title: Nanoparticles engineered with rituximab and loaded with Nutlin-3 show promising therapeutic activity in B-leukemic xenografts.
abstract: OBJECTIVE
  Because the nongenotoxic inhibitor of the p53/MDM2 interactions Nutlin-3 has shown promising in vitro therapeutic activity against a variety of p53(wild-type) cancer cells, in this study we evaluated an innovative strategy able to specifically target Nutlin-3 toward CD20(+) malignant cells.
  
  
  METHODS
  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 NPs 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 showed that NP-Nut and NP-Rt-Nut exhibited a comparable ability to activate the p53 pathway in the p53(wild-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 intratumoral injection in JVM-2 B-leukemic/xenograft mice showed 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 show for the first time the potential antileukemic activity of rituximab-engineered Nutlin-3-loaded NPs in xenograft SCID mice.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Voltan
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruozi
authors.forename: Flavio
authors.initials: F
authors.lastname: Forni
authors.forename: Chiara
authors.initials: C
authors.lastname: Agostinis
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Caruso
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Vandelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003167:Complement Activation; D007093:Imidazoles / Q000008:administration & dosage*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D016513:Mice, SCID; D053769:Nanocapsules / Q000737:chemistry*; D010316:Particle Size; D010879:Piperazines / Q000008:administration & dosage*; D011098:Polyglactin 910 / Q000737:chemistry; D000069283:Rituximab; D013499:Surface Properties; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D007093:Imidazoles; D053769:Nanocapsules; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011098:Polyglactin 910; D000069283:Rituximab; C482205:nutlin 3