Scintillating Nanoparticles as Energy Mediators for Enhanced Photodynamic Therapy

Abstract

Achieving effective treatment of deep-seated tumors is a major challenge for traditional photodynamic therapy (PDT) due to difficulties in delivering light into the subsurface. Thanks to their great tissue penetration, X-rays hold the potential to become an ideal excitation source for activating photosensitizers (PS) that accumulate in deep tumor tissue. Recently, a wide variety of nanoparticles have been developed for this purpose. The nanoparticles are designed as carriers for loading various kinds of PSs and can facilitate the activation process by transferring energy harvested from X-ray irradiation to the loaded PS. In this review, we focus on recent developments of nanoscintillators with high energy transfer efficiency, their rational designs, as well as potential applications in next-generation PDT. Treatment of deep-seated tumors by using radioisotopes as an internal light source will also be discussed.

Keywords: Cerenkov radiation; X-ray activatable nanoparticles; cancer therapy; energy mediator; photodynamic therapy; photosensitizer; radiosensitizer; scintillating nanoparticles; scintillator.

Figure 1

(a) Schematic of REs showing the lanthanide-doped core surrounded by an undoped shell. (b) TEM images of REs reveal spherical morphology. (c) Nanoprobe clearance visualized in mice 15 min post injection using X-IR imaging. (d) X-IR imaging of axillary and brachial lymph nodes. Reproduced with permission from [65]. Copyright 2015 American Chemical Society.

Figure 2

(a) A proposed formation mechanism of mesoporous LaF₃:Tb³⁺ nanoparticles. (b) Schematic represents mesoporous LaF₃:Tb³⁺-RB nanocomposites and their potential application in deep PDT. (c) Luminescence intensity at 544 nm under UV and X-ray stimulation of mesoporous LaF₃:Tb³⁺ ScNPs with varied Tb³⁺ doping ratios. (d) Spectrum overlap between luminescence of LaF₃:Tb³⁺ ScNPs and absorption of RB. (e) Decrease of emission intensity of 1,3-diphenylisobenzofuran treated with LaF₃:Tb³⁺ ScNPs, RB, and LaF₃:Tb-RB nanocomposites, respectively, after different irradiation times. Reproduced with permission from [82]. Copyright 2015 American Chemical Society.

Figure 3

Schematic representing the mechanism of a Y₂O₃ nanosystem with induced DNA cross-linking upon X-ray irradiation.

Figure 4

(a) A schematic illustration of the synthetic route to monodisperse SZNPs and (b) the mechanism of ionizing radiation-induced photodynamic therapy. TEM images at (c) low and (d) high magnifications, and (e) the corresponding size distribution of SZNPs. STEM image of SZNPs using (f) SEM, (g) dark-field, and (h) bright-field modes. (i) Corresponding element mappings of SZNPs. (j) In vivo ionizing-radiation-induced SZNPs-mediated synchronous radiotherapy and PDT. Reproduced with permission from [102]. Copyright 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 5

Uncaging reaction of DMNP-luciferin. Luciferin can be released from DMNP-luciferin by irradiation with UV 365 nm or with radiation luminescence generated from ¹⁸FDG.

Figure 6

(a) A schematic illustrating the synthesis of TiO₂-PEG, TiO₂-Tf and TiO₂-Tf-Tc. Below (left to right) are the TEM images of TiO₂-PEG, TiO₂ aggregates, TiO₂-Tf and TiO₂-Tf-Tc (right). (b) In vivo Cerenkov radiation-induced therapy (CRIT) through a one-time systemic administration of the constructs and ¹⁸FDG in HT1080-tumor-bearing Athymic nu/nu mice. (c) FDG-PET images of an untreated (left) mouse (15 days) with bilateral HT1080 tumors and after CRIT (30 days) (right). Reproduced with permission from [76]. Copyright 2015 Nature Publishing Group.

Scheme 1

A diagram demonstrating the outcomes when X-rays hit a high-Z substance.

Scheme 2

The principle of X-ray activatable nanoparticles for PDT. (a) Schematic represents scintillating nanoparticles (ScNPs) that act as an X-ray transducer to generate ¹O₂ through the energy transfer (ET) process. (b) Diagram represents the PDT mechanism that occurs when energy is transferred from ScNPs to activate the PS. The PS’s electrons from the ground state (S₀) will absorb energy and move to singlet-excited states (S₁). Some of the absorbed energy will be released via intersystem crossing (ISC), and the promoted electron will move to a triplet-excited state (T₁). This triplet state has a relatively long half-life, allowing energy to be transferred to nearby oxygen molecules. This generates ¹O₂ in most cases via the type II pathway, which can damage the cells in the surrounding area.

Scheme 3

Schematic depicting different PS loading strategies.

Scheme 4

(a) (Left) Direct excitation of porphyrin by 226 or 300 nm lasers. Porphyrin is excited to high vibrational energy levels and relaxes in a non-radiative decay to the S₂ then S₁ level. Relaxation from S₁ to S₀ results in visible emissions 1 and 2. (Right) Indirect excitation of porphyrin. Tb₂O₃@SiO₂ absorbs energy from light at 226 or 300 nm and is then excited to higher energy levels. Once nonradiative decays to ⁵D₄ level, Tb can either emit visible light 3 or transfer energy to porphyrin to emit red light 4. (b) Emission spectra measured under a 490 nm diode excitation after increasing X-ray irradiation time. The Tb₂O₃@SiO₂ grafted TPP is more efficient in generating ROS that oxidize APF under X-ray irradiation than porphyrin solution. Reproduced with permission from [86]. Copyright 2013 American Chemical Society.

Scheme 5

A schematic presenting the possible situation of when a high-energy photon (X-rays or γ-rays) hits QDs: (I) a high speed electron was released from a QD due to photon energy transfer to the electron (photoelectric ionization effect) or Compton scattering, where the incident photon continues scattering its travel with lower energy until the (II) photon annihilation on a nucleus of an atom and generation of an electron-positron pair. The positron will annihilate on a nucleus of an atom to generate an electron-positron pair with two 0.51 MeV photons. These particles will further lose their energy through the photoelectric effect or Compton scattering. Electrons generated in the incidents (I) and (II) will induce secondary high-speed electrons as well as Auger electrons. Such electrons that can escape into the environment will be captured by an acceptor (i.e. water, biomolecule, oxygen, nitrogen oxides), which localizes near the QDs and induces biomolecular radicals, superoxide, hydroxyl radicals, peroxynitrite anions, or nitric oxide radicals.

Scheme 6

Schematic illustration of radioisotope energy transfer processes. Radioisotopes can emit Cerenkov radiation to directly activate photosensitizers that can absorb light in the 200–500 nm range. Some radioisotopes can generate high energy photons, such as γ-radiation, that can be absorbed by certain types of nanoparticles (i.e. scintillating nanoparticles, ScNPs). In this case, the photosensitizers will be indirectly excited by the radionuclide. Once the PS is activated, ROS will be generated to damage the surrounding cell/tissue.