| Autor: |
Schnorenberg MR; Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States.; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, United States.; Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637, United States., Hawley KM; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, United States., Thomas-Toth AT; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, United States., Watkins EA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States., Tian Y; Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States.; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, United States., Ting JM; Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States., Leak LB; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, United States., Kucera IM; Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States.; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, United States., Raczy MM; Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States., Kung AL; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States., Hubbell JA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States., Tirrell MV; Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States., LaBelle JL; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, United States. |
| Abstrakt: |
Diffuse large B-cell lymphoma (DLBCL) remains a formidable diagnosis in need of new treatment paradigms. In this work, we elucidated an opportunity for therapeutic synergy in DLBCL by reactivating tumor protein p53 with a stapled peptide, ATSP-7041, thereby priming cells for apoptosis and enhancing their sensitivity to BCL-2 family modulation with a BH3-mimetic, ABT-263 (navitoclax). While this combination was highly effective at activating apoptosis in DLBCL in vitro , it was highly toxic in vivo , resulting in a prohibitively narrow therapeutic window. We, therefore, developed a targeted nanomedicine delivery platform to maintain the therapeutic potency of this combination while minimizing its toxicity via packaging and targeted delivery of a stapled peptide. We developed a CD19-targeted polymersome using block copolymers of poly(ethylene glycol) disulfide linked to poly(propylene sulfide) (PEG-SS-PPS) for ATSP-7041 delivery into DLBCL cells. Intracellular delivery was optimized in vitro and validated in vivo by using an aggressive human DLBCL xenograft model. Targeted delivery of ATSP-7041 unlocked the ability to systemically cotreat with ABT-263, resulting in delayed tumor growth, prolonged survival, and no overt toxicity. This work demonstrates a proof-of-concept for antigen-specific targeting of polymersome nanomedicines, targeted delivery of a stapled peptide in vivo , and synergistic dual intrinsic apoptotic therapy against DLBCL via direct p53 reactivation and BCL-2 family modulation. |
