Researchers are constantly looking for better alternatives for the treatment of cancer, which claims the lives of thousands of people around the world. One of the latest advances in this area is combination therapy, a treatment modality that uses two or more medications to fight tumors more effectively. Now, scientists have developed and synthesized an innovative combination prodrug called TTFA-Platin. This advance promises to improve the effectiveness of oncological therapies and reduce associated side effects.
Combination therapies have revolutionized cancer treatment by using multiple drugs that act on different disease mechanisms. This strategy makes it possible to simultaneously attack various tumor growth pathways, increasing the effectiveness of the treatment and decreasing the probability of resistance by cancer cells. However, coadministration of several medications may increase toxicity and adverse effects in patients.
Cancer cells continually grow and divide and spread to different parts of the body. It would be very difficult for a single drug to stop a cancer completely, as it could only target a specific aspect of the cancer. To overcome these challenges, prodrugs have been developed, inactive compounds that are activated only in the presence of specific stimuli from the tumor environment. This feature allows a controlled and targeted release of the active drug directly into the cancer cells, minimizing damage to healthy tissues and reducing side effects. The prodrug strategy is basically a smart key that has been specifically designed to open the door to cancer treatment only when it hits the right target.
Led by Megha Biswas, PhD student at IISER Berhampur, and Dr. Rakesh Kumar Pathak, faculty member at IISER Berhampur, whose work focuses on drug development involving synthetic chemistry, biology and nanotechnology to create therapeutic solutions innovative, the study has been published in the Journal of Medicinal Chemistry.
How combination therapies and this prodrug work to fight cancer
Megha Biswas explains it with a football metaphor: “Imagine an exciting football match between a well-organized team and a tough opponent. Each drug, in combination, plays a critical role and works together to mitigate the deadly disease. One drug takes the lead. role of a striker and attacks the cancer cells head-on with complete precision. The next drug plays the role of a midfielder and supports the striker by preventing the cancer’s defense mechanism from coming to the fore. Meanwhile, the third drug acts as a defender, protecting the healthy cells and minimizing drug resistance.
Using this prodrug strategy, Biswas explains how they have synthesized the new prodrug TTFA-Platin, which combines two powerful drugs: TTFA (which acts on the mitochondria, which are the engine of the cell) with cisplatin (which causes DNA damage). , a well-known anti-cancer drug that is already on the market. “By combining these two drugs in a single platform, we have synthesized a dual-acting prodrug that has a major impact against cancer.”
The secret lies in the unique design of TTFA-Platin. It has intermediate kinetic lability compared to cisplatin and carboplatin, which are the two known anticancer drugs used clinically to treat various types of cancer. Kinetic lability tells us the speed with which a drug can react to its environment. In the case of anti-cancer drugs, it is the speed with which it binds to its target, such as DNA.
Cisplatin, due to its high kinetic lability, does not distinguish between healthy and cancerous cells, which causes toxic side effects associated with its treatment. Carboplatin, which has a different structure in terms of leaving group, shows low kinetic lability, so it reacts very slowly. TTFA-Platin offers intermediate kinetic reliability, reducing side effects and improving overall therapeutic efficacy.
For a prodrug to display its therapeutic activity, it must travel through the blood circulation and reach the desired cancer site and release its active drug. If released or broken down too soon, the effect would be reduced. This proper balance between remaining intact (stability), arriving at the site at an appropriate rate (kinetic lability), and working at its target site (activity) is the unique feature of this engineered prodrug, TTFA-Platin.
In this study, we performed comprehensive 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 attack cancer cells effectively.
TTFA-platinum showed significant anticancer activity against a panel of cancer cell lines, including MDA-MB-468 (breast), MiaPaCa-2 (pancreas), DU145, and PC3 (colon) cells. TTFA-platinum enters the cancer cell and releases its active drugs, TTFA and active Pt(II) species. Interestingly, the prodrug form also shows interactions with biomolecules. Together, all of these forms alter mitochondrial function, 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 resulting in the death of cancer cells. Animal studies showed that TTFA-Platin was less toxic compared to cisplatin and carboplatin. Therefore, this dual-action prodrug successfully enhances the overall therapeutic efficacy of platinum treatment, addressing the drawbacks of existing therapies.
This development represents a significant advance in medicinal inorganic chemistry and offers new hope for improving outcomes in cancer treatment. Although despite these promising results, it is necessary to conduct clinical trials in humans to confirm the safety and effectiveness of TTFA-Platin in the treatment of cancer. Researchers are optimistic that this combined prodrug could become a valuable tool in the fight against this disease.
Source: Megha Biswas and Science
