Correlation of in vitro cell viability and cumulative singlet oxygen luminescence from protoporphyrin IX in mitochondria and plasma membrane.

SIGNIFICANCE: Photodynamic therapy (PDT) can be targeted toward different subcellular localizations, and it is proposed that different subcellular targets vary in their sensitivity to photobiological damage. Since singlet oxygen (1O2) has a very short lifetime with a limited diffusion length in cellular environments, measurement of cumulative 1O2 luminescence is the most direct approach to compare the PDT sensitivity of mitochondria and plasma membrane. APPROACH: PDT-generated near-infrared 1O2 luminescence at 1270 nm was measured together with cell viability for 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) and exogenous PpIX, at different incubation times. Confocal fluorescence microscopy indicated that ALA-induced PpIX (2 h) localized in the mitochondria, whereas exogenous PpIX (1 h) mainly localized to the plasma membrane. Cell viability was determined at several time points during PDT treatments using colony-forming assays, and the surviving fraction correlated well with cumulative 1O2 luminescence counts from PpIX in mitochondria and plasmas membrane, respectively. RESULTS: The mitochondria are more sensitive than the plasma membrane by a factor of 1.7. CONCLUSIONS: Direct 1O2 luminescence dosimetry's potential value for comparing the PDT sensitivity of different subcellular organelles was demonstrated. This could be useful for developing subcellular targeted novel photosensitizers to enhance PDT efficiency.

Quantitative analysis of lesion images to evaluate the efficiency of vascular-targeted photodynamic therapy for port-wine stains: Four case reports.

SIGNIFICANCE: Vascular-targeted photodynamic therapy (V-PDT) is a clinically approved therapeutic approach for treating vascular-related diseases, such as port-wine stains (PWS). For accurate treatment, varying light irradiance is required for different lesions due to the irregularity of vascular size, shape and degree of disease, which commonly alters during different stages of V-PDT. This makes quantitative analysis of the treatment efficiency urgently needed. APPROACH: Lesion images pre- and post- V-PDT treatment of patients with PWS were used to construct a quantitative method to evaluate the differences among lesions. Image analysis techniques were applied to evaluate the V-PDT efficiency for PWS by determining the Euclidean distances and two-dimensional correlation coefficients. RESULTS: According to the image analysis, V-PDT with good treatment efficiency resulted in a larger Euclidean distance and a smaller correlation coefficient compared with the case having lower V-PDT efficiency. CONCLUSIONS: A new method to quantify the Euclidean distances and correlation coefficients has been proposed, which is promising for the quantitative analysis of V-PDT efficiency for PWS.

Novel chlorin e6-based conjugates of tyrosine kinase inhibitors: Synthesis and photobiological evaluation as potent photosensitizers for photodynamic therapy.

Since tyrosine kinase inhibitor (TKI) could reverse ABCG2-mediated drug-resistance, novel chlorin e6-based conjugates of Dasatinib and Imatinib as photosensitizer (PS) were designed and synthesized. The results demonstrated that conjugate 10b showed strongest phototoxicity against HepG2 and B16-F10 cells, which was more phototoxic than chlorin e6 and Talaporfin. It could reduce efflux of intracellular PS by inhibiting ABCG2 in HepG2 cells, and localize in mitochondria, lysosomes, golgi and ER, resulting in higher cell apoptosis rate and ROS production than Talaporfin. Moreover, it could induce cell autophagy and block cell cycle in S phase, and significantly inhibit tumor growth and prolong survival time on BALB/c nude mice bearing HepG2 xenograft tumor to a greater extent than chlorin e6. Consequently, compound 10b could be applied as a promising candidate PS due to its good water-solubility and stability, low drug-resistance, high quantum yield of 1O2 and excellent antitumor efficacy in vitro and in vivo.

Acidity-Responsive Nanoreactors Destructed "Warburg Effect" for Toxic-Acidosis and Starvation Synergistic Therapy.

"Warburg Effect" shows that most tumor cells rely on aerobic glycolysis for energy supply, leading to malignant energy deprivation and an "internal alkaline external acid" tumor microenvironment. Destructing the "Warburg Effect" is an effective approach to inhibit tumor progression. Herein, an acidity-responsive nanoreactor (Au@CaP-Flu@HA) is fabricated for toxic acidosis and starvation synergistic therapy. In the nanoreactor, the fluvastatin (Flu) could reduce lactate efflux by inhibiting the lactate-proton transporter (monocarboxylate transporters, MCT4), resulting in intracellular lactate accumulation. Meanwhile, the glucose oxidase-mimic Au-nanocomposite consumes glucose to induce cell starvation accompanied by gluconic acid production, coupling with lactate to exacerbate toxic acidosis. Also, the up-regulated autophagic energy supply of tumor cells under energy deprivation and hypoxia aggravation is blocked by autophagy inhibitor CaP. Cellular dysfunction under pHi acidification and impaired Adenosine Triphosphate (ATP) synthesis under starvation synergistically promote tumor cell apoptosis. Both in vitro and in vivo studies demonstrate that this combinational approach of toxic-acidosis/starvation therapy could effectively destruct the "Warburg Effect" to inhibit tumor growth and anti-metastatic effects.

Internal light source for deep photodynamic therapy.

Photodynamic therapy (PDT) for deep-seated lesion is seriously hindered by the limited depth of visible light penetration. Most recently, researchers have designed a genetically-encoded NanoLuc-miniSOG with internal light source for self-excitation, which is highly beneficial for deep PDT.

Multi-step deep neural network for identifying subfascial vessels in a dorsal skinfold window chamber model.

Automatic segmentation of blood vessels in the dorsal skinfold window chamber (DWSC) model is a prerequisite for the evaluation of vascular-targeted photodynamic therapy (V-PDT) biological response. Recently, deep learning methods have been widely applied in blood vessel segmentation, but they have difficulty precisely identifying the subfascial vessels. This study proposed a multi-step deep neural network, named the global attention-Xnet (GA-Xnet) model, to precisely segment subfascial vessels in the DSWC model. We first used Hough transform combined with a U-Net model to extract circular regions of interest for image processing. GA step was then employed to obtain global feature learning followed by coarse segmentation for the entire blood vessel image. Secondly, the coarse segmentation of blood vessel images from the GA step and the same number of retinal images from the DRIVE datasets were combined as the mixing sample, inputted into the Xnet step to learn the multiscale feature predicting fine segmentation maps of blood vessels. The data show that the accuracy, sensitivity, and specificity for the segmentation of multiscale blood vessels in the DSWC model are 96.00%, 86.27%, 96.47%, respectively. As a result, the subfascial vessels could be accurately identified, and the connectedness of the vessel skeleton is well preserved. These findings suggest that the proposed multi-step deep neural network helps evaluate the short-term vascular responses in V-PDT.

Mitochondrial Ca2+-overloading by oxygen/glutathione depletion-boosted photodynamic therapy based on a CaCO3 nanoplatform for tumor synergistic therapy.

The Ca2+ buffering capacity of mitochondria maintains the balance of cell physiological activities. The exogenous reactive oxygen species (ROS) can be used to break the balance, resulting in mitochondrial dysfunction and irreversible cell apoptosis. Herein, the CaCO3-based tumor microenvironment (TME) responsive nanoplatform (CaNPCAT+BSO@Ce6-PEG) was designed for oxygen/GSH depletion-boosted photodynamic therapy (PDT) and mitochondrial Ca2+-overloading synergistic therapy. In acidic TME, CaCO3 decomposed and released the cargos (catalase (CAT), buthionine sulfoximine (BSO), chlorin e6 (Ce6), and Ca2+). The tumor hypoxia and reductive microenvironment could be significantly reversed by CAT and BSO, which greatly enhanced the PDT efficacy. The generated 1O2 during PDT process not only directly killed cancer cells but also destroyed the Ca2+ buffering capacity, leading to the mitochondrial Ca2+-overloading. The increased Ca2+ concentration promoted the process of oxidative phosphorylation and inhibited the production of adenosine triphosphate (ATP), resulting in the acceleration of cell death. Under the joint action of enhanced PDT and mitochondrial Ca2+-overloading, the CaNPCAT+BSO@Ce6-PEG NPs showed remarkable synergistic effects in tumor inhibition without any side effects. STATEMENT OF SIGNIFICANCE: In the manuscript, a CaCO3-based nano-platform for tumor microenvironment response was designed. With the decomposition of CaNPCAT+BSO@Ce6-PEG NPs in the acidic tumor microenvironment, the released catalase (CAT) and buthionine sulfoximine (BSO) could relieve the tumor hypoxia and inhibit GSH production. Under 660 nm laser irradiation, the photodynamic effect was enhanced and caused apoptosis. Meanwhile, the Ca2+ buffering capacity was destroyed which led to the mitochondrial Ca2+-overloading. The synergistic effect of enhanced PDT and mitochondrial Ca2+-overloading made the CaNPCAT+BSO@Ce6-PEG NPs present remarkable antitumor performance.

Thrombin Based Photothermal-Responsive Nanoplatform for Tumor-Specific Embolization Therapy.

The specific coagulation in the tumor vasculature has the potential for the ablation of solid tumors by cutting off the blood supply. However, the safe delivery of effective vessel occluding agents in the tumor-specific embolization therapy remains challenging. Herein, it is reported that the photothermal responsive tumor-specific embolization therapy based on thrombin (Thr) is delivered by intravenous injection via the phase-change materials (PCM)-based nanoparticles. The wax sealing profile of PCM enables safe delivery and prevents the preleakage of Thr in the blood circulation. While in the tumor site, the thermal effect induced by IR780 triggers the melting of PCM and rapidly releases Thr to generate coagulation in the tumor blood vessels. Based on the safe delivery and controllable release of Thr, thermal responsive tumor-specific embolization therapy could be achieved with high efficiency and no significant damage to normal organs and tissues. The safe administration of Thr to induce vascular infarction in tumors based on PCM nanoparticles in this work shows a promising strategy for improving the therapeutic specificity and efficacy of coagulation-based tumor therapy.

Revisiting the Graphitized Nanodiamond-Mediated Activation of Peroxymonosulfate: Singlet Oxygenation versus Electron Transfer.

Graphitized nanodiamonds (ND) exhibit outstanding capability in activating peroxymonosulfate (PMS) for the removal of aqueous organic micropollutants (OMPs). However, controversial observation and interpretation regarding the effect of graphitization degree on ND's activity and the role of singlet oxygen (1O2) in OMP degradation need to be clarified. Herein, we investigated graphitized ND-mediated PMS activation. Experiments show that the activity of ND increases first and then decreases with the monotonically increased graphitization degree. Further experimental and theoretical studies unveil that the intensified surface graphitization alters the degradation mechanism from singlet oxygenation to an electron-transfer pathway. Moreover, for the first time, we applied a self-constructed, time-resolved phosphorescence detection system to provide direct evidence for 1O2 production in the PMS-based system. This work not only elucidates the graphitization degree-dependent activation mechanism of PMS but also provides a reliable detection system for in situ analysis of 1O2 in future studies.

Nano-photosensitizers for enhanced photodynamic therapy.

Photodynamic therapy (PDT) utilizes photosensitizers (PSs) together with irradiation light of specific wavelength interacting with oxygen to generate cytotoxic reactive oxygen species (ROS), which could trigger apoptosis and/or necrosis-induced cell death in target tissues. During the past two decades, multifunctional nano-PSs employing nanotechnology and nanomedicine developed, which present not only photosensitizing properties but additionally accurate drug release abilities, efficient response to optical stimuli and hypoxia resistance. Further, nano-PSs have been developed to enhance PDT efficacy by improving the ROS yield. In addition, nano-PSs with additive or synergistic therapies are significant for both currently preclinical study and future clinical practice, given their capability of considerable higher therapeutic efficacy under safer systemic drug dosage. In this review, nano-PSs that allow precise drug delivery for efficient absorption by target cells are introduced. Nano-PSs boosting sensitivity and conversion efficiency to PDT-activating stimuli are highlighted. Nano-PSs developed to address the challenging hypoxia conditions during PDT of deep-sited tumors are summarized. Specifically, PSs capable of synergistic therapy and the emerging novel types with higher ROS yield that further enhance PDT efficacy are presented. Finally, future demands for ideal nano-PSs, emphasizing clinical translation and application are discussed.

Quenching effects of (-)-Epigallocatechin gallate for singlet oxygen production and its protection against oxidative damage induced by Ce6-mediated photodynamic therapy in vitro.

BACKGROUND: Singlet oxygen (1O2) is highly reactive to biological components such as lipids, proteins and DNA, which induces oxidative damage to cells and tissues. Natural antioxidants may function as 1O2 quencher to prevent 1O2 involved photosensitized oxidation in biological system. METHODS: Time-resolved measurement of 1O2 luminescence was employed to evaluate the 1O2 quenching abilities of natural antioxidants in air-statured phosphate buffered saline (PBS), including (-)-Epigallocatechin gallate (EGCG), Proanthocyanidins, L-carnosine and Vitamin C. The 1O2 quenching effects and rate constant of EGCG were investigated by detecting the absorption, fluorescence and 1H-NMR spectroscopy and 1O2 luminescence decay curves, respectively. In addition, the protective activity of EGCG against 1O2 oxidative damage caused by Ce6-mediated photodynamic therapy (PDT) was verified in cells. RESULTS: EGCG, proanthocyanidins, L-carnosine and Vitamin C efficiently quenched 1O2 luminescence at 1270 nm. The triplet-state quenching rate constants of EGCG for Rose Bengal (RB), Chlorin e6, AlPcS and HiPorfin are 2.21 × 109, 4.90 × 108, 3.30 × 108, 1.78 × 109 M-1s-1, while the 1O2 quenching rate constants are 2.80 × 108, 1.50 × 108, 1.30 × 108, 1.70 × 108 M-1s-1, respectively. Furthermore, EGCG could effectively quench 1O2 production to prevent NIH/3T3 cells oxidative damage induced by Ce6-mediated PDT. CONCLUSIONS: EGCG is an efficient quencher for both triplet-state photosensitizers and 1O2. The quenching ability of EGCG during photosensitization for selected photosensitizers is: RB > HiPorfin > Ce6 > AlPcS. EGCG could be used to protect normal cells and tissue against oxidative damage.

Rapid skin optical clearing enhancement with salicylic acid for imaging blood vessels in vivo.

BACKGROUND: Light penetration in deeper tissue is impeded by the skin scattering properties, which significantly limits the clinical applications of light in medical diagnosis and therapy. To overcome this problem, skin optical clearing methods using different optical clearing agents (OCAs) have been extensively developed to clear the dermis tissue. It is critically important to remove the outmost stratum corneum (SC) before the OCAs were applied for optical clearing, since the SC works as a natural barrier to the OCAs. For this, a controllable approach for the SC disruption through physical or chemical methods is highly required for enhanced skin optical clearing. METHODS: Salicylic acid (SA) was combined with OCAs as a rapid skin optical clearing method to create a transparent window within 5 min. The clearing efficacy of this method was demonstrated by using dorsal skin model of mice. In addition, the intensity variations of vessel gray images and diffuse reflectance (DR) spectra were used to quantify the optical clearing efficacy, which were acquired by a low-cost self-built white light imaging system and optical fiber spectrometer, respectively. RESULTS: Within a specific action time of the OCAs to the skin tissue, the enhanced images of the deeper blood vessels were obtained through the removal of the SC. It takes 5 min for the skin to turn transparent and 15 min to visualize the microvascular morphology for naked eyes. Furthermore, the intensity of blood vessel gray images was identified to be an evaluation parameter for quantifying the optical clearing efficacy. CONCLUSIONS: An efficient and easy-to-handle method for enhanced skin optical clearing was established by combining SA with OCAs, which could boost the clinical applications of light in medical diagnosis and therapy.

Carbon dot-assisted luminescence of singlet oxygen: the generation dynamics but not the cumulative amount of singlet oxygen is responsible for the photodynamic therapy efficacy.

A novel carbon dot-based luminescence probe for singlet oxygen (1O2) with a conventional optical detector has been implemented through the specific formation of electronically excited carbonyls from the breakdown of unstable endoperoxide intermediates, and its application in the real-time in vivo monitoring of 1O2 in photodynamic therapy (PDT) is achieved. More attractively, the relationship between the dynamics details of photosensitizer-generated 1O2 and the PDT efficacy has been established through a modified multiple-target survival model, enabling a direct and easy estimate of the surviving fraction of tumor cells from the generation dynamics of 1O2. Both in vitro and in vivo therapy results revealed that the rapid generation dynamics of 1O2 rather than its cumulative amount is responsible for better treatment efficacy in PDT. Overall, the deeper insight into the important roles of the generation dynamics of 1O2 in the PDT efficacy is irreplaceably advantageous in substantially reduced risks from deleterious treatment-related side effects by screening advanced photosensitizers and determining the light exposure end point.

Automatic protocol for quantifying the vasoconstriction in blood vessel images.

Vascular targeted photodynamic therapy (V-PDT) has been successfully utilized for various vascular-related diseases. To optimize the PDT dose and treatment protocols for clinical treatments and to elucidate the biological mechanisms for V-PDT, blood vessels in the dorsal skin-fold window chamber (DSWC) of nude mice are often chosen to perform in vivo studies. In this study, a new automatic protocol to quantify the vasoconstriction of blood vessels in the DSWC model is proposed, which focused on tracking the pixels of blood vessels in pre- V-PDT images that disappear after V-PDT. The disappearing pixels indicate that the blood vessels were constricted, and thus, the vasoconstriction image for pixel distribution can be constructed. For this, the image of the circular region of interest was automatically extracted using the Hough transform. In addition, the U-Net model is employed to segment the image, and the Speeded-Up Robust Features algorithm to automatically register the segmented pre- and post- V-PDT images. The vasoconstriction of blood vessels in the DSWC model after V-PDT is directly quantified, which can avoid by the potential of generating new capillaries. The accuracy, sensitivity and specificity of the U-Net model for image segmentation are 90.64%, 80.12% and 92.83%, respectively. A significant difference in vasoconstriction between a control and a V-PDT group was observed. This new automatic protocol is well suitable for quantifying vasoconstriction in blood vessel image, which holds the potential application in V-PDT studies.

Singlet Oxygen Luminescence Image in Blood Vessels During Vascular-Targeted Photodynamic Therapy.

Singlet oxygen (1 O2 ) is widely regarded as the main cytotoxic substance that induces the biological damage for photodynamic therapy (PDT). In this study, the previously developed near-infrared (NIR) optical imaging system was optimized for fast imaging of 1 O2 luminescence. The optical imaging system enables direct imaging of 1 O2 luminescence in blood vessels within 2 s during vascular-targeted PDT (V-PDT), which makes this system extremely practical for in vivo studies. The dependence of RB concentration on 1 O2 luminescence image was investigated for V-PDT, and the data imply that 1270 nm signal is attributed to 1 O2 luminescence. The imaging system operates with a field of view of 9.60 × 7.68 mm2 and a spatial resolution of 30 µm, which holds the potential to elucidate the correlation between cumulative 1 O2 luminescence and vasoconstriction for V-PDT.

Synthesis of Seven-Membered Azepino[3,2,1-hi]indoles via Rhodium-Catalyzed Regioselective C-H Activation/1,8-Diazabicyclo[5.4.0]undec-7-ene-Catalyzed Intramolecular Amidation of 7-Phenylindoles in One Pot.

An unprecedented rhodium-catalyzed regioselective C-H activation/1,8-diazabicyclo[5.4.0]undec-7-ene-catalyzed intramolecular amidation of 7-arylindoles with diazomalonates is described that provides a straightforward route to seven-membered azepino[3,2,1-hi]indoles in good to excellent yields in one pot. A wide range of functional groups, including F, OMe, NPh2, SiMe3, Cl, CN, CHO, COMe, CO2Me, CF3, and NO2, were all well-tolerated.

Transition-Metal-Controlled Synthesis of 11H-Benzo[a]carbazoles and 6-Alkylidene-6H-isoindo[2,1-a]indoles via Sequential Intermolecular/Intramolecular Cross-Dehydrogenative Coupling from 2-Phenylindoles.

A catalyst-controlled synthesis of 11H-benzo[a]carbazoles and 6-alkylidene-6H-isoindo[2,1-a]indoles is described. Pd(OAc)2 favored 6-alkylidene-6H-isoindo[2,1-a]indoles via intramolecular C-H/N-H CDC reaction, while [Cp*RhCl2]2 led to 11H-benzo[a]carbazoles through intramolecular C-H/C-H CDC reaction. Moreover, the synthesis of 11H-benzo[a]carbazoles via sequential intermolecular ortho C-H/olefin coupling and intramolecular C3-H/olefin coupling from 2-phenylindoles and alkenes can be operated in one pot.

Thieno[3,2-b]thiophene-DPP based near-infrared nanotheranostic agent for dual imaging-guided photothermal/photodynamic synergistic therapy.

Diketopyrrolopyrrole (DPP) based organic molecules have drawn significant research attention as phototheranostic agents. Herein, based on thieno[3,2-b]thienyl-DPP (TT-DPP), a near-infrared small molecule photosensitizer diethyl 3,3'-((((2,5-bis(2-decyltetradecyl)-3,6-dioxo-2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)bis(thieno[3,2-b]thiophene-5,2-diyl))bis-(4,1-phenylene))bis(7-bromo-10H-phenothiazine-10,3-diyl))(2E,2'E)-diacrylate (PDBr), with a high singlet oxygen (1O2) quantum yield of 67%, was developed. After nano-precipitation, the hydrophilic PDBr NPs present an encouraging photothermal conversion efficiency of 35.7% and excellent fluorescence/infrared-thermal imaging performance. In vitro studies disclosed the high phototoxicity but low dark cytotoxicity of PDBr NPs to tumor cells. Furthermore, PDBr NPs can effectively impede the tumor growth without noticeable side effects in living mice through imaging-guided synergistic photothermal/photodynamic therapy. Therefore, PDBr NPs could be a promising nanotheranostic agent for imaging-guided synergistic photothermal and photodynamic therapy in the clinic.

5-aminolevulinic acid mediated photodynamic therapy inhibits survival activity and promotes apoptosis of A375 and A431 cells.

OBJECTIVES: The purpose of this study was to investigate the effects of 5-aminolaevulinic acid mediated photodynamic therapy (ALA-PDT) on the survival activity and apoptosis of human melanoma cell line A375 and non-melanoma skin carcinoma cell line A431 cells. The mechanism for cellular apoptosis was explored. METHODS: The cell survival activity was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and the proportion of apoptotic cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The expression levels of Bcl-2, Bax, caspase-3, caspase-8 and caspase-9 protein were assessed by western blot. The subcellular localization of cytochrome c was comparatively investigated by immunohistochemistry between pre-ALA-PDT and post- ALA-PDT. RESULTS: ALA-PDT significantly inhibited the survival activity of A375 cells and A431 cells in a dose- and time-dependent manner. The optimum inhibition efficiencies for A375 cells and A431 cells were obtained at 0.6 mM ALA at 4 h and 8 h after ALA-PDT, respectively. The phenomena of apoptosis were observed in ALA-PDT treated cells by TUNEL assay. The apoptotic rates of A375 cells and A431 cells were 90.0% and 61.5% at 6 h after ALA-PDT, respectively. Apoptosis induced by ALA-PDT involved in down-regulation of Bcl-2 protein, up-regulation of Bax protein and cleaved-PARP protein. It was observed that the expression of cleaved- caspase-3, caspase-8 and caspase-9 proteins in A375 cells and A431 cells gradually increased in 2 h and 4 h but decreased at 4-6 h and 6-8 h after ALA-PDT, respectively. In apoptosis cells immunohistochemical localization show that cytochrome C diffused from the mitochondria into the cytosol. CONCLUSION: ALA-PDT could significantly inhibit the survival activity of A375 and A431 cells. The apoptosis induced by ALA-PDT in A375 and A431 cells was related to the caspase-dependent death-receptor pathway and Cytochrome c-dependent mitochondrial pathway.

Gadolinium-doped hollow CeO2-ZrO2 nanoplatform as multifunctional MRI/CT dual-modal imaging agent and drug delivery vehicle.

Developing multifunctional nanoparticle-based theranostic platform for cancer diagnosis and treatment is highly desirable, however, most of the present theranostic platforms are fabricated via complicated structure/composition design and time-consuming synthesis procedures. Herein, the multifunctional Gd/CeO2-ZrO2/DOX-PEG nanoplatform with single nano-structure was fabricated through a facile route, which possessed MR/CT dual-model imaging and chemotherapy ability. The nanoplatform not only exhibited well-defined shapes, tunable compositions and narrow size distributions, but also presented a well anti-cancer effect and MR/CT imaging ability. Therefore, the Gd/CeO2-ZrO2/DOX-PEG nanoplatform could be applied for chemotherapy as well as dual-model MR/CT imaging.