Targeted Nanomedicine to Treat Bone Metastasis

Abstract

Bone metastases are common complications of solid tumors, particularly those of the prostate, breast, and lungs. Bone metastases can lead to painful and devastating skeletal-related events (SREs), such as pathological fractures and nerve compressions. Despite advances in treatment for cancers in general, options for bone metastases remain inadequate and generally palliative. Anticancer drugs (chemotherapy and radiopharmaceuticals) do not achieve therapeutic concentrations in the bone and are associated with dose-limiting side effects to healthy tissues. Nanomedicines, with their tunable characteristics, have the potential to improve drug targeting to bone metastases while decreasing side effects for their effective treatment. In this review, we present the current state of the art for nanomedicines to treat bone metastases. We also discuss new treatment modalities enhanced by nanomedicine and their effects on SREs and disease progression.

Keywords: active targeting; bone marrow; drug delivery; nanoparticle; passive targeting.

Figure 1

Mechanism of bone metastasis. (1) Cancer cells from primary tumor detach and invade surrounding tissue before (2) intravasation into the circulatory and lymphatic systems. Lymph, and the cancer cells within it, ultimately enters the bloodstream through the subclavian vein, via the thoracic ducts. Cancer cells that evade the immune system (3) translocate through capillaries in the bone where they (4) extravasate into the bone marrow to (5) establish metastatic sites.

Figure 2

Passive targeting of nanoparticles to bone marrow. (A) Scheme showing passive targeting of NPs (green spheres) into bone. NPs pass through the fenestrations in sinusoidal capillaries to localize in bone marrow. NP (B) charge on blood residence time and (C) bone accumulation. Neutral charge NPs showed greater accumulation in tibia than similarly sized anionic and cationic NPs. (D) Neutral charge NPs showed greater localization in tibia with bone metastasis (white arrow) than healthy tibia. Reprinted with permission from Reference [93].

Figure 3

Active targeting of nanoparticles to bone using bisphosphonates. (A) Scheme showing targeting of bisphosphonate-functionalized NPs to bone. (B) Quantification of alendronate (Aln)-conjugated NPs accumulation into bone over time. (C) Representative image of Nile red-labelled NP localization in mouse femurs. (D) Quantification of number of NPs in the bone marrow. Reprinted with permission from Reference [96].

Figure 4

Drug delivery to the bone-marrow vasculature. (A) Scheme showing NP interaction with endothelial cells of bone-marrow capillaries. (B) Accumulation of E-selectin-targeted NPs (ESTA-PSP) to bone. Reprinted with permission from Reference [102].