X-ray-Induced Cherenkov Optical Triggering of Caged Doxorubicin Released to the Nucleus for Chemoradiation Activation

ACS Appl Mater Interfaces. 2020 Oct 7;12(40):44383-44392. doi: 10.1021/acsami.0c05189. Epub 2020 Sep 25.

Abstract

Concurrent chemoradiotherapy is used for advanced cancers, but the chemotherapy is dose limited by normal tissue toxicity. Localized X-ray activation of chemotherapy could overcome this, as studied here, with release from self-assembled nanomicelles (NMs) created from copolymers loaded with doxorubicin (DOX) having a photocleavable o-nitrobenzyl ester (o-Ne) group. The micelles demonstrated release of DOX from X-ray-induced Cherenkov light and conversion from a caged hydrophobic form to hydrophilic DOX, which achieves nuclear localization. Folate on the exterior of the NMs directed them for effective intracellular uptake prior to irradiation. Irradiation with 8 Gy released the DOX, which then entered the cell nucleus, providing near-complete in vivo tumor eradication and negligible off-target organ damage. Micelles were assembled from molecular component materials that are commonly in human use. This study realizes triple targeting in chemoradiation with potential for cell-receptor-mediated uptake, localized radiotherapy activation, and nuclear relocalization, all leading to limited off-target toxicity.

Keywords: Cherenkov; X-ray; folic acid; irradiation; nanoparticles; nanotechnology; theranostic.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacology*
  • Cell Nucleus / drug effects*
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacology*
  • Drug Liberation
  • Drug Screening Assays, Antitumor
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Micelles
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Particle Size
  • Surface Properties
  • Tumor Cells, Cultured
  • X-Rays*

Substances

  • Antibiotics, Antineoplastic
  • Micelles
  • Doxorubicin