Alendronate-coated long-circulating liposomes containing 99mtechnetium-ceftizoxime used to identify osteomyelitis

Abstract

Osteomyelitis is a progressive destruction of bones caused by microorganisms. Inadequate or absent treatment increases the risk of bone growth inhibition, fractures, and sepsis. Among the diagnostic techniques, functional images are the most sensitive in detecting osteomyelitis in its early stages. However, these techniques do not have adequate specificity. By contrast, radiolabeled antibiotics could improve selectivity, since they are specifically recognized by the bacteria. The incorporation of these radiopharmaceuticals in drug-delivery systems with high affinity for bones could improve the overall uptake. In this work, long-circulating and alendronate-coated liposomes containing 99m technetium-radiolabeled ceftizoxime were prepared and their ability to identify infectious foci (osteomyelitis) in animal models was evaluated. The effect of the presence of PEGylated lipids and surface-attached alendronate was evaluated. The bone-targeted long-circulating liposomal 99m technetium–ceftizoxime showed higher uptake in regions of septic inflammation than did the non-long-circulating and/or alendronate-non-coated liposomes, showing that both the presence of PEGylated lipids and alendronate coating are important to optimize the bone targeting. Scintigraphic images of septic or aseptic inflammation-bearing Wistar rats, as well as healthy rats, were acquired at different time intervals after the intravenous administration of these liposomes. The target-to-non-target ratio proved to be significantly higher in the osteomyelitis-bearing animals for all investigated time intervals. Biodistribution studies were also performed after the intravenous administration of the formulation in osteomyelitis-bearing animals. A significant amount of liposomes were taken up by the organs of the mononuclear phagocyte system (liver and spleen). Intense renal excretion was also observed during the entire experiment period. Moreover, the liposome uptake by the infectious focus was significantly high. These results show that long-circulating and alendronate-coated liposomes containing 99m technetium-radiolabeled ceftizoxime have a tropism for infectious foci.

In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice

“…This suggests that ALD does not reach sufficient concentrations in tumours to be therapeutically efficacious as a monotherapy, even when encapsulated in a liposomal formulation. L-ALD has also been used in the treatment of inflammatory conditions [32] , [33] , [34] , [35] . The ability of ALD liposomes to deplete monocytes and macrophages has been shown to inhibit restenosis and endometriosis in a rat model [35] .…”

“…However, its use in vivo was prohibited by the profound toxicity and sudden mice death [23] , [29] . Several studies have reported the use of L-ALD for therapeutic applications in cancer [31] and inflammatory conditions [32] , [33] , [34] , [35] pre-clinically. L-ALD has been shown to be effective when used with Vγ9Vδ2 T cells in an ovarian cancer model in vivo [23] .…”

Synthesis and antimicrobial evaluation of two peptide LyeTx I derivatives modified with the chelating agent HYNIC for radiolabeling with technetium-99m

“…Therefore, alternatives must be found in order to ensure an accurate diagnosis. In this sense, scintigraphic imaging is a promising approach since it is based on physiological changes, which occur earlier than anatomical modifications [ 2 – 4 ]. In this context, radiolabeled antimicrobial peptides have been investigated as possible suitable tools, since they accumulate in infectious sites instead of in aseptic inflammatory lesions, once they preferentially bind to bacteria and fungi [ 5 – 7 ].…”

Ultrasound-mediated cavitation enhances the delivery of an EGFR-targeting liposomal formulation designed for chemo-radionuclide therapy

“…The addition of radioisotope as the last step of the synthesis is of interest for in vivo studies and clinical translation as it minimises loss of therapeutic efficacy due to decay of the isotope during protracted manufacture. This is a clear advantage in comparison to some previously published nanoparticle-radionuclide constructs where the time required for formulation exceeds the half-life of the radionuclide 44. Physico-chemical characterisation of liposomal formulations are presented in the Figure S1.…”