Carboxymethylinulin–Chitosan Nanoparticles for the Delivery of Antineoplastic Mitoxantrone

Abstract

Mitoxantrone (MTX) is an antineoplastic agent whose use is limited by serious side effects on non-neoplastic cells. The aim of this study was the development of a new drug release system using an ionotropic gelation technique for microencapsulation of MTX in chitosan-carboxymethylinulin nanoparticles (CCInp), followed by evaluation of their cytotoxic effects on neoplastic MDA-MB-231 and non-neoplastic NIH3T3 cell lines. The CCInp were prepared through a new reliable method for easy functionalization of both inulin and chitosan. Both unloaded and drug-loaded nanoparticles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) and showed a spherical morphology with an average hydrodynamic diameter between 40 and 80 nm. Both nanoparticles were stable and easily degraded by lysozyme. MTX-loaded nanoparticles led to a greater mortality of MDA-MB-231 relative to free drug due to the ability of the nanoparticles to accumulate preferentially in neoplastic cells. The developed drug release system retains the ability to kill MDA-MB-231 cells in vitro, improving the survival of NIH3T3 cells.

Indium/Gallium Maltolate Effects on Human Breast Carcinoma Cells: In Vitro Investigation on Cytotoxicity and Synergism with Mitoxantrone

“…In fact, the InMal calculated IC 50 value was 3-fold lower than GaMal on MDA-MB-231 with respect to NIH-3T3 at shorter incubation times; the IC 50 value was a 1-fold lower than GaMal on the neoplastic cells in comparison with the fibroblast cell line at 144 h, making InMal an efficient anticancer compound. The GaMal IC 50 value calculated for the first time on MDA-MB-231 cell line was 4-fold higher in comparison to the IC 50 value previously detected on four hepatocellular carcinoma cell lines . The apoptosis tests (PSVue480) showed that both these metal complexes produced cytostatic rather than cytotoxic effects, clearly manifested on NIH-3T3 cells.…”

“…0.034 μM) for NIH-3T3. 37 Considering these results, GaMal and InMal were more effective than the standard drug MTX in reducing the viability of the neoplastic cell lines and at the same time in preserving the viability of the NIH-3T3 cell line (red lines in Figure 1).…”

“…The GaMal IC 50 value calculated for the first time on MDA-MB-231 cell line was 4-fold higher in comparison to the IC 50 value previously detected on four hepatocellular carcinoma cell lines. 37 The apoptosis tests (PSVue480) showed that both these metal complexes produced cytostatic rather than cytotoxic effects, clearly manifested on NIH-3T3 cells. Interestingly, the co-incubation of the complexes with iron citrate did not revert the toxicity toward MDA-MB-231 but exert a significant protective effect toward NIH-3T3 cells, indicating that InMal may act on iron metabolism.…”

“…MDA-MB-231, a triple negative breast cancer cell line and a perfect model for chemotherapy, 36 was selected as one of the classic target of MTX. 37 IC 50 values, apoptosis observations, quantitative determination of gallium and indium cell uptake, and toxicity reversion with the addition of iron citrate, on the basis of the proposed in vivo action mechanism of orally administered Ga, which bounds to serum transferrin, 1 were also determined. Finally, the synergic effect of both Ga or InMal and MTX was investigated to evaluate the lower dose to be used for MTX therapeutic treatments in combination with metallic complexes.…”

“…Starting from these considerations and from the chemical properties of group IIIa metallic elements, indium­(III) maltolate (InMal) and GaMal were synthesized and tested at increasing doses and incubation times for their in vitro ability of killing cancerous cells such as MDA-MB-231 in comparison to a non-neoplastic cell line, NIH-3T3. MDA-MB-231, a triple negative breast cancer cell line and a perfect model for chemotherapy, was selected as one of the classic target of MTX . IC 50 values, apoptosis observations, quantitative determination of gallium and indium cell uptake, and toxicity reversion with the addition of iron citrate, on the basis of the proposed in vivo action mechanism of orally administered Ga, which bounds to serum transferrin, were also determined.…”