Simultaneous Delivery of siRNA and Paclitaxel <i>via</i> a “Two-in-One” Micelleplex Promotes Synergistic Tumor Suppression

TLDR

Combination of therapeutic strategies with distinct mechanisms can cooperatively inhibit cancer development, and chemotherapy combined with siRNA exemplifies this, but delivering both simultaneously to the same tumor cells via systemic administration remains challenging. The study demonstrates a “two‑in‑one” micelleplex approach to systemically deliver siRNA and a chemotherapeutic drug. The micelleplex employs micellar nanoparticles of a biodegradable triblock copolymer poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) to co‑encapsulate the payloads. The micelleplex delivers siRNA and paclitaxel simultaneously to tumor cells in vitro and in vivo, and systemic administration of Plk1 siRNA with paclitaxel achieves synergistic tumor suppression in a xenograft model, requiring a thousand‑fold less paclitaxel than monotherapy and without immune activation or carrier toxicity.

Abstract

Combination of two or more therapeutic strategies with different mechanisms can cooperatively prohibit cancer development. Combination of chemotherapy and small interfering RNA (siRNA)-based therapy represents an example of this approach. Hypothesizing that the chemotherapeutic drug and the siRNA should be simultaneously delivered to the same tumoral cell to exert their synergistic effect, the development of delivery systems that can efficiently encapsulate two drugs and successfully deliver payloads to targeted sites via systemic administration has proven to be challenging. Here, we demonstrate an innovative "two-in-one" micelleplex approach based on micellar nanoparticles of a biodegradable triblock copolymer poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) to systemically deliver the siRNA and chemotherapeutic drug. We show clear evidence that the micelleplex is capable of delivering siRNA and paclitaxel simultaneously to the same tumoral cells both in vitro and in vivo. We further demonstrate that systemic administration of the micelleplex carrying polo-like kinase 1 (Plk1) specific siRNA and paclitaxel can induce a synergistic tumor suppression effect in the MDA-MB-435s xenograft murine model, requiring a thousand-fold less paclitaxel than needed for paclitaxel monotherapy delivered by the micelleplex and without activation of the innate immune response or generation of carrier-associated toxicity.