One way of dealing with a complex problem is employing a strategy that utilizes the best of multiple approaches, also known as a combinatorial approach. Powered by the expertise of two scientists working towards a common problem, a recent study uses such a combinatorial approach to restrict tumour progression in mice.

Cancer specialists argue that the best way to restrict tumour growth and manage drug resistance is to target multiple biological pathways. However, combining multiple drugs into one therapeutic delivery system is challenging, mainly because of the varied chemistry of anticancer drugs.

Avinash Bajaj and his team at Regional Centre for Biotechnology, Faridabad, experts in the field of biomaterials and nanomedicine, have designed an efficient drug delivery system that packs three different drugs that counter tumour growth. The other member of the collaboration, Ujjaini Dasgputa, faculty at Amity University, Haryana, and an expert in lipid biology, investigated how this novel system manages to halt tumour growth.

Bajaj and his team used biomaterials derived from bile acid (lithocholic acid) to synthesize a hydrogel that could serve as a delivery courier for the three anti-tumour drugs. Hydrogels are water-insoluble crystals that expand by absorbing water and are used to pack drugs which are released when the hydrogel degrades or shrinks.

The drugs packed into the hydrogel target three biological processes that are key to tumour growth — uncontrolled cell proliferation, blood vessel invasion (angiogenesis), and inflammation. The drugs thus target the tumour microenvironment and are predicted to have a combinatorial effect against drug resistance. The scientists have termed the delivery package — TRI-Gel.

Scientists have earlier found it challenging to pack together drugs with varying chemical properties, especially their solubility in water. Bajaj and his team circumvented this problem by stitching a water-soluble moiety to the component of the gel that is water-insoluble or hydrophobic. This allowed the gel to be amphiphilic – able to interact with both water-soluble and water-insoluble drugs. As a result, the water-soluble drug (which targets cell proliferation) could be released at the tumour site via slow diffusion. The other two drugs, which are water-insoluble, are released when the gel eventually gets degraded inside the body. This allows TRI-Gel to release the drugs in a slow and sustained manner, leading to efficient drug action.

Bajaj also hopes to address complex diseases such as diabetes and tuberculosis using this intervention. ​“I hope to create implants that can be placed in the body for a desired and sustained release of a single drug or combination of drugs.”

The scientists injected mouse models of lung carcinoma with TRI-gel to test its efficacy. Interestingly, they discovered that TRI-Gel was better at inhibiting tumour growth than a direct injection of the three drugs, highlighting the effectiveness of the hydrogel. By day 20 of the injection, the researchers found a significant decrease in tumour volume.

Ujjaini Dasgupta and her young team then elucidated the mechanism of TRI-Gel induced tumour regression. They periodically analysed RNA and protein from the mice injected with TRI-Gel and found that TRI-Gel increased the level of GBA1, a protein involved in sphingolipid metabolism. Sphingolipids are important components of cell membranes and their metabolism can give rise to certain lipid metabolites that can either cause cell death or uncontrolled cell division.

On TRI-Gel therapy, enhanced GBA1 activity led to a decrease in a small lipid biomolecule known as ​‘glucosylceramide’ which is implicated in tumour progression and drug resistance. Dasgupta is thrilled at this finding and says, ​“Though most studies assess the genomic impact of a therapy, the cellular or biological effects are a result of the action of small molecules.” Dasgupta postulates a decrease in glucosylceramide to be a mechanism of TRI-Gel induced cell death and tumour regression.

Chittranjan Patra, a scientist at Indian Institute of Chemical Technology, not associated with the study, says, ​“It is interesting to note that the delivery system targets the tumour microenvironment via post-transcriptional modulation of gene expression,” pointing out that TRI-gel impacts the mRNA that codes for GBA1. He believes that quite a number of studies discuss therapy-induced changes in gene expression but don’t explain how such changes actually come about.

Both the group leaders talk about the far-reaching impacts of this collaboration. Dasgupta says, ​“I am a relatively new faculty, just 3 years old. This collaboration has widened the experience of my students; they got to experience the benefits of interdisciplinary science at its complementary best.” Bajaj says, ​“I am a biological chemist with expertise in drug delivery design – Ujjaini’s perspective has added a biological value to this project.” Bajaj adds that without Ujjaini’s and her group’s insights the study would have lacked mechanistic details into the action of TRI-Gel.

On being asked whether this hydrogel can be used for accommodating non-traditional, specific cancer therapy (such as therapeutic antibodies), Bajaj says that the fabrication process needs to be optimized to package drugs with varying chemical and structural properties. Dasgupta, on the other hand, plans to expand her focus to understand other mechanisms (for e.g. epigenetic effects) via which other nano therapeutics may act on tumours.

Pralay Maiti, a biomaterial specialist at the Indian Institute of Technology (IIT) BHU, though excited about the study, wants to visualize a step ahead, ​“Tumour suppression is well proven in the paper, but would TRI-Gel lead to complete remission – could it be curative?” Bajaj points out that it would be difficult to answer this question using mouse models since their tumours tend to be highly aggressive in nature. However, the efficacy of TRI-Gel in inducing tumour shrinkage in such models shows promise for the future of this new therapy.

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