Dewhurst Rebecca Marie, Scalzone Annachiara, Buckley Joseph, Mattu Clara, Rankin Kenneth S, Gentile Piergiorgio, Ferreira Ana Marina
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
School of Engineering, Newcastle University, Newcastle upon Tyne, United Kingdom.
Front Bioeng Biotechnol. 2020 Jul 9;8:754. doi: 10.3389/fbioe.2020.00754. eCollection 2020.
Osteosarcoma (OS) accounts for 60% of all global bone cancer diagnoses. Intravenous administration of Doxorubicin Hydrochloride (DOXO) is the current form of OS treatment, however, systemic delivery has been linked to the onset of DOXO induced cardiomyopathy. Biomaterials including calcium phosphate cements (CPCs) and nanoparticles (NPs) have been tested as localized drug delivery scaffolds for OS cells. However, the tumor microenvironment is critical in cancer progression, with mesenchymal stem cells (MSCs) thought to promote OS metastasis and drug resistance. The extent of MSC assisted survival of OS cells in response to DOXO delivered by CPCs is unknown. In this study, we aimed at investigating the effect of DOXO release from a new formulation of calcium phosphate-based bone cement on the viability of OS cells cocultured with hMSC in vitro. NPs made of PLGA were loaded with DOXO and incorporated in the formulated bone cement to achieve local drug release. The inclusion of PLGA-DOXO NPs into CPCs was also proven to increase the levels of cytotoxicity of U2OS cells in mono- and coculture after 24 and 72 h. Our results demonstrate that a more effective localized DOXO delivery can be achieved via the use of CPCs loaded with PLGA-DOXO NPs compared to CPCs loaded with DOXO, by an observed reduction in metabolic activity of U2OS cells in indirect coculture with hMSCs. The presence of hMSCs offer a degree of DOXO resistance in U2OS cells cultured on PLGA-DOXO NP bone cements. The consideration of the tumor microenvironment via the indirect inclusion of hMSCs in this study can act as a starting point for future direct coculture and investigations.
骨肉瘤（OS）占全球所有骨癌诊断病例的60%。静脉注射盐酸多柔比星（DOXO）是目前骨肉瘤的治疗方式，然而，全身给药与DOXO诱导的心肌病的发生有关。包括磷酸钙骨水泥（CPCs）和纳米颗粒（NPs）在内的生物材料已被测试作为骨肉瘤细胞的局部药物递送支架。然而，肿瘤微环境在癌症进展中至关重要，间充质干细胞（MSCs）被认为会促进骨肉瘤转移和耐药性。CPCs递送DOXO时，MSCs对骨肉瘤细胞存活的辅助程度尚不清楚。在本研究中，我们旨在研究一种新型磷酸钙基骨水泥释放的DOXO对体外与hMSC共培养的骨肉瘤细胞活力的影响。由聚乳酸-羟基乙酸共聚物（PLGA）制成的纳米颗粒负载DOXO并掺入配制的骨水泥中以实现局部药物释放。将PLGA-DOXO纳米颗粒掺入CPCs中也被证明可在24小时和72小时后增加单培养和共培养中U2OS细胞的细胞毒性水平。我们的结果表明，与负载DOXO的CPCs相比，通过使用负载PLGA-DOXO纳米颗粒的CPCs可以实现更有效的局部DOXO递送，这通过与hMSCs间接共培养的U2OS细胞代谢活性的降低得以观察到。hMSCs的存在使在PLGA-DOXO纳米颗粒骨水泥上培养的U2OS细胞具有一定程度的DOXO耐药性。本研究通过间接纳入hMSCs来考虑肿瘤微环境可作为未来直接共培养和研究的起点。
