Title:Nanoparticles Loaded with Nutlin-3 Display Cytotoxicity Towards p53wildtype JVM-2 But Not Towards p53mutated BJAB Leukemic Cells
Volume: 20
Issue: 21
Author(s): R. Voltan, P. Secchiero, B. Ruozi, L. Caruso, F. Forni, M. Palomba, G. Zauli and M.A. Vandelli
Affiliation:
Keywords:
PLGA nanoparticles, B-cell leukemia, nutlin-3, p53, apoptosis, cell cycle.
Abstract: The small molecule Nutlin-3 is a potent antagonist of the murine double minute 2 (MDM2)/p53 interaction exhibiting
promising therapeutic anti-cancer activity. Nutlin-3 has been proposed as an anti-neoplastic agent for the treatment
of onco-hematological diseases characterized by a lower incidence of p53 mutation with respect to solid tumors. Indeed,
based on its selective non-genotoxic p53 activation, Nutlin-3 might represent an alternative to the current cytotoxic
chemotherapy. To overcome the poor bioavailability of Nutlin-3, we have assessed the potential efficacy of Nutlin-3
loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) against hematological malignancies. To test the specificity
of the anti-leukemic activity, we have used leukemic cell lines characterized by different p53 status (JVM-2 and BJAB).
NP loaded with Nutlin-3 (NP-Nutlin) were rapidly taken up by the leukemic cells and were as effective as native Nutlin-3
in promoting both induction of apoptosis and cell cycle arrest in p53wild-type JVM-2 cells, but not in p53mutated BJAB cells.
Moreover, injection of NP-Nutlin, but not of free Nutlin-3, in a JVM-2-derived xenograft mouse model, reduced the subcutaneous
tumor volume and promoted induction of apoptosis in the tumor mass. Overall, the chemical and structural
characteristics of the NP-Nutlin-3, as well as their biological activity in vitro and in vivo, made them promising for further
preclinical evaluations as potentially useful anti-leukemic carriers.
