Eli Lilly’s recent acquisition of Point Biopharma steps the market closer to wider adoption of radiopharmaceuticals for cancer therapy. Perhaps surprising to some, sonicated microsphere technology, like that being pioneered by Vesselon, has already been demonstrated to radiosensitize cancer cells to external beam radiation therapy. So, the concept of “endoradiotherapy” — coined 20 years ago — using IV administered radio-conjugates, can potentially be similarly optimized by using it in conjunction with gas microspheres and ultrasound.
Let’s look at this potential synergy of these disparate drug enhancing technologies.
Also referred to as Theranostic Nuclear Oncology, its advantage lies in the capability to predetermine the avidity of the radiopharmaceutical to a specific patient’s tumor on pre-treatment staging PET/CT imaging. Even with the radiolabeled targeting to tumor receptors and biomarkers, there still remains to be addressed the classical challenges of oncology biodistribution such as penetrating stroma as well as dealing with the limitations of short residence times in neoplastic lesions. Because they rely on nanomolar concentrations, radiopharmaceuticals could have markedly better effects if they were to be co-formulated with Vesselon’s Imagent® lipid microspheres to penetrate stroma and increase tumor uptake in a multifold manner. This effect was dramatically demonstrated with Vesselon augmenting a STING agonist with a 658% increase in tumor concentration of that small molecule.
In addition to a sonoporation-augmented delivery increase, multiple other cellular Modes of Action change the receive characteristics of cells, including one that enhances radiosensitization of tumors. El Kaffas’ review of this effect describes how multiple investigations have demonstrated that sonicated microspheres can mechanically perturb cell membranes resulting in a ceramide-based radiation enhancement that occurs even at low radiation doses (2–6 Gy), particularly with endothelial cells.
More recently, two papers confirm these effects with compelling in vivo work. McNabb demonstrated an enhancement of radiation effect and superior anti-tumor effect of the combination of microspheres, ultrasound and radiation therapy compared to single treatments of each alone. Tumor growth was maximally inhibited with fractionated radiotherapy combined with the ultrasound-stimulated microbubble-based therapy in New Zealand white rabbits bearing prostate tumor PC3 xenografts. And Sharma validated the efficacy of using fractionated schedules of acoustically stimulated microspheres and whole tumor radiation to enhance response to radiation therapy in a human PC3 tumor in a mouse model. The study concluded that it is the first long-term investigation of the combination of sonicated microspheres and XRT therapy that shows an effective control on solid tumor progression and paves the way to start clinical trials.
In essence, one can consider endoradiotherapy as the ultimate “fractionated dosing” using nanomolar concentrations and relying on targeted ligands to move the radionuclide in proximity of the tumor. Vesselon can both promote more radiopharmaceutical to be localized in the tumor microenvironment and then activate the biophysical stimulation of endothelial cells to promote radiosensitization.
Because Vesselon offers an unprecedented ability to self-assemble both gas microspheres and liposomes, every radiopharmaceutical co-formulated with Imagent would represent a new patented entity. In addition, the co-formulation process is a simple 5-minute on-site procedure that would work seamlessly with the rather involved dose preparations inherent in therapeutics that require an on-site radiopharmacy.
The radiopharmaceutical landscape is yet another class of drugs that Vesselon’s unique platform can improve clinical efficacy with a low regulatory friction profile and a business use case that fits well into clinical practice standards of even such new therapeutic procedures.
- Turner JH. An introduction to the clinical practice of theranostics in oncology. British J Radiology 2018; 91: 20180440.
- Galbiati A. A Dimeric FAP-Targeting Small-Molecule Radioconjugate with High and Prolonged Tumor Uptake. J Nuclear Medicine 2022 63 1852–1858
- Hennrich, U. Lutathera®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy. Pharmaceuticals (Basel). 2019 Sep; 12(3): 114.
- Xu, J. Sonoporation-Enhanced Delivery of STING Agonist Induced Robust Immune Modulation and Tumor Regression. Advanced Therapeutics. 2021, 2100154
- El Kaffas A. Biomechanical effects of microbubbles: from radiosensitization to cell death. Future Oncol. (2015) 11(7), 1093–1108
- McNabb E et al. Ultrasound stimulated microbubble radiation enhancement of tumors: Single-dose and fractionated treatment evaluation. (2020) PLoS ONE 15(9): e0239456
- Sharma et al. Ultrasound-stimulated microbubbles enhancement of fractionated radiation for tumor treatment. BMC Cancer (2023) 23:693
Vesselon develops patentable drug co-formulations using an FDA-approved, biophysically activated lipid microsphere and self-assembling liposomes. These co-formulations safely make targeted tissues more receptive to therapeutic drugs, producing unprecedented levels of efficacy.
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