has no therapeutic effect of its own; its entire function is to make tissue fluoresce under a specialised near-infrared camera during an operation.

Theoretical. immunogenicity on repeat dosing of a non-human peptide; off-target binding to normal tissues expressing the target complex, which would reduce the contrast that makes the agent useful.

Interactions. none established.

Markers researchers commonly monitor

No compound-specific biomarkers are established, and there is no self-directed use to monitor. In the clinical trials the relevant measures were surgical and radiological rather than laboratory:

Marker	Why it's watched
Extent of resection on post-operative MRI	the actual outcome the agent is meant to improve.
Histopathology of fluorescent versus non-fluorescent tissue	the measure of whether the signal means what it is supposed to mean (sensitivity and specificity at the margin).
Standard peri-operative bloods (CBC, CMP) and vital signs during infusion	general trial safety monitoring, plus watchfulness for hypersensitivity given the dye component.
Neurological examination	because the clinical question is whether more complete resection can be achieved without more deficit.

Free for everyone. Safety information is never behind a paywall.

5Research context and safety notes

Chlorotoxin and its conjugates are investigational diagnostic agents and laboratory reagents, not treatments. Three points define that context: - It is a targeting ligand, not a drug. Unconjugated chlorotoxin has no demonstrated therapeutic benefit. Its value lies entirely in what is attached to it and in the imaging hardware or radiation physics that reads the payload out. - The readout requires an operating theatre. The fluorescent signal is in the near-infrared range, invisible to the eye, and requires a dedicated intra-operative imaging system. There is no setting outside neurosurgery in which the agent does anything observable. - It is sourced synthetically, and the parent venom is dangerous. Clinical-grade material is made by chemical synthesis or recombinant expression, not extracted from scorpions. Any handling of whole venom is a different and genuinely hazardous proposition. No preparation, concentration or storage guidance is given here, because there is no use of this compound outside a clinical trial or a laboratory with its own handling protocols.

6Commonly studied alongside

5-aminolevulinic acid and fluorescein sodium (the established fluorescence-guided surgery agents chlorotoxin conjugates are compared against); indocyanine green alone; conotoxins (#194) and other venom-derived peptides as examples of the same discovery strategy.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not FDA-approved. Tozuleristide held orphan drug and rare paediatric disease designations; investigational, with an expanded access protocol on record †
European Union	Not authorised; no EMA marketing authorisation
United Kingdom	Not licensed
Australia	Not approved by the TGA
South Africa	Not registered with SAHPRA
Sport	Not listed by WADA. As a non-approved substance it would in principle fall under S0 if administered to an athlete, but it has no performance application

8Open questions

What is the actual molecular target? MMP-2 complex, ClC-3, annexin A2 and others have been proposed and the question is unresolved.
Does fluorescence guidance with this agent improve extent of resection, survival or neurological outcome? No controlled trial has answered this.
Why did a programme with clean Phase 1 data and orphan designations not progress — biology, signal-to-noise, or commercial factors?
Can the chlorotoxin scaffold carry a therapeutic rather than diagnostic payload with acceptable specificity?

9References

1DeBin JA, Maggio JE, Strichartz GR (1993). Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. Am J Physiol. PubMed · DOI
2Soroceanu L, Gillespie Y, Khazaeli MB, Sontheimer H (1998). Use of chlorotoxin for targeting of primary brain tumors. Cancer Res. PubMed
3Deshane J, Garner CC, Sontheimer H (2003). Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem. PubMed · DOI
4Mamelak AN et al. (2006). Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol. PubMed · DOI
5Patil CG et al. (2019). Phase 1 safety, pharmacokinetics, and fluorescence imaging study of tozuleristide (BLZ-100) in adults with newly diagnosed or recurrent gliomas. Neurosurgery. PubMed · DOI
6Wang D et al. (2020). Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci Transl Med. PubMed · DOI
7ClinicalTrials.gov. NCT02234297; NCT02462629; NCT04343274. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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11Page history

31 Oct 2026Profile published — awaiting medical review

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