Targeted Polymersome Delivery of a Stapled Peptide for Drugging the Tumor Protein p53:BCL-2-Family Axis in Diffuse Large B‑Cell Lymphoma

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.