Accumulation of malignant plasma cells in the bone marrow causes lytic bone lesions in 80% of multiple myeloma patients. Frequently fracturing, they are challenging to treat surgically. Myeloma cells surviving treatment in the presumably protective environment of bone lesions impede their healing by continued impact on bone turnover and can explain regular progression of patients without detectable minimal residual disease (MRD). Locally applicable biomaterials could stabilize and foster healing of bone defects, simultaneously delivering anti-cancer compounds at systemically intolerable concentrations, overcoming drug resistance. We developed silica-collagen xerogels (sicXer) and bortezomib-releasing silica-collagen xerogels (boXer) for local treatment of osteolytic bone disease and MRD. In vitro and in vivo (tissue sections) release of bortezomib was assessed by ultrahigh-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Material impact on bone formation was assessed in vitro regarding osteoclast/osteoblast numbers and activity. In vivo, drilling defects in a rat- and the 5T33-myeloma mouse model were treated by both materials and assessed by immunohistochemistry, UPLC-MS/MS, µCT, and ToF-SIMS. The material’s anti-myeloma activity was assessed using ten human myeloma cell lines (HMCLs) and eight primary myeloma cell samples including four patients refractory to systemic bortezomib treatment. sicXer and boXer show primary stability comparable to trabecular bone. Granule size and preparation method tailor degradation as indicated by release of the xerogel components (silica and collagen) and bortezomib into culture medium. In vitro, both materials reduce osteoclast activity and do not negatively interfere with osteoblast differentiation and function. The presumed resulting net bone formation with maintained basic remodeling properties was validated in vivo in a rat bone defect model, showing significantly enhanced bone formation for boXer compared to non-treated defects. Both materials induce myeloma cell apoptosis in all HMCLs and primary myeloma cell samples. In the 5T33-myeloma mouse model, both materials stabilized drilling defects and locally controlled malignant plasma cell growth. The combination of stabilization of fracture-prone lesions, stimulation of bone healing, and anti-tumor effect suggest clinical testing of sicXer and boXer as part of a combined systemic/local treatment strategy in multiple myeloma and non-malignant diseases.

中文翻译：

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硼替佐米释放二氧化硅胶原干凝胶用于多发性骨髓瘤溶骨和微小残留病的局部治疗


恶性浆细胞在骨髓中的积累导致 80% 的多发性骨髓瘤患者出现溶骨性病变。他们经常破裂，很难通过手术治疗。骨髓瘤细胞在骨病变的可能保护性环境中存活治疗，通过持续影响骨转换来阻碍其愈合，并且可以解释没有可检测到的微小残留病 （MRD） 的患者的正常进展。局部适用的生物材料可以稳定和促进骨缺损的愈合，同时以全身无法耐受的浓度提供抗癌化合物，克服耐药性。我们开发了二氧化硅-胶原干凝胶 （sicXer） 和硼替佐米释放二氧化硅-胶原干凝胶 （boXer），用于溶骨性骨病和 MRD 的局部治疗。通过超高效液相色谱-串联质谱 （UPLC-MS/MS） 和飞行时间二次离子质谱 （ToF-SIMS） 评估硼替佐米的体外和体内 （组织切片） 释放。在体外评估破骨细胞/成骨细胞数量和活性对骨形成的物质影响。在体内，大鼠和 5T33 骨髓瘤小鼠模型中的钻孔缺陷用两种材料处理，并通过免疫组织化学、UPLC-MS/MS、μCT 和 ToF-SIMS 进行评估。使用 10 个人骨髓瘤细胞系 （HMCL） 和 8 个原发性骨髓瘤细胞样本（包括 4 例全身性硼替佐米治疗难治性患者）评估了该材料的抗骨髓瘤活性。sicXer 和 boXer 显示出与小梁骨相当的初级稳定性。颗粒大小和制备方法定制降解，如将干凝胶成分（二氧化硅和胶原蛋白）和硼替佐米释放到培养基中所示。 在体外，这两种材料都会降低破骨细胞活性，并且不会对成骨细胞的分化和功能产生负面影响。在大鼠骨缺损模型中进行了体内验证，推测产生的净骨形成具有保持的基本重塑特性，显示与未治疗的缺损相比，boXer 的骨形成显着增强。两种材料均诱导所有 HMCL 和原发性骨髓瘤细胞样本中的骨髓瘤细胞凋亡。在 5T33 骨髓瘤小鼠模型中，两种材料都稳定了钻孔缺陷和局部控制的恶性浆细胞生长。稳定骨折易感病变、刺激骨愈合和抗肿瘤作用的结合表明，sicXer 和 boXer 的临床试验是多发性骨髓瘤和非恶性疾病全身/局部联合治疗策略的一部分。