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

Sci Adv. 2020 Apr 1;6(14):eaaz9798. doi: 10.1126/sciadv.aaz9798. eCollection 2020 Apr.

Abstract

Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin'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 BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity.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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD20 / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Compounding
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / metabolism
  • Humans
  • Imidazoles / administration & dosage
  • Immunophenotyping
  • Lymphoma, Non-Hodgkin / drug therapy
  • Lymphoma, Non-Hodgkin / metabolism*
  • Lymphoma, Non-Hodgkin / pathology
  • Nanoparticles*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Quinolines / administration & dosage
  • TOR Serine-Threonine Kinases / metabolism*
  • Tissue Distribution
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD20
  • HLA-DR Antigens
  • Imidazoles
  • Protein Kinase Inhibitors
  • Quinolines
  • TOR Serine-Threonine Kinases
  • dactolisib