Australian Institute of Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia.
Department of Pathology/Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, China.
ACS Appl Bio Mater. 2021 Mar 15;4(3):2490-2501. doi: 10.1021/acsabm.0c01455. Epub 2021 Feb 12.
Bone and bone-related diseases are the major cause of mobility hindrance and mortality in humans and there is no effective and safe treatment for most of them, especially, for bone and bone metastatic cancers. Bisphosphonates (BPs) are a group of small-molecule drugs for treating osteoporosis and bone cancers but have a very short half-life in circulation, requiring high doses and long-term repeat use that can cause severe side effects. Previous attempts of using nanoparticles to deliver BPs have issues of drug loading capacity and endosome escape/drug release. The present study reports the direct synthesis of BP nanoparticles by precipitating bone-favorable calcium ions and a third-generation BP, risedronate (Ca-RISNPs), to achieve high drug loading, endosomal release, and strong bone-targeting properties. The Ca-RISNPs are monodispersed with high stability at physiological pH but readily dissociate at endosomal pH conditions. They demonstrate strong penetration ability and uniform distribution in human bone and cartilage tissues and the superior drug and DNA (plasmid and oligo double strand DNA) delivery capacity in bone cells. These NPs also exhibit high specificity in killing tumor-associated macrophages (TAMs) and inhibit TAM-induced tumor cell migration. Collectively, our data indicate that this BP nanodrug platform has a great potential in managing bone-related diseases and cancers as a prolonged BP nanodrug and simultaneously as the bone-targeted drug delivery system.
骨骼和骨骼相关疾病是导致人类行动障碍和死亡的主要原因，而且大多数此类疾病（尤其是骨骼和骨骼转移性癌症）目前尚无有效且安全的治疗方法。双膦酸盐（BPs）是一类用于治疗骨质疏松症和骨癌的小分子药物，但在血液循环中的半衰期非常短，需要高剂量和长期重复使用，这会导致严重的副作用。以前使用纳米颗粒递送 BPs 的尝试存在药物载药量和内涵体逃逸/药物释放的问题。本研究通过沉淀有利于骨骼的钙离子和第三代 BPs（利塞膦酸盐，Ca-RISNPs）来直接合成 BP 纳米颗粒，以实现高载药量、内涵体释放和强骨骼靶向特性。在生理 pH 值下，Ca-RISNPs 呈单分散且具有高稳定性，但在内涵体 pH 值条件下易于解离。它们在人骨骼和软骨组织中表现出很强的穿透能力和均匀分布，并具有优越的药物和 DNA（质粒和寡双链 DNA）在骨细胞中的递送能力。这些 NPs 还表现出对肿瘤相关巨噬细胞（TAMs）的高特异性，并抑制 TAM 诱导的肿瘤细胞迁移。总的来说，我们的数据表明，这种 BP 纳米药物平台作为一种延长的 BP 纳米药物和同时作为骨靶向药物递送系统，在治疗骨骼相关疾病和癌症方面具有巨大的潜力。
