Selective vascular disrupting therapy by lipid nanoparticle-mediated Fas ligand silencing and stimulation of STING
Rikito Endo1, Tomoki Ueda1, Takumi Nagaoki1
1Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
Abstract:
Although recent therapeutic developments have greatly improved the outcomes of patients with cancer, it remains on ongoing problem, particularly in relation to acquired drug resistance. Vascular disrupting agents (VDAs) directly damage tumor blood vessels, thus promoting drug efficacy and reducing the development of drug resistance; however, their low molecular weight and resulting lack of selectivity for tumor endothelial cells (TECs) lead to side effects that can hinder their practical use. Here, we report a novel tumor vascular disrupting therapy using nucleic acid-loaded lipid nanoparticles (LNPs). We prepared two LNPs: a small interfering RNA (siRNA) against Fas ligand (FasL)-loaded cyclic RGD modified LNP (cRGD-LNP) to knock down FasL in TECs and a stimulator of interferon genes (STING) agonist-loaded LNP to induce systemic type I interferon (IFN) production. The combination therapy disrupted the tumor vasculature and induced broad tumor cell apoptosis within 48 h, leading to rapid and strong therapeutic effects in various tumor models. T cells were not involved in these antitumor effects. Furthermore, the combination therapy demonstrated a significantly superior therapeutic efficacy compared with conventional anti-angiogenic agents and VDAs. RNA sequencing analysis suggested that reduced collagen levels may have been responsible for TEC apoptosis. These findings demonstrated a potential therapeutic method for targeting the tumor vasculature, which may contribute to the development of a new class of anti-cancer drugs.
Insights
This study introduces novel lipid nanoparticles (LNPs) for cancer therapy. The combination therapy effectively disrupts tumor vasculature and induces cancer cell death, offering a promising new approach to combat drug resistance.
Area of Science:
- Oncology
- Nanotechnology
- Immunology
Background:
- Cancer remains a significant challenge, with acquired drug resistance limiting treatment efficacy.
- Vascular disrupting agents (VDAs) target tumor blood vessels but suffer from poor selectivity and side effects.
- Novel therapeutic strategies are needed to overcome limitations of current cancer treatments.
Purpose of the Study:
- To develop a novel tumor vascular disrupting therapy using nucleic acid-loaded lipid nanoparticles (LNPs).
- To evaluate the efficacy of a combination therapy involving siRNA against Fas ligand and a STING agonist delivered via LNPs.
- To assess the potential of this approach as a new class of anti-cancer drugs.
Main Methods:
- Preparation of two types of LNPs: cRGD-LNP carrying siRNA against FasL and LNP carrying a STING agonist.
- Administration of combination therapy to various tumor models.
- Assessment of tumor vasculature disruption, tumor cell apoptosis, and therapeutic effects.
- RNA sequencing analysis to investigate underlying mechanisms.
Main Results:
- The combination therapy rapidly disrupted tumor vasculature and induced apoptosis within 48 hours.
- Significant therapeutic effects were observed across various tumor models, independent of T cell involvement.
- The therapy showed superior efficacy compared to conventional anti-angiogenic agents and VDAs.
- Reduced collagen levels were identified as a potential factor in tumor endothelial cell apoptosis.
Conclusions:
- Nucleic acid-loaded LNPs offer a novel and effective strategy for tumor vascular disruption.
- This combination therapy demonstrates potent anti-tumor effects and potential for overcoming drug resistance.
- The findings support the development of a new class of vascular-targeting anti-cancer drugs.
