HMN 2025: The story of the TTFA-Platinum combination prodrug

Cancer is a deadly disease that claims the lives of thousands of people around the world and researchers are constantly looking for better treatment alternatives. One of the major advances is combination therapy, a treatment modality that uses two or more drugs more effectively to treat cancer.

We synthesized the combination drug TTFA-Platin as a more targeted anticancer treatment. Our work is published in the Journal of Medicinal Chemistry.

Combination therapy: how it works

Cancer cells continually grow and divide and spread to different parts of the body. It would be very difficult for a single drug to completely stop a cancer, because it might only target a specific aspect of the cancer. But using two or more drugs combined in a single platform, forming prodrugs that can target different aspects of the cancer, could prove to be a very effective treatment strategy.

Imagine an exciting football match between a well-organized team and a tough opponent. Each drug, in combination, plays a crucial role, working together to alleviate this deadly disease. A drug plays the role of attacker, attacking cancer cells head-on with complete precision. The next drug plays the role of the midfielder, supporting the attacker by preventing the cancer defense mechanism from coming to the fore. Meanwhile, the third drug acts as a defender, protecting healthy cells and minimizing drug resistance.

What are prodrugs?

Prodrugs are the inactive form of combination drugs that will only be activated in the presence of certain stimuli specific to cancer cells, providing a more targeted approach to cancer treatment. The prodrug strategy is essentially a smart key designed specifically to open the door to cancer treatment only when it hits the right target.

Using this prodrug strategy, we synthesized the novel prodrug TTFA-Platin, which combines two powerful drugs: TTFA (which targets mitochondria, which are the powerhouse of the cell) with cisplatin (which causes damage to the ‘DNA), a well-known anticancer drug. drug already on the market. By combining these two drugs on a single platform, we have synthesized a dual-action prodrug that has a powerful impact against cancer.

But what makes TTFA-Platinum so unique?

The secret lies in the unique design of TTFA-Platinum. It has intermediate kinetic lability compared to cisplatin and carboplatin, which are the two well-known anticancer drugs used clinically to treat various cancers. Kinetic lability tells us how quickly a drug can respond to its environment. In terms of cancer drugs, it’s how quickly they bind to their target, like DNA.

Cisplatin, due to its high kinetic lability, fails to distinguish between healthy and cancerous cells, leading to toxic side effects associated with its treatment. Carboplatin, which has a different structure in terms of leaving group, has low kinetic responsibility and therefore reacts very slowly. TTFA-Platin provides intermediate kinetic reliability, thereby reducing side effects and improving overall therapeutic efficacy.

Importance of stability and activity of an anticancer prodrug

For a prodrug to show therapeutic activity, it must travel through the bloodstream, reach the desired cancer site, and release its active drug. If it comes loose or breaks too soon, then the effect will be diminished. This good balance between remaining intact (stability), reaching the site at an appropriate rate (kinetic lability) and working on its target site (activity) is the unique feature of this designed prodrug TTFA-Platin.

In this study, we performed extensive stability and speciation analyzes in various biological environments to map how TTFA-Platin interacts with biomolecules such as DNA and proteins. The results demonstrated that the prodrug maintains its molecular integrity for prolonged periods, allowing it to cross physiological barriers and effectively target cancer cells.

Mechanism of action of TTFA-Platin

TTFA-Platin showed significant anticancer activity against a panel of cancer cell lines, including MDA-MB-468 (breast), MiaPaCa-2 (pancreatic), DU145, and PC3 (colon). TTFA-Platin enters the cancer cell and releases its active drugs, TTFA and active Pt(II) species. Interestingly, the prodrug form also exhibits interactions with biomolecules. Collectively, all of these forms disrupt mitochondrial function, thereby causing cellular stress and releasing reactive oxygen species due to the combined effects of the TTFA and Pt(II) forms.

Active forms of Pt(II) also cause significant DNA damage, ultimately leading to cancer cell death. Animal studies have shown that TTFA-Platin is less toxic than cisplatin and carboplatin. Thus, this dual-action prodrug successfully increases the overall therapeutic efficacy of platinum-based drug treatment, thereby addressing the drawbacks of existing therapies.

This development represents a significant advance in medicinal inorganic chemistry, offering new hope for improving outcomes in cancer treatment.

This story is part of Science X Dialoguewhere researchers can report the results of their published research articles. Visit this page for more information about Science X Dialog and how to get involved.

Megha Biswas holds a Ph.D. student at IISER Berhampur. Dr. Rakesh Kumar Pathak, faculty member at IISER Berhampur, focuses on drug development involving coordination chemistry and nanomedicine. His research integrates synthetic chemistry, biology and nanotechnology to create innovative therapeutic solutions.