Polymer composite microspheres loading ¹⁷⁷ Lu radionuclide for interventional radioembolization therapy and real-time SPECT imaging of hepatic cancer

Abstract

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

Polymer Microspheres and Their Application in Cancer Diagnosis and Treatment

“…For instance, Lee et al utilized a single emulsification-solvent evaporation technique to encapsulate the hydrophobic drug erlotinib in PLGA materials for sustained-release microspheres [ 5 ]. Additionally, Xiao and Wei et al employed single emulsification-crosslinking curing to develop chitosan microspheres and magnetic microspheres, respectively [ 38 , 39 ]. While the single emulsification technique is straightforward to use and has a low equipment cost, the particle size distributions of the microspheres produced tend to be wider due to increased aggregation and deformation of droplets during emulsification.…”

“…As a result, there is a growing focus on the research and development of biodegradable materials. Chitosan microspheres [ 39 ], sodium alginate microspheres [ 18 ], filipin protein microspheres [ 30 , 91 ], and CelMA microspheres [ 48 ] are among the widely utilized options. Apart from biodegradability and good biocompatibility, which are necessary for microsphere re-embolization, uniform and controllable size, as well as good elasticity, are also crucial characteristics for radioactive microspheres [ 48 ].…”

“…Carboxymethyl cellulose Breast cancer [66] Carboxymethyl starch Colorectal cancer [69] Gelatin Osteosarcoma [20] Gelatin Hepatocellular carcinoma [19] Gelatin/methacrylated alginate hydrogel composite Gastric cancer [71] Hyaluronic acid Non-small-cell lung cancer [5] Methacrylate fish gelatin Gastric cancer [42] Methacrylate gelatin Melanoma/Breast cancer [75] PLA Melanoma [74] PLGA Lung cancer [68] PLGA Osteosarcoma [27] PLGA Malignant pleural mesothelioma [73] PLGA Non-small-cell lung cancer [28] Polybutylene adipate co-terephthalate/polyvinylpyrrolidone composite Non-small-cell lung cancer [76] Porous hydroxyapatite/gelatin composite Osteosarcoma [67] Immunotherapy Chitosan/sodium alginate composite Colorectal cancer [77] Gelatin Ovary carcinoma [78] Hyaluronic acid Pancreatic ductal adencarcinoma [79] Methacrylate gelatin/methacrylate hyaluronic acid composite Breast cancer [80] PLGA Breast cancer/melanoma [81] PLGA Melanoma [82] Poly(ethylene glycol)diacrylate Non-small-cell lung cancer [83] Poly(N-isopropylacrylamide) Melanoma [84] Polyanhydride copolymer Head and neck squamous cell carcinoma [85] Silk fibroin Melanoma [21] Physiotherapy Alginate Hepatocellular carcinoma [18] Calcium alginate Hepatocellular carcinoma [86] Chitosan Hepatocellular carcinoma [39] Diallyl isophthalate Liver cancer [87] Gelatin Osteosarcoma [20] Gelatin Hepatocellular carcinoma [19] Gelatin, genipin, and sodium alginate composite Hepatocellular carcinoma [38] Liquid metals Hepatocellular carcinoma [88] Methacrylated gelatin Hepatocellular carcinoma [48] PLGA Breast ca...…”

“…In terms of nuclide selection, 90 Y-based microspheres such as TheraSphere and SIR-Spheres, approved by the FDA for hepatocellular carcinoma treatment, are pure betaemitters and are not suitable for nuclear imaging or post-treatment monitoring [90]. Recent advancements include microspheres loaded with 111 In, 131 I, 166 Ho, and 177 Lu, capable of therapeutic and imaging functions [39]. Regarding nuclide labeling, strict regulation is essential for safety.…”

Charged Gold Nanoparticles for Target Identification–Alignment and Automatic Segmentation of CT Image-Guided Adaptive Radiotherapy in Small Hepatocellular Carcinoma

“…Moreover, a novel approach was introduced to advance ART technology for other lower-resolution tumors in CT images. Previous investigations have demonstrated the accuracy of nanoreagent distribution and imaging in liver tumors. − However, the study focused on designing a nano-CT-enhanced contrast agent for prolonged imaging in sHCC and establishing its efficacy in automatic segmentation for AI. The study had limitations, such as the unvalidated imaging accuracy of sHCC using the charged AuNP contrast agent and the limited data set for training the deep learning-based segmentation model.…”