title: Nanoparticles loaded with Nutlin-3 display cytotoxicity towards p53(wild-type) JVM-2 but not towards p53(mutated) BJAB leukemic cells.
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 p53(wild-type) JVM-2 cells, but not in p53(mutated) 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.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and LTTA, University of Ferrara, Ferrara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Voltan
authors.forename: P
authors.initials: P
authors.lastname: Secchiero
authors.forename: B
authors.initials: B
authors.lastname: Ruozi
authors.forename: L
authors.initials: L
authors.lastname: Caruso
authors.forename: F
authors.initials: F
authors.lastname: Forni
authors.forename: M
authors.initials: M
authors.lastname: Palomba
authors.forename: G
authors.initials: G
authors.lastname: Zauli
authors.forename: M A
authors.initials: MA
authors.lastname: Vandelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D053758:Nanoparticles / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011098:Polyglactin 910 / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D011098:Polyglactin 910; C482205:nutlin 3