With an aim of developing a bacteria-specific molecular imaging agent, ciprofloxacin has been modified with a propylamine spacer and linked to two common bifunctional chelators, p-SCN-Bz-DOTA and p-SCN-Bz-NOTA. The two ciprofloxacin conjugates, CP-PA-SCN-Bz-DOTA (1) and CP-PA-SCN-Bz-NOTA (2), were radiolabeled with (68)Ga in >90% radiochemical yield and were moderately stable in vitro for 4 h. The efficacy of (68)Ga-1 and (68)Ga-2 has been investigated in vitro in Staphylococcus aureus cells where bacterial binding of the radiotracers (0.9-1.0% for (68)Ga-1 and 1.6-2.3% for (68)Ga-2) could not be blocked in the presence of excess amount of unlabeled ciprofloxacin. However, uptake of radiotracers in live bacterial cells was significantly higher (p < 0.01) than that in non-viable bacterial cells. Bacterial infection targeting efficacy of (68)Ga-1 and (68)Ga-2 was tested in vivo in rats where the infected muscle-to-inflamed muscle ((68)Ga-1: 2 ± 0.2, (68)Ga-2: 3 ± 0.5) and infected muscle-to-normal muscle ratios ((68)Ga-1: 3 ± 0.4, (68)Ga-2: 6.6 ± 0.8) were found to improve at 120 min p.i. Fast blood clearance and renal excretion was observed for both the radiotracers. The two (68)Ga-labeled infection targeting radiotracers could discriminate between bacterial infection and inflammation in vivo and are worthy of further detailed investigation as infection imaging agents at the clinical level.
Galectin-3 (gal-3) plays a crucial role in various cellular events associated to tumor metastasis and progression. In this direction, gal-3 binding core–shell glyconanoparticles based on citrus pectin (CP) have been designed for targeted, trigger-responsive combination drug delivery. Depolymerization via periodate oxidation in heterogeneous medium yielded low-molecular weight dialdehyde oligomers (CPDA) of CP with a gal-3 binding property (K d = 160.90 μM). CPDA-based core–shell nanoparticles prepared to enhance the gal-3 binding specificity via a multivalent ligand presentation have shown to reduce homotypic cellular aggregation, tumor cell binding with endothelial cells, and endothelial tube formation, the major steps involved in the progression of cancer. Immune-fluorescence and flow cytometric analysis confirmed significant reduction in gal-3 expression on MDA-MB 231 cancer cells upon incubation with nanoparticles. An on-demand tumor microenvironment-responsive release of drugs at low pH and high concentrations of glucose and glutathione prevailing in tumor milieu was achieved by introducing a cleavable Schiff’s base, a boronate ester, and disulfide linkages within the shell of the nanoparticles. Nanoparticles with encapsulated sulindac in the core and doxorubicin (DOX) in the shell demonstrated target specificity and enhanced internalization with synergistic cytotoxic effects with a 30-fold reduction in IC50 in DOX-resistant, triple-negative MDA-MB 231 breast cancer cells. Nanoparticles were radiolabeled with 131I radioisotopes with ≥80% efficiency while retaining its gal-3 binding property. Biodistribution studies of radiolabeled placebo nanoparticles and drug-loaded CPDA nanoparticles demonstrated proof of concept of gal-3 targeting seen as preferential accumulation in the gal-3-expressing tissues of the gastric tract. The CPDA core–shell nanoparticles are thus promising platforms for gal-3 targeting and inhibition of gal-3-mediated processes involved in cancer progression with a potential of radiolabeling for in vivo monitoring or delivering therapeutic doses of radiation and on-demand triggered, target-specific drug release.
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