PURPOSE: Since the non-genotoxic inhibitor of the p53/MDM2 interactions Nutlin-3 has shown promising in vitro therapeutic activity against a variety of p53wild-type cancer cells, in this study we evaluated an innovative strategy able to specifically target Nutlin-3 towards CD20+ malignant cells. EXPERIMENTAL DESIGN: The cytotoxic effects of Nutlin-3 encapsulated into poly(lactide-co-glycolide) nanoparticles (NP-Nut) and into Rituximab (anti-CD20 Antibody)-engineered NP (NP-Rt-Nut) as well as of nanoparticles engineered with Rituximab alone (NP-Rt) were initially analyzed in vitro in JVM-2 B-leukemic cells, by assessing both the functional activation of the p53 pathway (by Nutlin-3) and/or the activation of the complement cascade (by Rituximab). Moreover, the potential therapeutic efficacy of NP-Nut, NP-Rt and NP-Rt-Nut were comparatively assessed in vivo in CD20+ JVM-2 leukemic xenograft SCID mice. RESULTS: Functional in vitro assays demonstrated that NP-Nut and NP-Rt-Nut exhibited a comparable ability to activate the p53 pathway in the p53wild-type JVM-2 leukemic cells. On the other hand, NP-Rt and NP-Rt-Nut, but not NP nor NP-Nut, were able to promote activation of the complement cascade. Of note, the in vivo intra-tumoral injection in JVM-2 B leukemic/xenograft mice demonstrated that NP-Rt-Nut displayed the maximal therapeutic activity promoting a survival rate significantly higher not only with respect to control animals, treated either with vehicle or with empty NP, but also with respect to animals treated with NP-Nut or NP-Rt. CONCLUSIONS: Our data demonstrate for the first time the potential anti-leukemic activity of Rituximab-engineered Nutlin-3 loaded NP in xenograft SCID mice.
Nanoparticles engineered with Rituximab and loaded with Nutlin-3 show promising therapeutic activity in B leukemic xenografts
VOLTAN, Rebecca;SECCHIERO, Paola;CARUSO, Lorenzo;ZAULI, Giorgio
2013
Abstract
PURPOSE: Since the non-genotoxic inhibitor of the p53/MDM2 interactions Nutlin-3 has shown promising in vitro therapeutic activity against a variety of p53wild-type cancer cells, in this study we evaluated an innovative strategy able to specifically target Nutlin-3 towards CD20+ malignant cells. EXPERIMENTAL DESIGN: The cytotoxic effects of Nutlin-3 encapsulated into poly(lactide-co-glycolide) nanoparticles (NP-Nut) and into Rituximab (anti-CD20 Antibody)-engineered NP (NP-Rt-Nut) as well as of nanoparticles engineered with Rituximab alone (NP-Rt) were initially analyzed in vitro in JVM-2 B-leukemic cells, by assessing both the functional activation of the p53 pathway (by Nutlin-3) and/or the activation of the complement cascade (by Rituximab). Moreover, the potential therapeutic efficacy of NP-Nut, NP-Rt and NP-Rt-Nut were comparatively assessed in vivo in CD20+ JVM-2 leukemic xenograft SCID mice. RESULTS: Functional in vitro assays demonstrated that NP-Nut and NP-Rt-Nut exhibited a comparable ability to activate the p53 pathway in the p53wild-type JVM-2 leukemic cells. On the other hand, NP-Rt and NP-Rt-Nut, but not NP nor NP-Nut, were able to promote activation of the complement cascade. Of note, the in vivo intra-tumoral injection in JVM-2 B leukemic/xenograft mice demonstrated that NP-Rt-Nut displayed the maximal therapeutic activity promoting a survival rate significantly higher not only with respect to control animals, treated either with vehicle or with empty NP, but also with respect to animals treated with NP-Nut or NP-Rt. CONCLUSIONS: Our data demonstrate for the first time the potential anti-leukemic activity of Rituximab-engineered Nutlin-3 loaded NP in xenograft SCID mice.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
