Table 1.

Summary of the most meaningful studies published on nanotechnology to deliver BPs in cancer.

Delivery system	Strategy	Bisphosphonate	Main findings	References
Liposomes	Macrophage depletion	Clodronate	Macrophage elimination in the spleen and liver following i.v. administration.	[21–25]
Liposomes	Macrophage depletion	Clodronate, pamidronate, etidronate	Macrophage elimination in the bloodstream following i.v. administration.	[26]
Liposomes	Macrophage depletion	Clodronate, pamidronate, etidronate	BPs were found to be even 1000 times less active, compared with the corresponding liposome-based formulations; high calcium extracellular concentration resulted in a stronger macrophage depletion; negatively charged unilamellar liposomes favour macrophage depletion.	[23, 24, 27]
Liposomes	Macrophage depletion	Clodronate	Macrophage elimination in draining lymph nodes following subcutaneous footpad administration.	[28]
Liposomes	Macrophage depletion	Clodronate	Intratracheal administration exclusively eliminates macrophages from lung tissues.	[29]
Liposomes	Macrophage depletion	Clodronate	Enhanced tumor growth in an experimental model of liver metastasis.	[30]
Liposomes	Macrophage depletion	Clodronate	Inhibition of the tumor growth in different experimental animal models of cancer; reduction of the blood vessel density in the tumor tissue; reduction of the tumor-associated macrophages and tumor-associated dendritic cells.	[31–33]
Liposomes	Macrophage depletion	Clodronate in combination with sorafenib	Significant inhibition of tumor growth and lung metastasis; reduced tumor angiogenesis.	[34]
Liposomes	Macrophage depletion	Clodronate as adjuvant agent in radiotherapy	Adjuvant agent in the cancer radiotherapy with delayed tumor regrowth.	[35, 36]
Liposomes	Macrophage depletion	Clodronate	Reduced metastasis of human prostate cancer in bone.	[37]
Liposomes	Inhibitory effect on cancer cells	Clodronate	Significant tumor regression.	[38]
Liposomes	Inhibitory effect on cancer cells	Neridronate	Inhibition of cell growth.	[39]
PEGylated liposomes	Targeting of extraskeletal tumors	Zoledronate	Enhanced cytotoxic effect in vitro; enhanced inhibition of tumor growth (prostate cancer and multiple myeloma).	[40, 41]
Folate-coupled PEGylated liposomes	Targeting of extraskeletal tumors	Zoledronate	Enhanced cytotoxic effect in vitro.	[42]
Self-assembling NPs	Targeting of extraskeletal tumors	Zoledronate	Enhanced cytotoxic effect in vitro; enhanced inhibition of tumor growth (prostate cancer).	[41, 43]
Superparamagnetic iron oxide nanocrystals	Theranostic purposes	Alendronate, zoledronate	Decrease cell proliferation in vivo and inhibition of tumour growth in vivo, only in combination with a magnetic field.	[44–46]
Liposomes	Targeting of doxorubicin to bone tumors	Bisphosphonate head group in a novel amphipathic molecule	Increased cytotoxicity in vitro on human osteosarcoma cell line associated to hydroxyapatite.	[47]
Poly(lactide-co-glycolide) NPs	Targeting of doxorubicin to bone tumors	Alendronate conjugated on the nanocarrier surface	Reduced incidence of metastases associated to a significant reduction of the osteoclast number at the tumor site.	[48]
Poly(lactide-co-glycolide) NPs	Targeting of docetaxel to bone tumors	Zoledronate conjugated on the nanocarrier surface	Enhanced cytotoxic effect in vitro.	[49]
Poly(ethylene glycol)-dendrimer	Targeting of paclitaxel to bone tumors	Alendronate conjugated to the nanocarrier	Significant improvement of paclitaxel in vivo half-life.	[50]