Dr. Dipika Ramdas Kalambhe, Ph.D.

Triple-negative breast cancer is difficult to treat because it does not depend on a single mechanism. It remodels its own blood supply, alters its cells so they can travel, and turns the surrounding immune environment to its advantage.

My doctoral work at the Shanghai Institute of Materia Medica — the Chinese Academy of Sciences' principal drug discovery institute — started from the position that combination therapy is won or lost in the delivery system, not only the drug. Two agents with incompatible solubility and release behaviour have to reach the same cell at the same time, or the synergy stays theoretical. So the carrier was designed around that constraint rather than chosen after the fact.

I work across the full arc of a preclinical project: formulation design and physicochemical characterisation, the molecular and cell biology that explains why something works, and the in vivo efficacy, biodistribution and toxicology that decide whether it is worth pursuing. In practice that means a project does not have to change hands to move forward.

Triple-negative breast cancer lacks the three receptors that most targeted breast cancer drugs are built against, so there is no hormonal or HER2-directed option. Chemotherapy remains the standard, relapse is common, and the disease reaches the lungs early. That is the gap this project was aimed at.

The two agents, and why neither works alone

Shikonin is a red-violet naphthoquinone isolated from the root of purple gromwell, Lithospermum erythrorhizon — a pigment used in traditional medicine long before its mechanism was understood. It inhibits PKM2, an enzyme controlling the final step of glycolysis, which starves the tumour of the rapid sugar metabolism it depends on and lowers the lactate output that helps it suppress local immune cells. Its weakness is pharmaceutical rather than biological: it is poorly water-soluble, cleared quickly, and toxic enough at free-drug doses to limit how much can be given.

JQ1 is a synthetic BET bromodomain inhibitor. BET proteins act as readers that keep certain gene programmes switched on; JQ1 displaces them, turning down the transcriptional programmes an aggressive tumour relies on. On its own it is also poorly soluble and has a short half-life.

Combining them is an obvious idea and a hard one to execute. The two molecules have incompatible physicochemical requirements — different solubility behaviour and different release kinetics — so simply co-administering them means they do not arrive at the same cell at the same concentration ratio. The synergy stays theoretical. The delivery system is therefore the experiment, not a detail of it.

The carrier

The solution was a mesoporous polydopamine-based Pickering emulsion. Two ideas are stacked here. A conventional emulsion needs surfactants to stop oil and water separating; a Pickering emulsion is stabilised instead by solid particles that park themselves at the oil–water interface, forming a shell of tiny beads around each droplet. That gives better stability without the irritant chemistry.

The particles forming that shell are mesoporous polydopamine — a synthetic relative of melanin, so biologically well tolerated, and riddled with nanoscale pores that act as sponges for drug molecules. The result is one carrier with two distinct compartments: an oily core and a porous shell. Each drug sits where its chemistry suits it, and both travel, arrive and release together.

What it did, and why the mechanism matters

In triple-negative breast cancer models the combination suppressed both primary tumour growth and lung metastasis. The interesting part is that it did so through three independent mechanisms at once. It induced apoptosis, the programmed cell-death pathway tumours switch off. It blocked epithelial–mesenchymal transition — the TGF-β-driven change by which anchored cells acquire the ability to detach and travel, which is how metastasis begins. And it blocked vasculogenic mimicry, a route where tumour cells line up to form vessel-like channels and supply themselves directly, bypassing the blood-vessel growth that anti-angiogenic drugs are designed to stop.

That last one matters more than it first appears. A tumour that can fake its own vasculature has an escape route from an entire drug class. Closing apoptosis resistance, migration and self-supply simultaneously is the argument the thesis makes: against a disease with several independent survival strategies, a single-mechanism drug leaves the others open.

Carrying it toward the clinic

Surgery is where triple-negative breast cancer is usually treated first, and the period immediately afterwards is when residual cells seed recurrence. The same formulation was loaded into a thermosensitive hydrogel — liquid when cool, setting to a soft solid at body temperature — so it can be placed directly into the resection cavity, hold its position, and release drug locally over the window that matters. The work is published in Acta Pharmacologica Sinica with joint first authorship.