Activating TiO₂ Nanoparticles: Gallium-68 Serves as a High-Yield Photon Emitter for Cerenkov-Induced Photodynamic Therapy

Abstract

The classical photodynamic therapy (PDT) requires external light to activate photosensitizers for cancer treatment. However, limited tissue penetration of light has been a long-standing challenge for PDT to cure malignant tumors in deep tissues. Recently, Cerenkov radiation (CR) emitted by radiotracers such as F-fluorodeoxyglucose (F-FDG) has become an alternative and promising internal light source. Nevertheless, fluorine-18 (F-18) only releases 1.3 photons per decay in average; consequently, injection dose of F-18 goes beyond 10-30 times more than usual to acquire therapeutic efficacy because of its low Cerenkov productivity. Gallium-68 (Ga-68) is a favorable CR source owing to its ready availability from generator and 30-time higher Cerenkov productivity. Herein, we report, for the first time, the use of Ga-68 as a CR source to activate dextran-modified TiO nanoparticles (D-TiO NPs) for CR-induced PDT. Compared with F-FDG,Ga-labeled bovine serum albumin (Ga-BSA) inhibited the growth of 4T1 cells and exhibited significantly stronger DNA damage to tumor cells. In vivo studies showed that the tumor growth was almost completely inhibited when tumor-bearing mice were treated with a combination of D-TiO NPs and Ga-BSA. This study proved that Ga-68 is a more potent radionuclide for PDT than F-18 both in vitro and in vivo offered a promising strategy of using a diagnostic dose of radioactivity to achieve depth-independent cancer therapy without using any external light source.

Design of Cerenkov Radiation–Assisted Photoactivation of TiO2 Nanoparticles and Reactive Oxygen Species Generation for Cancer Treatment

“…The CR spectrum from the model followed the Frank-Tamm equation (number of photons a 1/l 2 ), and the number of photons generated also matched that in a previous report (28). The model was compared with 2 different experimental studies (15,23). The experiments revealed a change in tumor cell viability as a function of the 18 F-FDG dose; this change was then converted into the ROS concentration using a constant scaling factor, and this ROS concentration was compared with the ROS concentration predicted from the model using the experimental parameters from those studies.…”

“…Kamkaew et al (16) reported a system with a 89 Zr radionuclide (Cerenkov radiation source) and chlorin e6 (photocatalyst) and demonstrated its advantage in ROS generation through CR. Two radionuclides-68 Ga and 18 F-were recently studied for their cellular uptake and effectiveness in cancer treatment (23,24).…”

Radionuclide‐Activated Nanomaterials and Their Biomedical Applications

“…Forexample,while 18 Fand 64 Cu give 1.32 and 0.56 photons per decay,respectively,higher energy b emitters such as 90 Yand 68 Ga produce 47.3 and 33.9 photons per decay, respectively. [9,58] Thei nfluence of the isotope choice was tested by Duan et al, [58] who reported the first use of 68 Ga as aC Rs ource to activate oxide (TiO 2 )N Ps for PDT.T he authors compared the PDT efficiencyo ft he same nanoparticles when activated by CR from 18 F-FDG or 68 Ga-BSA. In vitro studies indicated that despite the cellular uptake of F-FDG being much higher than that of 68 Ga-BSA, 68 Ga-BSA promoted more efficient growth suppression.…”

“…Although the studies mentioned above demonstrated the applicability of CR-PDT,t he intensity of the photons generated was still much lower than those of excited by external sources. [58] In ar ecent publication, we introduced an ew strategy to improve the therapeutic efficacy of CR-PDT [74] by overcoming both the depth and external light dependence of traditional PDT.I nt his strategy, (Zn 0.4 Mn 0.6 )Fe 2 O 4 nanoparticles (MNPs) were guided to the desired tissue by an external magnetic field. TheMNPs were labeled chelator-free with 89 Zr as as ource of CR as well as conjugated with porphyrin molecules of meso-tetrakis(4carboxyphenyl)porphyrin (TCPP) to be excited for ROSmediated tumor-cell damage (Figure 15 a).…”

Radionuklidaktivierte Nanomaterialien und ihre biomedizinische Anwendung

“…0.56 Photonen pro Zerfall produzieren, liefern höherenergetische β‐Emitter, wie 90 Y und 68 Ga, 47.3 bzw. 33.9 Photonen pro Zerfall . Der Einfluss des gewählten Isotops wurde von Duan und Mitarbeitern evaluiert, die erstmals den Einsatz von 68 Ga als CR‐Quelle zur Aktivierung oxidischer NPs (TiO 2 ) für die PDT publizierten.…”