Osteosarcoma is a malignant bone tumor disease, usually accompanied by clinical manifestations such as osteolytic destruction, local swelling and pain, fracture, and early lung metastasis, which seriously affects the quality of life and physical and mental health of patients. At present, the main treatment strategies for osteosarcoma include limb-salvage surgery (osteosarcoma resection) combined with postoperative chemotherapy and radiotherapy. However, the effectiveness of surgical resection is limited by incomplete resection of tumor tissue, and the presence of residual tumor cells can lead to osteosarcoma recurrence. Postoperative chemotherapy and radiotherapy can cause adverse reactions such as hair loss, decreased immunity, and vomiting, which seriously affect the quality of life of patients. In addition, osteosarcoma is very aggressive and often causes severe bone defects that are difficult to repair on their own, resulting in impaired mobility and even disability for patients. Therefore, there is an urgent need to design and develop effective treatment strategies to meet the dual needs of tumor elimination and bone defect repair without compromising the immune system.
In order to solve the above problems, Yao Jiaxin, a doctoral student at Northwest University, prepared an injectable hydrogel system with mild photothermal effect and ion release activity, which can kill tumor cells remaining after osteosarcoma surgery and promote the formation of new bone (Fig. 1). The injectable hydrogel system consists of Se and Mg co-doped hydroxyapatite (Se15%/Mg30%-HAp) nanorods (Fig. 2b), polydopamine-coated CaO2 nanospheres (CaO2-PDA NSs), hydrazide-bonded sericin (Ser-ADH), and chondroitin oxide sulfate (OCS). They form SOH1(CP)1 injectable hydrogel systems with shear-thinning and dynamic cross-linking reconstruction properties through dynamic Schiff base cross-linking and polymer-nanoparticle interactions.
Figure 1. Mechanistic diagram of SOH1(CP)1 injectable hydrogel system for antitumor and bonotropic defect repair
Figure 2. TEM diagram of Sex/Mgy-HAp nanorods (these nanorods were screened by cytotoxicity assays, and Se15%/Mg30%-HAp nanorods were selected for subsequent physicochemical property characterization and biological efficacy experiments). CaO2-PDA NSs in the SOH1(CP)1 injectable hydrogel system have a mild photothermal conversion (41-45°C) function, which converts light energy into heat energy through only 10 minutes of near-infrared light irradiation per day, resulting in significant anti-tumor activity, achieving rapid ablation of tumor cells while avoiding thermal damage to normal tissues and skin around the tumor (Fig. 3). In the non-irradiated phase, the Se15%/Mg30%-HAp slow-release SeO32− in the injectable hydrogel system can effectively inhibit the proliferation and metastasis of tumor cells. In addition, the release of O2 from CaO2-PDA NSs can modulate the hypoxic microenvironment of tumors, thereby reversing tumor immunosuppression and increasing the sensitivity of tumor cells to mild photothermal and SeO32−chemotherapy synergistic therapy, further enhancing the anti-tumor efficacy of the injectable hydrogel system.
Figure 3. Characterization of the efficacy of mild PTT in the SOH1(CP)1 injectable hydrogel system was confirmed by osteosarcoma cell experiments, which can strongly kill tumor cells in a short period of time through mild PTT with rapid characteristics, and by seO32−chemotherapy with time-dependent release characteristics, it can kill tumor cells stably and continuously by long-term ion release (Fig. 4). This SOH1(CP)1 injectable hydrogel system achieved a 100% tumor eradication rate after 18 days of treatment of underarm bearing tumors (osteosarcoma) in nude mice (Figure 5).
Figure 4. Cell-based experimental validation of the anti-tumor efficacy of SOH1(CP)1 injectable hydrogel system
Figure 5. Animal experiments on the anti-tumor efficacy of SOH1(CP)1 injectable hydrogel system were verified Finally, the problem that large bone defects are difficult to repair after osteosarcoma is eliminated is solved. In this SOH1(CP)1 injectable hydrogel system, the degradation behavior of the hydrogel matches the bone repair cycle, including the nutritional support of the hydrogel skeleton degradation products to promote the proliferation of mesenchymal stem cells, and the positive regulatory effect of Ca2+, Mg2+ and PO43- released from inorganic nanoparticles on promoting osteogenic differentiation. The injectable hydrogel system has shown excellent efficacy in bone defect repair (Figure 6).
Figure 6. Verification of the Bone Defect Repair Efficacy of SOH1(CP)1 Injectable Hydrogel SystemThis organic-inorganic composite injectable hydrogel system not only has a high anti-osteosarcoma effect, but also has a strong bone repair promotion effect, which provides a novel tool to solve the problems of "incomplete surgical resection, easy recurrence" and "bone defect difficult to repair caused by strong tumor invasion" under the existing osteosarcoma-related bone defect repair treatment strategies. This dual-ion-assisted mild photothermal therapy provides a new strategy for the postoperative treatment of osteosarcoma. The research results were published online in Advanced Functional, a top journal in the field of Wiley materials, with the title of "An injectable hydrogel system with mild photothermal effects combined with ion release for osteosarcoma-related bone defect repair". Materials. Source: Frontiers of Polymer Science