The therapeutic efficacy of drug coatings depends fundamentally on the selection of the drug system and the rationality of its mechanism of action. Paclitaxel and sirolimus (rapamycin), as the two mainstream drugs for drug coatings, meet the release requirements of DCB and DES respectively, and the differences in their mechanisms of action determine their respective clinical application scenarios. This article provides an in-depth analysis of the mechanisms of action of the two drugs and clarifies their core differences.

The core drug formulations of drug-coated balloons (DCB) and drug-eluting stents (DES) both aim to inhibit vascular smooth muscle cell proliferation and prevent restenosis. Currently, DES mainly adopts sirolimus derivatives as the mainstream (the use of paclitaxel has decreased due to toxicity concerns); DCB, on the other hand, relies on the high permeability of paclitaxel, while sirolimus-based formulations are making rapid breakthroughs. The following is a detailed analysis of the mechanisms of action and mechanistic differences between the two mainstream drugs.

1 Mechanism of Action of Paclitaxel

As the mainstream drug for DCB, paclitaxel is highly lipophilic, enabling it to rapidly penetrate the vessel wall and remain there for a long time. Its mechanisms of action mainly include:

• Local drug release: During balloon dilation, paclitaxel is rapidly released from the coating into the vessel wall, achieving high local concentrations at the lesion site, reducing systemic exposure and side effects.

• Inhibition of smooth muscle cell proliferation: By stabilizing microtubules, it inhibits mitosis of vascular smooth muscle cells (VSMCs), preventing their proliferation and fundamentally preventing restenosis (smooth muscle cell proliferation is the main cause of vascular restenosis).

• Anti-inflammatory effect: Inhibits the release of inflammatory factors, reduces the accumulation of inflammatory cells in the vessel wall, and alleviates the inflammatory response after vascular injury.

• Inhibition of neointimal hyperplasia: Inhibits the proliferation of smooth muscle cells and endothelial cells, reducing neointimal formation and maintaining vascular patency.

• Microtubule stabilization: Binds to tubulin, promotes microtubule polymerization and inhibits their depolymerization, interfering with the normal function of the cytoskeleton, arresting cells in the G2/M phase, preventing cell division and inducing apoptosis.

• Long-acting inhibitory effect: Remains in the vessel wall for a long time, and can continue to exert anti-proliferative and anti-inflammatory effects even after the DCB is withdrawn, providing long-term therapeutic effects.

• Targeted therapy: Acts directly on the diseased vascular site via DCB, avoiding side effects caused by systemic administration and achieving precise treatment.

2 Mechanism of Action of Sirolimus (Rapamycin)

Sirolimus and its derivatives are the mainstream drugs for DES. They achieve precise anti-proliferation by inhibiting the m-TOR pathway and are more friendly to endothelial healing. Their mechanisms of action mainly include:

• Inhibition of the m-TOR pathway: m-TOR is a core regulatory protein for cell growth, proliferation, metabolism and survival. Sirolimus first binds to the intracellular receptor FKBP12 (immunophilin) to form a complex, which then inhibits mTORC1 (m-TOR complex 1), thereby blocking downstream effector molecules (such as S6K1 and 4E-BP1) and inhibiting cell cycle progression and protein synthesis.

• Cell cycle arrest: By inhibiting the m-TOR pathway, it prevents cells from entering the S phase from the G1 phase, effectively inhibiting the proliferation of vascular smooth muscle cells and endothelial cells and preventing vascular restenosis.

• Anti-inflammatory effect: Reduces the production of pro-inflammatory factors (such as IL-6, TNF-α), inhibits the activation of T cells and macrophages, and alleviates vascular wall inflammation and local immune responses.

• Anti-migration effect: Blocks the migration ability of vascular smooth muscle cells, reducing their accumulation at the injury site, thereby inhibiting neointimal hyperplasia.

• Promotion of endothelial healing: Unlike paclitaxel, sirolimus has a weaker inhibitory effect on normal endothelial cells, allowing endothelial cells to gradually repair while inhibiting smooth muscle proliferation, reducing the risk of late thrombosis.

• Long-acting anti-proliferative effect: Remains in the vessel wall for a long time, and combined with sustained-release technology, can maintain local effective concentrations to achieve long-term stable anti-proliferative effects.

• Anti-angiogenesis: Indirectly inhibits the activity of vascular endothelial growth factor (VEGF), reducing pathological angiogenesis.

3 Comparison of Mechanistic Differences Between Paclitaxel and Sirolimus

Paclitaxel’s rapid penetration property adapts to the short-term release requirements of DCB, while sirolimus’s long-acting sustained-release mechanism aligns with the long-term support positioning of DES. The differences in their mechanisms provide the core basis for the formulation design of drug coatings. Clarifying the action logic and differences of the two drugs is a key prerequisite for optimizing drug coating performance and improving clinical treatment efficacy.