Zielińska Monika, Pacholak Amanda, Orwat Bartosz, Sandomierski Mariusz, Kownacki Ireneusz, Kaczorek Ewa, Voelkel Adam
Institute of Chemical Technology and Engineering, Poznan University of Technology, Berdychowo 4, 60-965, Poznań, Poland.
Department of Molecular Physics, Lodz University of Technology, Lodz, Poland.
Pharmacol Rep. 2025 Apr;77(2):517-531. doi: 10.1007/s43440-025-00703-y. Epub 2025 Feb 10.
Bisphosphonates (BPs) are widely used for treating bone diseases such as osteoporosis due to their strong affinity for hydroxyapatite (HA) in bones. Minor structural variations among BPs can significantly affect their therapeutic potential. This study aimed to synthesize risedronate (RSD) and its two regioisomers (2-RSD, 4-RSD) and investigate the impact of these variations on bone affinity, permeability, and cytotoxicity.
RSD and its regioisomers were synthesized using a microwave-assisted method. Bone affinity was assessed through sorption studies on HA and two polymer-ceramic materials mimicking bone properties. Compound permeability was predicted using the Parallel Artificial Membrane Permeability Assay (PAMPA). Cytotoxicity was evaluated by analyzing the response of bacterial cells to BPs using metabolic activity assays.
2-RSD demonstrated a higher bone affinity and similar permeability than commercially available RSD. 2-RSD also showed reduced cytotoxicity in bacterial cell assays, indicating enhanced biocompatibility. These findings suggest that minor structural changes can lead to significant differences in therapeutic efficacy.
The study highlights the potential of the 2-RSD as a more effective treatment for bone diseases. Structural variations in BPs can greatly influence their biological properties, paving the way for the development of improved therapeutic agents.
双膦酸盐（BPs）因其对骨中羟基磷灰石（HA）具有很强的亲和力，而被广泛用于治疗骨质疏松症等骨疾病。双膦酸盐之间微小的结构变化会显著影响其治疗潜力。本研究旨在合成利塞膦酸盐（RSD）及其两种区域异构体（2-RSD、4-RSD），并研究这些变化对骨亲和力、渗透性和细胞毒性的影响。
采用微波辅助法合成RSD及其区域异构体。通过对HA以及两种模拟骨特性的聚合物-陶瓷材料进行吸附研究来评估骨亲和力。使用平行人工膜渗透性测定法（PAMPA）预测化合物的渗透性。通过代谢活性测定分析细菌细胞对双膦酸盐的反应来评估细胞毒性。
2-RSD表现出比市售RSD更高的骨亲和力和相似的渗透性。在细菌细胞试验中，2-RSD还表现出降低的细胞毒性，表明其生物相容性增强。这些发现表明，微小的结构变化可导致治疗效果的显著差异。
该研究突出了2-RSD作为一种更有效的骨疾病治疗药物的潜力。双膦酸盐的结构变化可极大地影响其生物学特性，为开发改良治疗药物铺平了道路。
