Tyroserleutide

Summary

Tyroserleutide (YSL) is a synthetic tripeptide (tyrosyl‑seryl‑leucine) investigated as an antineoplastic agent, primarily for hepatocellular carcinoma. It is being studied in injectable form and within various nanocarrier systems for oral or targeted delivery. Pre‑clinical work shows tumor‑growth inhibition and survival benefits, while an early Phase I trial reported tolerability and modest clinical responses.

Mechanism of Action

Tyroserleutide appears to trigger tumor cell apoptosis and necrosis, partly by disrupting mitochondrial function and interfering with endocytic pathways (reticulin‑ and caveolae‑mediated uptake). In nanoplatforms it also acts as an immunotherapy peptide, enhancing tumor‑specific immune responses and, when combined with Mn²⁺‑mediated oxygen generation, can activate the cGAS‑STING pathway to reduce hypoxia and boost anti‑PD‑1 efficacy.

What the Research Shows

Animal studies demonstrated that YSL prolongs survival of mice bearing H22 ascitic hepatocarcinoma and inhibits growth of human Bel‑7402 xenografts, with dose‑dependent effects and histological evidence of apoptosis. A Phase I continuous‑infusion trial in advanced HCC patients (6–24 mg/day for five days) showed no treatment‑related mortality, a 25% response in early‑stage disease, and acceptable tolerability. Multiple nanocarrier approaches—PLGA oral nanoparticles, cyclodextrin‑based particles, and artificial peptide transporters—have improved cellular uptake, mitochondrial targeting, and antitumor efficacy in vitro and in mouse models. A photo‑immunotherapy platform incorporating YSL further enhanced tumor control and sensitised tumours to PD‑1 blockade in pre‑clinical tests.

Reported Benefits

Pre‑clinical data consistently indicate that tyroserleutide can inhibit hepatocellular carcinoma growth, induce tumor cell apoptosis, and improve survival in mouse models. Early clinical experience suggests the peptide can be administered continuously with manageable safety and yields modest response rates, especially at lower doses. Nanocarrier formulations appear to enhance oral bioavailability and tumour targeting, and when combined with immunomodulatory agents, YSL may synergise with checkpoint inhibitors.

Limitations of the Evidence

Evidence is largely limited to animal models and a single small Phase I study; no Phase II/III efficacy data exist. The optimal therapeutic dose, schedule, and route remain undefined, and the peptide is not approved for any indication. Mechanistic insights are based on indirect observations (mitochondrial disruption, endocytosis) and require confirmation in humans. Potential benefits observed in nanoplatforms may not translate to the peptide alone.

Safety Considerations

The Phase I trial reported no treatment‑related deaths but noted frequent abnormal liver‑function tests and hematologic changes. Dose‑limiting toxicities at 24 mg/day included abdominal distention, severe nausea, hyponatremia, myocardial ischemia, and significant blood count abnormalities. Lower doses (6–12 mg/day) were better tolerated, with most adverse events being mild to moderate. Pre‑clinical nanocarrier studies did not detect major organ toxicity, but human safety data remain limited.

How It Is Administered

Tyroserleutide is investigational and has been delivered by continuous intravenous infusion using a portable pump in clinical studies. Pre‑clinical work explores subcutaneous, intramuscular, and oral administration via PLGA or cyclodextrin nanoparticles, as well as delivery through artificial peptide transporters. Formulations are typically aqueous solutions or nanoparticle suspensions.

Routes of Administration

Goals & Uses

• Anti-angiogenic activityOncologyLow
• Inhibition of tumor metastasisOncologyLow
• Inhibition of hepatocellular carcinoma recurrence post-resectionOncologyModerate
• Tumor cell apoptosis inductionOncologyModerate
• Immune modulationImmunologyLow

Contraindications

• Severe hepatic or renal impairmentOrgan ImpairmentModerate
• Known hypersensitivity to tyroserleutide or any component of the formulationAllergyHigh
• PregnancyPopulationHighPotential fetal risk or insufficient safety data

Adverse Effects

• Allergic reactionsImmunologicalRare
• Fever / mild pyrexiaSystemicUncommon
• Injection site reactionsLocalCommon
• Gastrointestinal discomfortGastrointestinalUncommon

Drug Interactions

• Chemotherapeutic agents (e.g., cisplatin, 5-FU)Low
• ImmunosuppressantsModeratePotential interaction with immune pathways or infection risk

Population Constraints

• Pediatric patientsAgeRelative
• Lactating womenReproductiveRelative
• Pregnant womenReproductiveRelative

Regulatory Status

• European UnionUnapprovedNot approved by the EMA; no marketing authorization granted.
• United StatesInvestigationalNot approved by the FDA; no active IND publicly listed as of knowledge cutoff.
• United KingdomUnapprovedNot approved by the MHRA.

Tyroserleutide has been investigated primarily in China for hepatocellular carcinoma. It has received investigational status and has undergone clinical trials in China. It is not approved by the FDA or EMA as of the current knowledge cutoff.

Evidence & Sources

• Effective Antitumor of Orally Intestinal Targeting Penetrating Peptide-Loaded Tyroserleutide/PLGA Nanoparticles in Hepatocellular Carcinoma
  Journal ArticleLowMa C, et al.2021-01-01T00:00:00.000000Z
• Endogenous nanoplatforms for tumor photoimmunotherapy: Hypoxia modulation and STING pathway activation
  Journal ArticleLowYang Y, et al.2025-01-01T00:00:00.000000Z
• Artificial Tyroserleutide Transporters for Synergistic Cancer Therapy
  Journal ArticleLowLuo D, et al.2025-01-01T00:00:00.000000Z
• The effect of tripeptide tyroserleutide (YSL) on animal models of hepatocarcinoma
  Journal ArticleLowYao Z, et al.2006-01-01T00:00:00.000000Z
• Phase I clinical trial of continuous infusion of tyroserleutide in patients with advanced hepatocellular carcinoma
  Journal ArticleModerateXiao ZY, et al.2012-01-01T00:00:00.000000Z
• Effect and mechanism of actionin vitroof cyclodextrin derivative nanoparticles loaded with tyroserleutide on hepatoma
  Journal ArticleLowWu X, et al.2021-01-01T00:00:00.000000Z

Frequently Asked Questions