Anti-Tumor Synergy

Nanomedical Treatment Concept

Biocompatible nanocapsules, loaded with an amino acid and equipped with an enzyme, combine two anti-tumor strategies into a synergistic treatment concept. Researchers hope this increases the effectiveness and decreases the side effects of the treatment. In the journal Angewandte Chemie, the scientists explain the concept: tumor cells are deprived of their nutrient, glucose, as this is converted into gluconic acid and hydrogen peroxide (H₂O₂). The generated acidic H₂O₂ can oxidize L-Arginine (L-Arg) into nitrogen monoxide (NO).

NO is a toxic gas. However, in low concentrations in the body, it is an important messenger molecule that regulates such things as circulation and libido. It is also a physiological defense weapon against fungi and bacteria. In higher concentrations, NO is capable of killing tumor cells and increasing the effectiveness of photodynamic and radiological treatments. For clinical use, NO needs to be released in the target area from a biocompatible precursor.

The natural amino acid L-arginine (L-Arg) may be useful in such a system because the native enzyme inducible NO synthase (iNOS) makes NO from L-Arg. NO is also formed when L-Arg is oxidized by H₂O₂. This is interesting because the microenvironment around tumors is rich in H₂O₂. This approach to NO gas therapy is being pursued by researchers at Shenzhen University, China, the National Institutes of Health, Bethesda, MD, USA, and the University of Maryland, College Park, USA. Their special twist is to combine this gas therapy with a method for starving cancer cells in a synergistic treatment.

Starvation of Tumor Cells

Instead of starving a tumor by blocking the blood vessels that feed it, the researchers intend to remove the glucose that the tumor needs for nutrition by consuming it in a metabolic reaction: The enzyme glucose oxidase (GOx) converts the glucose into gluconic acid and H₂O₂. The increased H₂O₂ concentration is a useful side effect because H₂O₂ is both cytotoxic and accelerates the release of NO from L-Arg. Another useful side effect is that H₂O₂ and NO react to form highly toxic peroxynitrites that damage the tumor cells.

The research team led by Peng Huang, Tianfu Wang, and Xiaoyuan Chen has reached an important milestone in the development of this concept. They have developed biocompatible, biodegradable, porous nanocapsules made of organosilicates that transport GOx and L-Arg into tumor cells simultaneously. GOx is bound to the surface; L-Arg is stored inside the capsule. While GOx is active immediately after injection of the nanocapsules into the tumor, L-Arg is released little by little, first through the capsule pores, then as the capsule disintegrates. Their large cavity also allows the capsules to serve as an ultrasound contrast material for better localization of the tumor.

Experiments with both cell cultures and mice have demonstrated the significant synergistic effect of this combination therapy, which successfully inhibits cell growth, initiates cell death, and shrinks tumors in mice.