Bone targeted nano-drug and nano-delivery

Abstract

There are currently no targeted delivery systems to satisfactorily treat bone-related disorders. Many clinical drugs consisting of small organic molecules have a short circulation half-life and do not effectively reach the diseased tissue site. This coupled with repeatedly high dose usage that leads to severe side effects. With the advance in nanotechnology, drugs contained within a nano-delivery device or drugs aggregated into nanoparticles (nano-drugs) have shown promises in targeted drug delivery. The ability to design nanoparticles to target bone has attracted many researchers to develop new systems for treating bone related diseases and even repurposing current drug therapies. In this review, we shall summarise the latest progress in this area and present a perspective for future development in the field. We will focus on calcium-based nanoparticle systems that modulate calcium metabolism and consequently, the bone microenvironment to inhibit disease progression (including cancer). We shall also review the bone affinity drug family, bisphosphonates, as both a nano-drug and nano-delivery system for bone targeted therapy. The ability to target and release the drug in a controlled manner at the disease site represents a promising safe therapy to treat bone diseases in the future.

Fig. 1

Calcium homoeostasis and oscillation. a Calcium gradient under resting conditions. b Intracellular calcium signals detected by a cytosolic FRET-based calcium sensor suggesting the calcium oscillation occurs in hMSC. Red and blue colours represent the high and low FRET ratios, respectively. Images were captured in 10 s interval, scale bar, 20 μm. c A computer-generated Ca²⁺ oscillatory wave frequency modulated by agonist concentration. (a Created with BioRender.com. Reprinted with copyright permissions)

Fig. 2

The effects of cellular calcium on bone diseases. a Intracellular calcium signalling in regulating key bone metabolic processes. Elevated intracellular calcium affects critical bone metabolic processes. b Intracellular calcium concentration interacts with various subcellular organelles including mitochondrion, endo-lysosome, endoplasmic reticulum (ER) and ribosome. c Extracellular calcium concentration modulates bone metabolism. d The vicious circle between tumour cells and the local bone-related cells in bone cancer progression interfere with bone matrix proteins and cytokines secretion and causes cancer-related hypercalcemia. Figure created with BioRender.com

Fig. 3

Calcium scaffolds with nano- and macro-structures for bone repair. a The SEM analysis of calcium phosphate bioceramics (CaP), CaP with a micro-whiskers structure (wCaP) and micro- /nano- CaP (nmCaP); b The three-dimensionally reconstructed micro-CT images of femoral bone defect model showed the implanted materials (white) and newly formed bone (yellow). More bone was formed in nwCaP and wCaP. c–f The calcium scaffold with different material surface curvature (G0, G2, G4 and G6) modulated osteoclacin (OCN) expression, more vinculin around nucleus and cell contractility. g, h The SO₃H^- coated polyetheretherketon (PEEK) affected osteogenesis and osteoclastogenesis of osteoporotic bone defect. (Reprinted with copyright permissions)

Fig. 4

Calcium based nanoparticles for ameliorating osteoporosis. a The calcium-aluminium layered double hydroxides (CALC) modulate osteoporosis through neutralising pH and regulating immune environment including macrophage repolarization and Treg recruitment. b, c The metal-poly DNA nanoparticles consisting calcium exert acidic neutralisation, calcium release and bone remineralization against osteoporosis. (Reprinted with copyright permissions)

Fig. 5

Calcium-based materials for bone cancer therapy and diagnosis. The calcium-based nanomaterials regulate tumour microenvironment and facilitate tumour diagnosis through neutralising acidic pH in tumour microenvironment, causing calcium overload in cancer cells, regulating redox in tumour conditions and elevating diagnostic efficacy. Mouse photo, ultrasound and micro-CT images were modified and reprinted with copyright permissions. Figure created with BioRender.com

Fig. 6

Calcium-based nanocarriers for bone-related anticancer agent delivery. a, b The Zoledronate, as a bisphosphate drug, formed calcium-based nanomaterials as Zol-NP to treat bone cancer. The Zol-NP showed retained Zol release and increased cytotoxicity to tumour cells and macrophages. Compared with free Zol, the Zol-NP showed significantly decreased Zol accumulation in bones, increased Zol accumulation in tumour and tumour inhibition. (c) The nHA (nano size) and mHA (micro size) were formed by loading doxorubicin (DOX) to hydroxyapatite to treat tumour. The locally delivery of DOX by HA showed improved anticancer efficacy comparing with intravenous injection of DOX. The released DOX from nHA through endocytosis by lysosome and unreleased DOX were delivered to mitochondria and resulted in insufficient ATP synthesis, less cell migration and more apoptosis. The released DOX from mHA extracellularly was up-taken in nucleus and caused more DNA damage and cell apoptosis. (Reprinted with copyright permissions)

Fig. 7

Chemical structure overview of BP family members. a BP chemical structure and groups of some common family members. b The representative members in different generations of bisphosphonates in acid forms

Fig. 8

Perspective design of bone-targeting NPs for cancer and other bone diseases. a The bone dual targeting NPs with bone and disease specific targeting motifs can be administrated via local or systemic injections; b The dual targeted NPs can be directed to bone from blood vessel and further go to the precise tumour cells of the bone site to affect tumour cells and TME. If the NPs have a disease responsive property (like to heat or cytokines) they can also release the payload in situ. Figure created with BioRender.com