Calcium-bisphosphonate Nanoparticle Platform as a Prolonged Nanodrug and Bone-Targeted Delivery System for Bone Diseases and Cancers

• Published in: ACS applied bio materials 2021-03, Vol.4 (3), p.2490-2501
• Main Authors: Lin, Yanling, Villacanas, Maria G, Zou, Hong, Liu, Hangrui, Carcedo, Ines G, Wu, Yilun, Sun, Bing, Wu, Xiaoxin, Prasadam, Indira, Monteiro, Michael J, Li, Li, Xu, Zhi Ping, Gu, Wenyi
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Biocompatible Materials - chemistry; Bone Diseases - drug therapy; Bone Diseases - pathology; Bone Neoplasms - drug therapy; Bone Neoplasms - pathology; Calcium - chemistry; Cell Movement - drug effects; Cell Survival - drug effects; Diphosphonates - chemistry; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Carriers - chemistry; Drug Delivery Systems; Drug Screening Assays, Antitumor; Humans; Materials Testing; Mice; Molecular Structure; Nanoparticles - chemistry; Particle Size; RAW 264.7 Cells
• ISSN: 2576-6422; 2576-6422
• DOI: 10.1021/acsabm.0c01455

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.