Tumor specific delivery and radiation-enhanced tumor penetration of mesoporous silica nanoparticles for effective radionuclide therapy of ovarian peritoneal metastasis

Abstract

Advanced ovarian cancer with peritoneal metastasis is challenging to treat. Limited tumor delivery and penetration of the therapeutics to deep tumor regions are significant barriers to effective treatment. The rising radiopharmaceuticals offer hopes for patients through targeted delivery. However, site specific delivery avoiding off target effect remain critical and challenging. We have developed radioactive ¹⁶⁶Holmium loaded mesoporous silica nanoparticles (¹⁶⁶Ho-MSNs) that exhibited predominant accumulation to peritoneal metastases of ovarian cancer upon intraperitoneal administration. It was observed that fluorescence labeled radioactive ¹⁶⁶Ho-MSNs distributed throughout the tumor tissues, while non-radioactive fluorescent ¹⁶⁵Ho-MSNs showed mainly tumor surface deposition of MSNs. The deep penetration leads to uniform therapeutic radiation distribution and absorbed doses within tumors as demonstrated by the dosimetry analysis. The radiation dosing regimen consisting of two 100 µCi ¹⁶⁶Ho-MSN doses separated by 7 days decreased tumor activity and increased the overall lifespan and ascites free survival in several models of IP tumor-bearing mice. These findings illustrate that ¹⁶⁶Ho-MSN is promising for the treatment of ovarian peritoneal metastasis, with selective targeting advantage of the nanoparticles and limited off-target radiation exposure.

Keywords: Holmiun-166; Internal radiation therapy; Intraperitoneal delivery; Neutron activation; Ovarian cancer; Peritoneal metastasis.