A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release

Abstract

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. Graphical Abstract

Repurposed Drugs Celecoxib and Fmoc-L-Leucine Alone and in Combination as Temozolomide-Resistant Antiglioma Agents—Comparative Studies on Normal and Immortalized Cell Lines, and on C. elegans

“…The observed profile of toxicity, proliferation, apoptosis, and migration are consistent with those obtained by others. Celecoxib significantly destroyed A172 glioma cells via the apoptosis pathway after 24 h incubation from 25 µM concentration upward [ 46 ]. In a mouse model of malignant glioma (glioma stem cells GSC), celecoxib was toxic (IC 50 = 60 µM), with overexpression of apoptosis marker (cleaved PARP and caspases) [ 47 ].…”

“…The latest studies on the effect of celecoxib on four glioma cell lines (U87, U-118 MG, H4, and A172) after 24 h of incubation showed that the IC 50 values for celecoxib ranged from 100 to 400 µM; U-118 MG cells turned out to be the most resistant (IC 50 around 400 µM). Cell death occurred by apoptosis [ 46 ].…”

Microfluidic-on-a-chip for designing celecoxib-based amorphous solid dispersions: when the process shapes the product

“…The Quality Target Product Profile (QTPP) is a fundamental element of the QbD approach, wherein the essential attributes a drug product should attain are prospectively summarized envisioning the quality features intended to be reached, with a focus on ensuring the safety and efficacy of the drug product (Mendes et al, 2023;Step, 2017). A risk estimation matrix (REM) was constructed to identify and prioritize potential high-risk process parameters that could influence the critical quality attributes.…”