@article{d6636dc90cd04c03811ee18607114e0d,
title = "Pretargeted delivery of PI3K/mTOR small-molecule inhibitor–loaded nanoparticles for treatment of non-Hodgkin{\textquoteright}s lymphoma",
abstract = "Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin{\textquoteright}s lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)–based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR–expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.",
author = "Au, {Kin Man} and Wang, {Andrew Z.} and Park, {Steven I.}",
note = "Funding Information: We thank the Microscopy Service Laboratory Core, Animal Study Core, Small Animal Imaging Facility, Animal Clinical Laboratory, Animal Histopathology Core Facility, Translation Pathology Laboratory, UNC Flow Cytometry Core Facility, UNC Macromolecular Interactions Facility and UNC Michael Hooker Proteomics Center in the School of Medicine, and Chapel Hill Analytical and Nanofabrication Laboratory (CHANL) at the UNC at Chapel Hill for their assistance with procedures in this manuscript. The UNC Flow Cytometry Core Facility is supported, in part, by P30CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. This work was supported by the University Cancer Research Fund from the UNC and R01CA178748 grant from the NIH/ National Cancer Institute. A.Z.W. was also supported by NIH Center for Nanotechnology Excellence grant U54-CA151652. S.I.P. was also supported by the American Cancer Society Mentored Research Scholar Grant in Tumor Biology and Genomics (126601-MRSG-14-215-01-TBG). Publisher Copyright: Copyright {\textcopyright} 2020 The Authors.",
year = "2020",
month = apr,
day = "1",
doi = "10.1126/sciadv.aaz9798",
language = "English (US)",
volume = "6",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "14",
}