Researchers have developed a sodium-triggered gel using isosteviol-1,6-diester sodium sulfonate to safely deliver bacterial cancer therapies by encapsulating attenuated Salmonella strains and reducing treatment-related toxicity in mouse models.
Drug Target Review reported that the novel delivery system addresses a longstanding challenge in oncology: the severe systemic inflammation caused when therapeutic bacteria accumulate in healthy organs such as the liver and spleen. The approach relies on a small molecule derived from stevioside that remains liquid inside a syringe before undergoing rapid gelation upon contact with sodium ions in the abdominal cavity.
- Targeted Encapsulation: The gel traps therapeutic bacteria safely away from healthy tissues until mechanical movement triggers their controlled release.
- Reduced Toxicity: By preventing bacteria from accumulating prematurely in the liver and spleen, the system significantly lowers organ damage and inflammation.
- Maintained Efficacy: Encapsulated bacterial strains retain their tumor-shrinking potency while dropping treatment-associated side effects.
The core of the delivery platform is 1,6-DAS, a derivative of the diterpenoid isosteviol. Its acid precursor stays liquid under cooling conditions. Exposure to sodium ions triggers the formation of ribbon-like fibers that trap water and establish a stable gel in less than 60 seconds at half the salt concentration found in physiological saline.
The matrix accommodates one billion colony-forming units of bacteria within a 100 microliter volume, which equals one thousand times the standard therapeutic dose. Mechanical movement acts as the primary release trigger. Undisturbed gel releases virtually no bacteria over 72 hours, whereas gentle agitation simulating physiological movement releases roughly 80 percent of the encapsulated payload.
The research team tested the delivery system using VNP-TNF-α nb, an engineered strain carrying a nanobody that targets TNF-α. While this strain demonstrates enhanced tumor-shrinking activity, administering it without encapsulation causes severe spleen damage. Encapsulation reduced treatment-associated weight loss by 78.8 percent, dropping it from 5.47 grams down to 1.16 grams.
Residual 1,6-DAS molecules coat the released bacteria, altering their surface properties. Simulations indicate the molecule binds to flagellin, a bacterial protein recognized by the immune system, helping evade inflammatory responses. Levels of inflammatory markers TNF-α and IL-6 in the liver and spleen fell back to control baselines.
Testing in a two-tumour mouse model showed that four out of five animals receiving the encapsulated bacteria cleared their untreated tumor, compared to just one out of five given free bacterial strains.
Although the approach shows preclinical promise, it remains restricted to laboratory animal models.
Current experiments rely on intraperitoneal administration in mice, and researchers did not use direct tracers to visualize precise gel distribution in vivo. Establishing clinical potential will require rigorous human pharmacokinetic and pharmacodynamic trials to confirm safety profiles.
- The Innovation — Sodium-triggered gel reduces toxicity of bacterial cancer therapy. Cell Press.
