ABSTRACT
Transarterial radioembolization (TARE) is a local radionuclide therapy and is successfully used in hepatocellular carcinoma (HCC) treatment. Radioactive microspheres have been widely studied for TARE. Preparation of ideal radioactive microspheres is significant for clinical research and patient treatment. In this study, we have designed a novel multifunctional microsphere, i.e., polydopamine (PDA)-coated 177Lu-radiolabeled silica microspheres (MS) denoted as 177Lu-MS@PDA, which can be used for TARE and photothermal therapy (PTT). The radiostability of 177Lu-MS@PDA was significantly improved by coating 177Lu-MS with PDA. In addition, the coating of PDA makes microspheres have excellent photothermal performance. MicroSPECT/CT images showed that 177Lu-MS@PDA was accurately embolized and remained in the tumor during the observation time. At the time, it also showed that 177Lu-MS@PDA was very stable in vivo. Furthermore, the anti-tumor results demonstrated that TARE combined with PTT of 177Lu-MS@PDA can significantly inhibit tumor growth without obvious side effects. 177Lu-MS@PDA holds great potential as a promising radioactive microsphere for HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Microspheres , Photothermal TherapyABSTRACT
Radiotherapy (RT) is a frequently used means in clinical tumor treatment. The outcome of RT varies, however, to a great extent, due to RT resistance or intolerable dose, which might be resolved by the development of radio-sensitizing strategies. Here, we report redox-sensitive iodinated polymersomes (RIP) carrying histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA, vorinostat), as a new dual-functional nano-radiosensitizer for breast cancer radiotherapy. SAHA-loaded RIP (RIP-SAHA) with a size of about 101 nm exhibited good colloidal stability while the reduction-activated release of SAHA, giving rise to better antitumor effect to 4T1 breast carcinoma cells than free SAHA. Accordingly, RIP-SAHA combined with a 4 Gy dose of X-ray radiation led to significantly enhanced suppression of 4T1 cells compared with SAHA combined 4 Gy of X-ray radiation, as a result of enhanced DNA damage and impeded DNA damage repair. The pharmacokinetics and biodistribution studies by single-photon emission computed tomography (SPECT) with 125I-labeled SAHA (125I-SAHA) showed a 17.3-fold longer circulation and 237.7-fold better tumor accumulation of RIP-SAHA over SAHA. The systemic administration of RIP-SAHA greatly sensitized radiotherapy of subcutaneous 4T1 breast tumors and brought about significant inhibition of tumor growth, without causing damages to major organs, compared with radiotherapy alone. RIP not only enhanced SAHA delivery but also acted as a radiosensitizer. RIP-SAHA emerges as a smart dual-functional nano-radiosensitizer to effectively enhance tumor radiotherapy.
Subject(s)
Breast Neoplasms/pathology , Histone Deacetylase Inhibitors/administration & dosage , Oxidation-Reduction/radiation effects , Radiation-Sensitizing Agents/administration & dosage , Vorinostat/administration & dosage , Animals , Cell Line, Tumor , Cell Proliferation/radiation effects , Cell Survival/radiation effects , Chemistry, Pharmaceutical , DNA Damage/radiation effects , Drug Carriers/chemistry , Drug Liberation , Female , Histone Deacetylase Inhibitors/pharmacokinetics , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Polymers/chemistry , Radiation-Sensitizing Agents/pharmacokinetics , Tissue Distribution , Vorinostat/pharmacokineticsABSTRACT
Efficacious cancer treatment largely relies on accurate imaging diagnosis and imaging-guided surgery, which can be achieved by combining different mode imaging probes on one single nanoplatform. Herein, a novel radiolabeled NIR-II nanoprobe (125I-MT NP) was developed to enable versatile single-photon emission computed tomography (SPECT) and second near-infrared (NIR-II) fluorescence dual-modal imaging against breast cancer. 125I-MT was precipitated with an amphiphilic triblock copolymer (PEO-PPO-PEO) to form 125I-MT NPs. The 125I-MT NPs exhibited high labeling efficiency (98 ± 2%) with a hydrodynamic diameter of 91.3 ± 5.5 nm. In vitro and in vivo studies demonstrated that 125I-MT NPs emitted intensive NIR-II fluorescence and SPECT signals, and possessed good biocompatibility. By using a breast tumor xenograft mouse model after intravenous injection of 125I-MT NPs, the SPECT imaging and NIR-II imaging showed clear images of tumor tissues at 8 h and 48 h postinjection, respectively, suggesting the feasibility of using 125I-MT NPs to detect tumors before surgery and visualize the dissection area during surgery. In addition, the SPECT scan of a lymph node mapping was performed at 1 h postinjection and NIR-II fluorescence imaging was carried out at 4 h postinjection. This further guarantees the accurate imaging of lymph nodes before and during surgery for lymphadenectomy. Overall 125I-MT NP is a promising, practical imaging probe for sequential imaging and precision cancer therapy.
