Polymer composite microspheres loading ¹⁷⁷Lu radionuclide for interventional radioembolization therapy and real-time...

Transarterial radioembolization (TARE) with ⁹⁰Y-labeled glass and resin microspheres is one of the primary treatment strategies for advanced-stage primary and metastatic hepatocellular carcinoma (HCC). However, difficulties of real-time monitoring post administration and embolic hypoxia influence treatment prognosis. In this study, we developed a new biodegradable polymer microsphere that can simultaneously load ¹⁷⁷Lu and MgO nanoparticle, and evaluated the TARE therapeutic efficacy and biosafety of ¹⁷⁷Lu-PDA-CS-MgO microspheres for HCC treatment.

Chitosan microspheres were synthesized through emulsification crosslink reaction and then conducted surface modification with polydopamine (PDA). The ¹⁷⁷Lu and nano MgO were conjugated to microspheres using active chemical groups of PDA. The characteristics of radionuclide loading efficiency, biodegradability, blood compatibility, and anti-tumor effectwere evaluated both in vitro and in vivo. SPECT/CT imaging was performed to monitor bio-distribution and bio-stability of ¹⁷⁷Lu-PDA-CS-MgO after TARE treatment. The survival duration of each rat was monitored. HE analysis, TUNEL analysis, immunohistochemical analysis, and western blot analysis were conducted to explore the anti-tumor effect and mechanism of composited microspheres. Body weight, liver function, blood routine examination were monitored at different time points to evaluate the bio-safety of microspheres.

The composite ¹⁷⁷Lu-PDA-CS-MgO microsphere indicated satisfactory degradability, biocompatibility, radionuclide loading efficiency and radiochemical stability in vitro. Cellular evaluation showed that ¹⁷⁷Lu-PDA-CS-MgO had significant anti-tumor effect and blocked tumor cell cycles in S phase. Surgical TARE treatment with ¹⁷⁷Lu-PDA-CS-MgO significantly prolonged the medial survival time from 49 d to 105 d, and effectively inhibited primary tumor growth and small metastases spreading. Moreover, these microspheres indicated ideal in vivo stability and allowed real-time SPECT/CT monitoring for up to 8 weeks. Immunostaining and immunoblotting results also confirmed that ¹⁷⁷Lu-PDA-CS-MgO had potential in suppressing tumor invasion and angiogenesis, and improved embolic hypoxia in HCC tissues. Further evaluations of body weight, blood test, and pathological analysis indicated good biosafety of ¹⁷⁷Lu-PDA-CS-MgO microspheres in vivo.

Our study demonstrated that ¹⁷⁷Lu-PDA-CS-MgO microsphere hold great potential as interventional brachytherapy candidate for HCC therapy. Polymer composite microspheres loading ¹⁷⁷Lu radionuclide and MgO nanoparticles for interventional radioembolization therapy and real-time SPECT imaging of hepatic cancer.