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Bladder cancer has one of the highest incidence rates in the world, and is also the fourth most common tumor in men. Although it does not have a high mortality rate, almost half of bladder tumors reappear after 5 years, so continuous monitoring of the patient is required, with frequent visits to the hospital and the need to repeat the treatment. . For all this, bladder cancer is one of the most expensive to cure.
Current treatments that involve administering drugs directly into the bladder have demonstrated good survival rates, but low therapeutic efficacy. A promising alternative is the use of nanoparticles, capable of delivering the therapeutic agent directly to the tumor. In particular, nanorobots stand out, nanoparticles with the ability to self-propel themselves inside the body.
Now, a study published in the prestigious journal Nature Nanotechnology shows how a research team has been able to reduce the extent of bladder tumors in mice by 90% by administering a single dose of urea-powered nanorobots.
These tiny nanomachines are made of a porous sphere of silica. On their surface, they incorporate several components with specific functions. One is the enzyme urease, a protein that reacts with urea, present in urine, making the nanoparticle capable of propelling itself. Another key component is radioactive iodine, a radioisotope commonly used for localized treatment of tumors.
The work, led by the Institute of Bioengineering of Catalonia (IBEC) and CIC biomaGUNE and developed with the collaboration of the Institute of Biomedical Research (IRB Barcelona) and the Autonomous University of Barcelona (UAB), opens the door to new treatments for bladder cancer, which reduce hospitalization time, which would imply lower costs and more comfort for the patient.
“With a single dose we see a 90% decrease in tumor volume. It is much more efficient, taking into account that it is usual for patients with this type of tumor to go to the hospital between 6 and 14 times. With this type of treatment we would increase efficiency, reducing hospitalization time and the cost of treatment,” explains Samuel Sánchez, ICREA research professor at IBEC and leader of the study.
The next step, on which the team is already working, is to study whether these tumors reappear after treatment.
An amazing journey inside the bladder
In previous research, scientists confirmed that the nanorobots’ ability allowed them to reach all the walls of the bladder. This feature is an advantage over the current procedure, where once the treatment is administered directly into the bladder, the patient has to change position every half hour to ensure that the drug reaches all the walls.
The new work goes further by demonstrating not only the mobility of the nanoparticles in the bladder, but also their specific accumulation in the tumor. This was possible thanks to different techniques, including positron emission tomography (PEDO) medical imaging of the mice, as well as microscopy images on the tissues removed after the completion of the study. The latter were taken using a fluorescence microscopy system developed specifically for this project at IRB Barcelona. The system allows you to observe the entire bladder, scanning the different layers of the organ and then obtaining a 3D reconstruction.
“The innovative optical system that we have developed allowed us to cancel the light reflected by the tumor itself and thus identify and locate the nanoparticles throughout the organ, without prior labeling, with an unprecedented resolution. Thus we saw that the nanorobots not only managed to reach the tumor, but rather they were able to access its interior, thus favoring the action of the radiopharmaceutical”, explains Julien Colombelli, leader of the Advanced Digital Microscopy scientific platform at IRB Barcelona.
Deciphering why nanorobots are able to access the inside of the tumor was a challenge. Nanorobots do not contain specific antibodies to recognize the tumor, and tumor tissue is typically stiffer than healthy tissue.
“However, we observed that these nanorobots have the ability to decompose the extracellular matrix of the tumor by locally increasing the pH through a self-propulsion chemical reaction. This phenomenon could favor greater tumor penetration and was beneficial to achieve preferential accumulation in the tumor” , details Meritxell Serra Casablancas, co-first author of the study and IBEC researcher.
Thus, the scientists came to the conclusion that the nanorobots collide with the urothelium as if it were a wall, but in the tumor, since it is more spongy, they penetrate and accumulate inside. A key factor is the mobility of the nanobots, which increases the likelihood that they will reach the tumor.
Furthermore, according to Jordi Llop, researcher at CIC biomaGUNE and co-leader of the study, “the localized administration of the nanorobots carrying the radioisotope reduces the probability of generating adverse effects, and the high accumulation in the tumor tissue favors the radiotherapeutic effect.”
“The results of this study open the door to the use of other radioisotopes with a greater capacity to induce the therapeutic effect, but whose use is restricted when radiopharmaceuticals have to be administered systemically,” adds Cristina Simó, first author of the study. .
Years of work and a spin-off
The study brings together the results of more than three years of collaborative work between several institutions. Part of the data derives from the doctoral theses of Meritxell Serra and Ana Hortelao, both researchers in the IBEC Intelligent Nanobiodevices group, led by Sánchez. Also from the thesis of Cristina Simó, co-first author of the study, that she carried out her predoctoral research in the Radiochemistry and Nuclear Imaging Laboratory led by Jordi Llop at the CIC biomaGUNE. The experience in the animal model of the disease is added by the group from the Department of Genetics and Microbiology of the UAB led by Esther Julián. In addition, the project has received funding from the European Research Council (ERC) and the “la Caixa” Foundation.
The technology on which these nanorobots are based, on which Samuel Sánchez and his team have worked for more than seven years, has been recently patented and is the basis of Nanobots Therapeutics, a spin-off of IBEC and ICREA created in January 2023.
The company, founded by Sánchez, represents a bridge between research and clinical application: “obtaining good financing for the spin-off is crucial to be able to continue developing this technology and, if all goes well, it can reach the market and the society. In June, only after 5 months since the creation of Nanobots Therapeutics, we successfully closed the first round of financing, and we are excited for the future,” highlights Sánchez.
Technological innovation in microscopy to locate nanorobots
Work with nanorobots has represented an important scientific challenge in bioimaging techniques for the visualization of these elements in tissues and the tumor itself. The most common non-invasive techniques used in the clinical setting—such as PET—do not have the necessary resolution to locate these very small particles on a microscopic scale. For this reason, the IRB Barcelona Scientific Microscopy Platform used a microscopy technique that involves the use of a sheet of laser light to illuminate the samples and allows three-dimensional images to be obtained by scattering light when colliding with tissues and particles. Observing that the tumor itself scattered part of the light, generating interference, they developed a new technique based on polarized light that cancels out all the dispersion coming from the tissue and cells of the same tumor. This allowed the nanorobots to be visualized and located without the need to have previously marked them with molecular techniques.