Another way to deliver drugs to cancer cells

An effective way to solve the problem of selectivity of chemotherapeutic drugs is proposed

Roman Ivanov, Computer

The developers of chemotherapeutic agents are still only dreaming of creating selective drugs that attack only malignant cells. French scientists propose in the journal Angewandte Chemie a new approach to solving an old problem: the enzyme beta-galactosidase generates an active drug from an inactive precursor, the so-called prodrug, which can only be captured by cancer cells.

In recent years, many specific tumor markers have been discovered: these are receptors that are usually present on the surface of the membranes of cancer cells, but are not found (or almost not found) on healthy cells. Previously, scientists have tried to use specific antibodies for selective drug delivery strictly to the surface of cancer cells. The main disadvantage of this approach is the constant risk of undesirable immune reactions of the body, not to mention the high cost, complexity of the development and production of specific antibodies.

Researchers led by Sebastien Papot from the University of Poitiers (France) have proposed a simpler approach to achieving selectivity, unencumbered by antibodies. Their method is based on the use of a prodrug consisting of four components: an actual cytotoxic agent, a ligand capable of recognizing one of the specific cancer receptors (what is the fundamental difference from an antibody?), a "trigger" for the release of the drug (galactose) and a linker that binds all the parts together.

At the beginning, the ligand binds to a specific receptor on the surface of the cancer cell. Then the cell membrane folds to form a "bubble" containing the receptor and prodrug, which is drawn into the cell (receptor-mediated endocytosis). After that, the "bubble" is filled with lysosomes – cellular organelles containing, among other things, the enzyme beta-galactosidase, whose task is to cleave galactose from polysaccharides. That is why the "trigger" that is part of the prodrug is galactose. When the "trigger" is cleaved off by an enzyme, the linker spontaneously disintegrates and the active drug is released, which kills tumor cells by blocking cell division.

In addition, the active drug is able to leave the primary cancer cell in which it was formed and immediately absorbed by neighboring, no less malignant cells, killing them too. This is a very useful property, since tumors are often made up of different types of cells. At the same time, more distant healthy cells are practically not affected (they do not have time). They are also unable to interact with the prodrug, since they do not exactly have the specific cancer receptors necessary for this.

Preliminary results of animal tests showed high efficacy of the prodrug: tumors sharply decreased in size, while the introduction of a simple cytostatic (a substance that stops cell division) had no effect.

The progress of the tumor in the treatment of prodrug (lower row) and simple cytostatic (upper row).
The ineffectiveness of the cytostatic is visible to the naked eye, and the prodrug relieved the mouse of the ailment (fig. Wiley-VCH).

Prepared based on the materials of Angewandte Chemie: Targeted Attack on Tumors.

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