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

Abstract

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.

Preparation and application of calcium phosphate nanocarriers in drug delivery

“…For example, Gu et al. [ 136 ] prepared the bone-targeted drug delivery system (Ca-RISNPs) using a third-generation BP (risedronate) and drugs (plasmid and oligo double strand DNA). These Ca-RISNPs exhibited high specificity in killing tumor-associated macrophages (TAMs) and inhibit TAM-induced tumor cell migration.…”

Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review

“…One of the most investigated agents is bisphosphonates, which are analogs of pyrophosphate, a natural inhibitor of bone demineralization [33,111]. These small-molecule drugs have a short half-life in circulation, requiring high doses and longterm repeat use, but they can achieve strong penetration ability and uniform distribution in bone cells [112]. Bisphosphonates ameliorate pain, reduce fracture, and display antimyeloma and antitumor effects activity with prolonged overall survival registered for various malignancies [33].…”

Targeting Drug Delivery in the Elderly: Are Nanoparticles an Option for Treating Osteoporosis?

“…Despite their potential clinical use as biomarkers in the assessment of osteoporosis, several of these molecules present in the lacuna additionally offer chemically specific targets for drug delivery. We consider the following targets with a combination of features that should be exploitable to allow appropriately designed nanoparticles to accumulate in the bone-repair site (by a mixture of EPR and true targeting), releasing a drug there in a milieu-specific fashion: Bone Mineral (Hydroxyapatite): Bisphosphonates have already been studied for use in directing drug molecules and nanoparticles to bone [93,94]. The results are mixed, and it is evident that appropriate linker-bisphosphonate combinations will need to be identified.…”

“…Limiting these side effects by site-directed drug application is the major driver of nanoparticle research focusing on osteoporosis. This is also reflected by the immense and active literature that is available [7,[113][114][115][116], and nanoparticles for such applications are under continuous development [94,111,[117][118][119].…”