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.

Nanoparticles Loaded with Nutlin-3 Display Cytotoxicity Towards p53wildtype JVM-2 But Not Towards p53mutated BJAB Leukemic Cells / R., Voltan; P., Secchiero; Ruozi, Barbara; L., Caruso; Forni, Flavio; M., Palomba; G., Zauli; Vandelli, Maria Angela. - In: CURRENT MEDICINAL CHEMISTRY. - ISSN 0929-8673. - STAMPA. - 20(21):(2013), pp. 2712-22.-2722. [10.2174/0929867311320210007]

Nanoparticles Loaded with Nutlin-3 Display Cytotoxicity Towards p53wildtype JVM-2 But Not Towards p53mutated BJAB Leukemic Cells

RUOZI, Barbara;FORNI, Flavio;VANDELLI, Maria Angela
2013

Abstract

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.
20(21)
2712-22.
2722
Nanoparticles Loaded with Nutlin-3 Display Cytotoxicity Towards p53wildtype JVM-2 But Not Towards p53mutated BJAB Leukemic Cells / R., Voltan; P., Secchiero; Ruozi, Barbara; L., Caruso; Forni, Flavio; M., Palomba; G., Zauli; Vandelli, Maria Angela. - In: CURRENT MEDICINAL CHEMISTRY. - ISSN 0929-8673. - STAMPA. - 20(21):(2013), pp. 2712-22.-2722. [10.2174/0929867311320210007]
R., Voltan; P., Secchiero; Ruozi, Barbara; L., Caruso; Forni, Flavio; M., Palomba; G., Zauli; Vandelli, Maria Angela
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/982314
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