Intelligent design of polymer nanogels for full-process sensitized radiotherapy and dual-mode computed tomography/magnetic resonance imaging of tumors

Abstract

Rationale: Development of intelligent radiosensitization nanoplatforms for imaging-guided tumor radiotherapy (RT) remains challenging. We report here the construction of an intelligent nanoplatform based on poly( N -vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) and manganese dioxide (MnO 2 ) nanoparticles (NPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging-guided “full-process” sensitized RT of tumors. Methods: PVCL NGs were synthesized via precipitation polymerization and in situ loaded with Au and MnO 2 NPs. The created PVCL-Au-MnO 2 NGs were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular oxygen and ·OH production, and cell cycle arrest in vitro , evaluated to disclose their RT sensitization effects of cancer cells and a tumor model, and assessed to validate their dual-mode CT/MR imaging potential, pharmacokinetics, biodistribution, and biosafety in vivo . Results: The formed PVCL-Au-MnO 2 NGs with a size of 121.5 nm and good stability can efficiently generate reactive oxygen species through a Fenton-like reaction to result in cell cycle distribution toward highly radiosensitive G2/M phase prior to X-ray irradiation, sensitize the RT of cancer cells under X-ray through the loaded Au NPs to induce the significant DNA damage, and further prevent DNA-repairing process after RT through the continuous production of O 2 catalyzed by MnO 2 in the hybrid NGs to relieve the tumor hypoxia. Likewise, the in vivo tumor RT can also be guided through dual mode CT/MR imaging due to the Au NPs and Mn(II) transformed from MnO 2 NPs. Conclusion: Our study suggests an intelligent PVCL-based theranostic NG platform that can achieve “full-process” sensitized tumor RT under the guidance of dual-mode CT/MR imaging.

Nanomaterial-based CT contrast agents and their applications in image-guided therapy

“…MnO 2 with a catalase-mimic catalytic activity can catalyze overexpressed H 2 O 2 in tumors to generate O 2 , thus relieving tumor hypoxia 148 - 150 . Shi et al synthesized intelligent Au/MnO 2 -coloaded poly(N-vinylcaprolactam) (PVCL-Au-MnO 2 ) nanogels (NGs) for CT image-guided RT; PVCL-Au-MnO 2 NGs with a catalase-mimic catalytic activity could convert H 2 O 2 in tumors to generate O 2 to improve the radio-sensitization effect ( Figure 9 F ) 151 . The CT value increased linearly as a function of the PVCL-Au-MnO 2 NG concentration.…”

“…(A-E) Adapted with permission from 15 , Copyright 2016 American Chemical Society. (F-I) Adapted with permission from 151 , Copyright 2022 Ivyspring International Publisher. (J-M) Adapted with permission from 153 , Copyright 2022 American Chemical Society.…”

Advances of MnO2 nanomaterials as novel agonists for the development of cGAS-STING-mediated therapeutics

“…Mn 2+ can be used as an effective T1 weighted MRI contrast agent because of its five unpaired 3d electrons ( 70 ).Zhang et al. constructed an intelligent nanoplatform based on poly (N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) and manganese dioxide (MnO 2 ) nanoparticles (NPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging ( 71 ). MnO 2 nanomaterials can release Mn 2+ more efficiently under tumor microenvironment conditions, which therefore provided an enhanced signal for MRI imaging and can be used for imaging-guided therapy.…”

Oxygen switches: Refueling for cancer radiotherapy

“…Zhang et al. reported a nanoplatform based on poly(N-vinyl caprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) and manganese dioxide (MnO 2 ) nanoparticles (NPs) for sensitized radiotherapy ( 28 ). MnO 2 displayed the CAT-mimic catalytic activity that decomposed H 2 O 2 to form O 2 and alleviate tumor hypoxia ( Figure 2C ).…”