胶质母细胞瘤（GB）是最致命的肿瘤之一。其生物学侵袭性质和血脑屏障（BBB）的存在限制了标准治疗的疗效。目前正在开发多种策略，旨在克服BBB并将药物准确地递送到肿瘤细胞。本研究提出了一种应对GB的双重方法：通过药物重用与Celecoxib（CXB）进行药物重配，并使用超小型纳米结构脂质载体（usNLCs）进行纳米制剂。通过生物信息学检查CXB的抗肿瘤活性，并在四种胶质瘤细胞系中筛选，旨在与标准治疗Temozolomide（TMZ）进行比较。在制剂设计中，通过调整药物溶解度/装载性能、采用低熔点脂质基质进行热触发药物释放、选择对肿瘤细胞具有靶向性的模板来增强细胞毒作用。为此，在质量设计的指导下，进行了关键材料属性（CMAs）、关键过程参数（CPPs）和关键质量属性（CQAs）的综合分析。对于usNLCs的最终质量和性能具有高风险水平的CMAs包括药物在固体和液体脂质中的溶解度、脂质组成（着眼于热响应性方法）、脂质比例（固体与液体之间）、以及表面活性剂种类和浓度。探索结果表明颗粒大小取决于脂质-表面活性剂的相互作用，其次是表面活性剂种类。药物包封不会影响胶体特性，使其成为脂溶性药物的有希望的载体。总体而言，usNLCs在37°C下表现出了控制的药物释放性能，在72小时内释放量约为25%，而在45°C下翻倍。体外细胞性能取决于表面活性剂种类和脂质组成，其中含有单一固体脂质（Suppocire® NB）和Kolliphor® RH40作为表面活性剂的配方具有最强细胞毒性。产生了平均直径约为70nm和窄尺寸分布（PdI低于0.2）的usNLCs，具有高稳定性、药物保护性、持续和热敏感释放性能以及对胶质瘤细胞的高细胞毒性，满足了静脉注射合适的CQAs要求。这种制剂或为改善GB治疗开辟了多元用途的途径。©2023. 作者。

Glioblastoma (GB) is one of the most lethal types of neoplasms. Its biologically aggressive nature and the presence of the blood-brain barrier (BBB) limit the efficacy of standard therapies. Several strategies are currently being developed to both overcome the BBB and deliver drugs site specifically to tumor cells. This work hypothesizes a two-pronged approach to tackle GB: drug repurposing with celecoxib (CXB) and a nanoformulation using ultra-small nanostructured lipid carriers (usNLCs). CXB antitumor druggable activity was inspected bioinformatically and screened in four glioma cell lines aiming at the comparison with temozolomide (TMZ), as standard of care. Delving into formulation design, it was tailored aiming at (i) improving the drug solubility/loading properties, (ii) assigning a thermal-triggerable drug release based on a lipid matrix with a low melting point, and (iii) enhancing the cytotoxic effect by selecting a template targetable to tumor cells. For this purpose, an integrated analysis of the critical material attributes (CMAs), critical process parameters (CPPs), and critical quality attributes (CQAs) was conducted under the umbrella of a quality by design approach. CMAs that demonstrate a high-risk level for the final quality and performance of the usNLCs include the drug solubility in lipids (solid and liquid), the lipid composition (envisioning a thermoresponsive approach), the ratio between lipids (solid vs. liquid), and the surfactant type and concentration. Particle size was shown to be governed by the interaction lipid-surfactant followed by surfactant type. The drug encapsulation did not influence colloidal characteristics, making it a promising carrier for lipophilic drugs. In general, usNLCs exhibited a controlled drug release during the 72 h at 37 °C with a final release of ca. 25%, while at 45 °C this was doubled. The in vitro cellular performance depended on the surfactant type and lipid composition, with the formulations containing a sole solid lipid (Suppocire® NB) and Kolliphor® RH40 as surfactant being the most cytotoxic. usNLCs with an average diameter of ca. 70 nm and a narrow size distribution (PdI lower than 0.2) were yielded, exhibiting high stability, drug protection, sustained and thermo-sensitive release properties, and high cytotoxicity to glioma cells, meeting the suitable CQAs for parenteral administration. This formulation may pave the way to a multi-addressable purpose to improve GB treatment.© 2023. The Author(s).