Innovative Radiopharmaceutical Therapy for Metastatic Cancers

Nanocarrier technologies have long been employed to deliver therapeutic agents to solid tumors to decrease toxicity while also increasing efficacy. The safety profiles of therapeutic agents have been improved when delivered in a nanocarrier system, while effective cancer treatment using nanocarriers continues to be impeded by limited delivery efficiency to tumors. It has been highlighted recently that, on average, only 0.7% of IV-injected nanoparticles are delivered to tumors, with most of the agent accumulating instead in the liver, spleen, or lungs. The delivery of nanoparticles to peritoneal metastatic tumors with a limited blood supply is particularly challenging. Peritoneal metastasis is one of the most common forms of metastatic disease in patients with ovarian, gastric, pancreatic, bladder and colon cancer, all of which have a very poor prognosis.

We have developed a radionuclide-containing nanocarrier for tumor-specific delivery to peritoneal tumors through intraperitoneal administration. This radiotherapeutic agent (166Ho) is produced by neutron activation of non-radioactive holmium atoms (165Ho) entrapped within a mesoporous silica nanoparticle (MSN) matrix. Through preclinical models in mice bearing peritoneal human ovarian tumors, we have demonstrated that the 166Ho-MSNs specifically accumulate in the peritoneal tumors following IP injection producing targeted irradiation of these tumors, with minimal exposure to outside tissues and limited off-target effects in tumor-bearing mice. We found that the emitted beta radiation promoted deeper penetration of MSNs into tumor tissues as compared to stable (non-radioactive) 165Ho-MSNs. The treatment significantly reduced tumor burden and prolonged the survival of mice bearing peritoneal metastasis in multiple human ovarian and pancreatic cancer models. However, those were in immunocompromised mice and the tumor eventually progressed aggressively to mortality. Recently we tested mouse peritoneal metastasis model in immunocompetent mice. A single dose of 166Ho-MSNs not only eliminated the disseminated tumors in the peritoneal cavity, but also inhibited the growth of subcutaneous tumors when tumor cells were reimplanted one week after the treatment. The talk will illustrate the intraperitoneal delivery of tumor-specific radioactive nanoparticles as a novel avenue for effectively eliminating hard-to-treat peritoneal metastasis and that may result in a new clinical practice paradigm.