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Review
. 2025 Jun 8;13(3):2756.
doi: 10.5599/admet.2756. eCollection 2025.

Targeting bone in cancer therapy: Advances and challenges of bisphosphonate-based drug delivery systems

Mohammadmahdi Eshaghi  1 , Fariba Ganji  1 , Hossein Shaki  1 , Lobat Tayebi  2
Affiliations
Review

Targeting bone in cancer therapy: Advances and challenges of bisphosphonate-based drug delivery systems

Mohammadmahdi Eshaghi et al. ADMET DMPK. .

Abstract

Background and purpose: Bisphosphonates (BPs) are well-known for their strong affinity toward bone mineral matrices and are widely used to inhibit excessive osteoclast activity associated with various bone disorders. Beyond their clinical use, their unique bone-targeting capability has positioned them as promising ligands for drug delivery systems aimed at treating bone-related cancers.

Approach: The review analyses published studies on BP-functionalized drug delivery systems, including direct drug conjugates, calcium-based nanomaterials, carbon-based nanostructures, and self-assembling systems such as micelles and liposomes. In vitro assays (e.g. hydroxyapatite binding, cell viability) and in vivo biodistribution studies are discussed to evaluate targeting efficiency and therapeutic outcomes. The impact of BP structure, linker chemistry, and carrier material on drug release and bone accumulation is examined.

Key results: BP-functionalized systems consistently demonstrate improved bone targeting and enhanced drug accumulation at tumour sites compared to non-targeted approaches. Both direct conjugates and nanocarrier-based systems show promising results, with some formulations offering controlled drug release and reduced systemic toxicity. Despite these advances, certain challenges such as burst release and incomplete clinical validation remain.

Conclusion: This review highlights the significant progress in BP-based drug delivery platforms for bone cancer therapy, demonstrating their potential to concentrate therapeutic agents at bone tumour sites while minimizing off-target effects. The integration of nanotechnology with BP targeting offers new opportunities for treating bone metastases and primary bone tumours. However, further research is needed to address current limitations and translate these findings into clinical practice.

Keywords: Nanomedicine; nanomaterials; targeted drug delivery; tumour.

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Conflict of interest statement

Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
(A) General chemical structure of BPs; (B) demonstration of BPs affinity for calcium ions
Figure 2.
Figure 2.
Chemical structure of (A) BP-21 (B) BP-15 (C) BP-22
Figure 3.
Figure 3.
The lower sensitivity of BG to the acidic environment compared with CP and HAp
Figure 4.
Figure 4.
(A) Chemical structure of GON-ALN, (B) demonstration of GON-ALN affinity for calcium ions
Figure 5.
Figure 5.
Strategies for Functionalizing PLGA NPs with BPs
See this image and copyright information in PMC

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