Table 3.

Features of free nanoformulated aminobisphosphonates (N-BPs) and nanoparticles (NP) charged with N-BPs.

N-BPs Form	Size nm	Cellular Biodistribution	In Vivo Biodistribution	In Vitro Functional Effects	In Vivo Functional Effects	Ref.
Free alendronic acid or free zoledronic acid	NA	Passive penetration and inhibition of FPPS, Generation of IPP and DMAPP	High plasma and renal excretion (min) and high bone concentration and release along time half-life (years)	Anti-tumor toxic effects triggering Vδ2 T cells	Potent anti-osteoporotic Effects Use for bone metastasis treatment	reviewed in [200]
high phase-transition phospholipids, cholesterol and pegylated liposomes for alendronic acid	85–100 nm Neg charged	High cellular penetration	High Plasma half-life (18 h) Low renal excretion High extraskeletal tissue	Anti-tumor toxic effects triggering Vδ2 T cells	Murine models Anti-tumor effects Synergistic effects with Vδ2 T cell administration	[200,209,210,211]
high phase-transition phospholipids, cholesterol and pegylated liposomes for zoledronic acid	85–100 nm Neg charged	High cellular penetration	High Plasma half-life (18 h) Low renal excretion High extraskeletal tissue	Anti-tumor toxic effects triggering Vδ2 T cells	Murine models anti-tumor effects and sudden death	[200,209,210,211]
ZOL-containing self-assembly PEGylated nanoparticles (NPs) or ZOL-encapsulating PEGylated liposomes DOTAP/chol/DSPE-PEG	147–245 nm +1.8–17.5 mV ζ pot	Not performed specific studies	Not performed specific studies	Not performed specific studies	Potent anticancer effect in murine model of prostate adenocarcinoma	[212]
PEGylated ZOL- charged NPs with CaPZ NPs and DOTAP/chol/DSPEG2000	147 nm +18 mv ζ pot	Strong effects on mesenchymal stromal cells and tumor cells	Not performed specific studies	Not performed specific studies	Not performed specific studies	[213]
Spheric polymeric nanoparticles DPPC:DSPE-PEG7.5:2.5 molar ratiocharged with zol	171 nm –43 mV ζpot	Penetration and generation of IPP in tumor cells and Mo, no toxicity on Mo	Not assessed as Zol charged NPs	Potent boost of Vδ2 T cell proliferation and cytolysis of 3D CRC spheroids and patient-derived organoids	Not assessed as Zol charged NPs Potent antitumor effects on orthotopic glioblastoma multiforme in murine models as docetaxel- and diclofenac-charged NPs	[214,215]

Abbreviations: FPPS: farnesyl pyrophosphate synthase; IPP: isopentenyl pyrophosphate; DMAPP: Dimethyl-allil pyrophosphate; DPPC:DSPE-PEG: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[succinyl(polyethylene glycol)-2000] (DSPE-PEG),DOTAP: 1,2-dioleoyl-3-trimethylammonium-propane chloride. Mo: monocytes; CRC: colorectal carcinoma.