AACR 2024 | Enhancing targeted radionuclide therapy with nanoparticles

So I am a part of DOE’s ARM initiative, which is basically accelerating radio therapeutics through advanced molecular nanoconstruct. We are trying to build a targeted radiotherapeutic strategy for delivering the alpha emitting radioisotope in the tumor cell. As I don’t think I’m in AACR, I need to emphasize on the fact that how devastating cancer is, it not only impacts the patient, but also the friends, family and the community also. So there are several strategies or there are several conventional therapeutic strategies exist which includes the chemotherapy and the non targeted radiotherapy also. But the most of the problems will all those uh treatment strategies is that they are highly nonspecific. They basically target, like it is untargeted. They basically target the population of cells that shows proliferation or tumors growth.

In recent year much greater emphasis has been placed on the targeted radionuclide therapy and Oak Ridge National Lab, or DOE. We are the foremost in the production for the alpha emitting radioisotope. And our intention was to you know lower the gap between the production and the application. So what we hypothesize or what we wanted to do is we wanted to make a platform which is based on, uh, nanoparticles or nano construct based platform by which we can deliver specifically the alpha emitting radioisotope, most importantly, the actinium 225 and radium 223 to the tumor cells, because the alpha emitting radioisotope can have multiple decay daughters and it has higher linear energy, but it can travel shorter distance. So it’s like a wrecking ball compared to the beta, which is like a bullet. So we want to deliver the higher lethal cytotoxic amount of dose to the tumor cell while having minimal exposure to the surrounding healthy tissue. And among the delivery strategy, nanoparticles have been pursued as a vehicle for the targeted radioisotope delivery.

And in my poster or in our research work, the key highlight is we generate nanoparticle based platform. And uh, we specifically presented lanthanum orthovanadate inorganic nanoparticles. We did surface functionalization methods. And we showed the key highlight. Or the most important thing that we showed in this presentation is that without adding any nuclear localization signal, we achieved the 80%, almost nuclear delivery of this nano construct just by doing surface functionalization methods, adding PEG molecules. Then second thing, we showed that when you use almost equivalent dose of radioactive isotope like actinium 225, I used for our study, we showed that when you use the equivalent amount of dose of actinium, you will achieve much higher cytotoxicity towards the tumor spheroid.

When those actinium is encapsulated in these lanthanum orthovanadate nanoparticles compared to the untargeted radioisotope. And how did we measure at Oak Ridge National Lab? We cannot use live animals, so we use, uh, three dimensional breast cancer spheroid as our model. And then we measured the cytotoxicity by using the Incucyte 65 live imaging analysis. And there we showed that there is a disintegration of the tumor spheroid after the treatment with nanoparticles encapsulated with actinium 225. And it lowers the spheroid size over 12 days as well as at the downstream mechanism, we showed that it induces much higher amount of DNA double stranded break compared to the equivalent dose of untargeted radioactive material, which is a breakthrough because it shows two different things. One, you developed a platform that could be useful not only for delivering these radioisotopes, but in future we have a plan or to do the encapsulation of two. Different radio isotope pair like one for diagnosis, other for therapy, so a perfect theranostics composition. And also we want to try these nanoparticles for the combination therapy for the immune therapy also for delivering the drug. And we also showed that um these nanoparticle actually with the radio nanoparticles radioman conjugate, they actually induces the apoptosis in the cancer cells higher, much higher, significantly higher compared to the untargeted radio isotope. But this is also a passive targeting of nanoparticles.

So our ultimate goal is to generate a toolbox for the active targeting or with the active targeting nanoparticle. So how we are going to make it actively targeting towards the tumor cells. So at Oak Ridge National Lab we have in-house nanobody production facilities like we are working on that and then we are using different nanobodies. Nanobodies are much smaller compared to the monoclonal antibody. And it is much more impactful using as a molecular targeting vector. So currently we are working with two different nanobodies. And one of them I presented here is that, HER2 specific nanobody. HER2 is overexpressed in several cancer, including the breast cancer. So immuno like nanobody targeting HER2 is uh, provides a great tool for the future radio immunotherapy.

So here in this poster I also showed that when we use that HER2 targeting nanobody conjugated with the macro alkyne chelator and radiolabeled with actinium, that shows a highly specific uptake, binding and internalization in the breast, HER2 positive breast cancer, but not in any HER2 negative cells. And then the HER2 targeting Nanobody when labeled with the actinium 225, shows much higher impact on cell death, clonogenicity and DNA double stranded break compared to the untargeted radioactive material. So currently what we are trying to do, we are trying to put these nanobody coating or I like to call it as a GPS tracker for my nano car. I call the nano particles as a car, like a cargo ship. It has the radioisotope inside it. And then we would like to put this nanobody on the surface and would like to deliver the specific lethal amount of toxic doses to the particular cancer cells where we want them to go, compared to the untargeted populations of random cells.