Periodic Reporting for period 1 - RADIOCONTROL (Breaching the protective cancer stroma with radiotherapy-responsive liposomes)
Berichtszeitraum: 2023-04-01 bis 2025-09-30
Liposomes are nanoparticles composed of phospholipids, the building blocks of cells and tissues, and such lipid nanoparticles are widely used to make chemotherapeutics safer and more effective. The liposomes resemble a spherical, thin lipid membrane and that envelopes a core of water. Liposomes can act as delivery vehicles by carrying non-water soluble chemotherapeutics within their lipid membrane, and water-soluble chemotherapeutics in their aqueous core. The delivery of these chemotherapeutics to cancer tissues is achieved by the leaky blood vessels that surround cancer tissues, allowing the liposomes to amass at high concentrations in malignant tissues. Nonetheless, the drug release is rather uncontrolled, and the toxicity to healthy tissues can still prevent patients from receiving an effective dose to manage their cancer. Perhaps more important is that for certain kinds of cancer, such as pancreatic cancer, chemotherapeutics remain very ineffective. The cause for this resistance is an extremely dense formation of scar tissue around the tumor, which prevents chemotherapeutics from actually reaching the cancerous cells. This project aims to tackle this problem by developing a new liposomal drug delivery system that can deliver chemotherapeutics with high specificity in cancer tissues, and using precise stereotactic radiosurgery to release the drugs on site. By including X-ray-absorbing nanomaterials within the liposomes, the radiosurgery will increase the damage to the protective scar tissue around the cancer compared to radiotherapy alone, which will ultimately make the chemotherapeutics more effective at eradicating the cancer cells. Such liposomes have already been developed to achieve these effects upon activation with visible light, but achieving this with standard-of-care radiotherapy would be a major technological and clinically impactful breakthrough.
Over the past years, the field of photodynamic therapy has garnered a lot of attention for its ability to increase the permeability of cancer tissues, thus enabling chemotherapeutics to more effectively and selectively kill cancer cells. Photodynamic therapy refers to a therapeutic process, in which non-toxic dyes called photosensitizers can transform into chemical catalysts upon activation with visible light. The chemical reactions that follow, transform oxygen molecules into highly toxic reactive oxygen species (ROS). By localizing the area that is illuminated with intense light, these toxic effects can be produced with high precision in cancer tissues only. But besides directly killing cancer cells, photodynamic therapy also destroys collagen fibers, the collagen-producing cells called fibroblast, and widens the blood vessels. Combined, these effects result in increased cancer tissue permeability which can be exploited to increase the efficiency of cancer drugs. These phenomena have been described extensively in our paper in Nature Reviews Bioengineering in September 2024. Yet despite all these positive aspects, the shallow penetration depth of light in tissues (1-2cm) has been identified as a major shortcoming, which limits the application to superficial tumors.
In our project, we therefore develop an approach to achieve similar therapeutic benefits, but adapting the technology to be activated by X-rays that deeply penetrate through tissues. We aim to achieve this by introducing heavy element nanoparticles into the liposomes. On X-ray scans, heavy elements such as gold can easily be identified. This is because such electron-dense elements absorb and scatter X-rays much more efficiently than surrounding soft tissues. When localized in cancer tissues, the heavy metal nanomaterials thus absorb higher amounts of radiation, which are locally deposited in the cancer tissues to generate ROS. This effect, called radiation dose-enhancement, is central to the technology we aim to develop in this project.
Our first study investigated the use of ultra-small gold nanoclusters of 2nm, which could be embedded within the lipid membrane of the liposomes. We showed that these liposomes can elevate the ROS produced during radiotherapy. When irradiated with X-ray irradiation from the European Synchrotron Radiation Facility, we observed that 30% of the drugs inside the liposomes could be released during the irradiation. This is thus far the highest amount of X-ray controlled drug release achieved with such liposomes. When further combining these liposomes with oxaliplatin chemotherapy, we observed significantly improved radiochemotherapy outcomes in 3D cancer cultures of pancreatic cancer. However, in mouse models of cancer, a significant challenge was encountered: the gold nanoclusters appear to exit the liposomes and be rapidly cleared, so that no treatment benefit can be expected in models that more closely resemble a clinical scenario. These findings were published in Advanced Materials in October 2024.
A second challenge with these gold nanoclusters was identified when using a preclinical radiotherapy research platform. While synchrotron radiation is powerful and can be tuned to maximize the effects of specific metallic materials, it is mostly used to obtain a fundamental understanding of the mechanisms underlying radiotherapy enhancement. In contrast, broad-spectrum X-ray irradiation sources are much more common and clinically relevant. Nonetheless, the liposomes containing gold nanoclusters were significantly less effective under such irradiation sources, leading us to abandon the chosen approach with gold nanoclusters. These findings are currently in submission for scientific publication.
Alternative approaches, in which the lipid membranes of liposomes are functionalized with different high-Z nanomaterials, are being investigated. Moreover, we now also explore the inverse approach, in which the liposome core contains a metal-organic framework. Such structures are like metallic sponges that can contain high concentrations of chemotherapeutics, but also increase the amount of high-Z elements as radioresponsive elements.
In our project, we therefore develop an approach to achieve similar therapeutic benefits, but adapting the technology to be activated by X-rays that deeply penetrate through tissues. We aim to achieve this by introducing heavy element nanoparticles into the liposomes. On X-ray scans, heavy elements such as gold can easily be identified. This is because such electron-dense elements absorb and scatter X-rays much more efficiently than surrounding soft tissues. When localized in cancer tissues, the heavy metal nanomaterials thus absorb higher amounts of radiation, which are locally deposited in the cancer tissues to generate ROS. This effect, called radiation dose-enhancement, is central to the technology we aim to develop in this project.
Our first study investigated the use of ultra-small gold nanoclusters of 2nm, which could be embedded within the lipid membrane of the liposomes. We showed that these liposomes can elevate the ROS produced during radiotherapy. When irradiated with X-ray irradiation from the European Synchrotron Radiation Facility, we observed that 30% of the drugs inside the liposomes could be released during the irradiation. This is thus far the highest amount of X-ray controlled drug release achieved with such liposomes. When further combining these liposomes with oxaliplatin chemotherapy, we observed significantly improved radiochemotherapy outcomes in 3D cancer cultures of pancreatic cancer. However, in mouse models of cancer, a significant challenge was encountered: the gold nanoclusters appear to exit the liposomes and be rapidly cleared, so that no treatment benefit can be expected in models that more closely resemble a clinical scenario. These findings were published in Advanced Materials in October 2024.
A second challenge with these gold nanoclusters was identified when using a preclinical radiotherapy research platform. While synchrotron radiation is powerful and can be tuned to maximize the effects of specific metallic materials, it is mostly used to obtain a fundamental understanding of the mechanisms underlying radiotherapy enhancement. In contrast, broad-spectrum X-ray irradiation sources are much more common and clinically relevant. Nonetheless, the liposomes containing gold nanoclusters were significantly less effective under such irradiation sources, leading us to abandon the chosen approach with gold nanoclusters. These findings are currently in submission for scientific publication.
Alternative approaches, in which the lipid membranes of liposomes are functionalized with different high-Z nanomaterials, are being investigated. Moreover, we now also explore the inverse approach, in which the liposome core contains a metal-organic framework. Such structures are like metallic sponges that can contain high concentrations of chemotherapeutics, but also increase the amount of high-Z elements as radioresponsive elements.
This project explores a novel concept, namely radiotherapy-controlled drug delivery. The findings of this project, both positive and negative, will shape the field in the years to come. When successful, such a drug delivery system could have significant scientific, medical, and economic value. Indeed, some of our studies have sparked the interest of technology transfer offices, and further exploitation of our innovative systems as radiosensitizers/drug delivery systems may be warranted.