Overactivation of the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling has been identified in a number of hematological malignancies, including non-Hodgkin lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to its poor solubility and on-target/off-tumor toxicity. Here, we present the development of a novel nanoparticle (NP)-based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HAL-DR-expressing lymphoma cells for combination targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies (Abs) as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. The pretargeting Abs were tailored to undergo rapid bioorthogonal ligation with the effector NPs at the target site, enhancing the therapeutic efficiency through increased amount of BEZ235 retained inside the tumor. Using four established lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual Ab pretargeted strategy effectively raises the number of NPs retained on the target tumor cells. This improves the <i>in vitro</i> antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Comprehensive <i>in vivo</i> studies using Namalwa and Raji mouse models confirm that the dual Ab pretargeted system effectively inhibits tumors growth, improves survival, and reduces the systemic side effects of BEZ235. Our data demonstrate that a novel NP-enabled pretargeted system consolidates the use of kinase inhibition with Ab-directed targeted therapy and improves the therapeutic window of small molecule inhibitors.

Pretargeted delivery of PI3K/mTOR small-molecule inhibitor-loaded nanoparticles for treatment of non-Hodgkin lymphoma

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.