Department of Chemistry "G. Ciamician", University of Bologna, via Selmi 2, 40126 Bologna, Italy.
Laboratory of Preclinical and Surgical Studies, Research Institute Codivilla Putti - Rizzoli Orthopaedic Institute, via di Barbiano 1/10, 40136 Bologna, Italy.
Acta Biomater. 2017 May;54:419-428. doi: 10.1016/j.actbio.2017.02.040. Epub 2017 Feb 24.
Development of new materials for the local administration of bisphosphonates (BPs) is aimed to avoid the negative side effects of prolonged systemic use of these potent drugs. In this work, we synthesized octacalcium phosphate (OCP) in the presence of two potent BPs and obtained a single crystalline phase up to a zoledronate and alendronate content of 3.5wt% and 5.2wt%, respectively. Both BPs provoke minor structural modifications and a reduction of the crystal dimensions of OCP, which suggests a preferential interaction of the BPs with the structure of the calcium phosphate. Alendronate containing samples display increased values of zeta potential with respect to that of OCP, and an initial burst release of the BP in solution. At variance, the zeta potential of zoledronate functionalized samples decreases on increasing the content of zoledronate, which is not appreciably released in solution. Bone microenvironment response to the composite materials was investigated in vitro using a triculture model. BP functionalized samples downregulate the viability of the cells, sustain osteoblast differentiation and accelerate the production of collagen type I and osteocalcin. At variance, they inhibit monocyte differentiation into osteoclast and provoke a dose dependent reduction of VEGF production, exhibiting antiresorptive and anti-angiogenetic properties that can be usefully exploited for the local treatment of abnormal bone losses.
Bisphosphonates (BPs) are powerful drugs for the treatment of bone diseases. However, BPs systemic administration suffers several undesirable side effects, which stimulate the development of suitable systems for their local administration. In this study we functionalized octacalcium phosphate (OCP) with alendronate and zoledronate in order to get biomaterials able to couple the good biological performance of OCP with the therapeutic properties of the BPs. The results provide novel information on the interaction between these two potent BPs and octacalcium phosphate. Moreover, the triculture in vitro study indicates that the synthesized composite materials stimulate the production of bone extracellular matrix, inhibit monocytes differentiation into osteoclasts and downregulate the release of Vascular Endothelial Growth Factor (VEGF) in a dose dependent way. The data allow to state that the new composite materials can be usefully employed for the local treatment of diseases involving abnormally high bone resorption.
开发新的局部用双膦酸盐（BPs）药物，以避免长期全身使用这些强效药物带来的负面作用。本研究在合成八钙磷酸盐（OCP）时加入了两种强效 BPs，获得了单一晶体相，唑来膦酸和阿仑膦酸盐的含量最高分别可达 3.5wt%和 5.2wt%。两种 BPs 仅引起 OCP 结构的轻微修饰和晶体尺寸减小，这表明 BPs 优先与磷酸钙结构相互作用。与 OCP 相比，含阿仑膦酸盐的样品具有更高的 ζ 电位值，并且在溶液中初始时会迅速释放 BP。相比之下，随唑来膦酸含量的增加，唑来膦酸功能化样品的 ζ 电位值降低，在溶液中几乎不释放。通过三培养模型在体外研究了复合材料对骨微环境的响应。BP 功能化样品降低了细胞活力，促进成骨细胞分化，并加速了 I 型胶原和骨钙素的产生。相反，它们抑制单核细胞向破骨细胞分化，并引起 VEGF 产生剂量依赖性降低，表现出抗吸收和抗血管生成特性，可用于局部治疗异常骨质流失。
双膦酸盐（BPs）是治疗骨骼疾病的有效药物。然而，BPs 的全身给药存在多种不良副作用，这刺激了适合其局部给药的合适系统的开发。在本研究中，我们用阿仑膦酸盐和唑来膦酸对八钙磷酸盐（OCP）进行了功能化，以获得能够将 OCP 的良好生物学性能与 BPs 的治疗特性相结合的生物材料。结果提供了有关这两种强效 BPs 与八钙磷酸盐相互作用的新信息。此外，三培养体外研究表明，合成的复合材料刺激骨细胞外基质的产生，抑制单核细胞向破骨细胞分化，并以剂量依赖性方式下调血管内皮生长因子（VEGF）的释放。这些数据表明，新的复合材料可用于局部治疗涉及异常高骨吸收的疾病。
