Reductive surfactant-assisted one-step fabrication of a BiOI/BiOIO₃ heterojunction biophotocatalyst for enhanced photodynamic theranostics overcoming tumor hypoxia

Abstract

Inorganic biophotocatalysts with suitable size are greatly attractive in photodynamic therapy (PDT) with enhanced permeability and retention effect and the capability to produce reactive oxygen species via type-I reaction for overcoming tumor hypoxia. Herein, we develop a facile one-step hydrothermal method to prepare biocompatible BiOI/BiOIO₃ heterostructure nanocomposites (BB NCs) by introducing reductive trithiol-terminated poly-(methacrylic acid) (PTMP-PMAA) as the surfactant, which can reduce partial KIO₃ (raw material) into KI, resulting in the generation of BiOI and BiOIO₃ in one nanocomposite. Under irradiation with a 650 nm laser, the photogenerated holes/electrons of the agent can effectively generate hydroxyl radicals (˙OH) and singlet oxygen (¹O₂) through a type I and O₂ self-supplying type II PDT process, respectively, under both normoxic and hypoxic environments, which could lead to a reduced mitochondrial membrane potential (MMP) and in turn inhibit the production of ATP to initiate the death of HeLa cells, eventually causing the complete destruction of the tumor at a low dose (0.64 mg kg⁻¹). In addition, the agent also shows extraordinary computed tomography imaging capability due to the high X-ray absorption coefficient (∼41.39 HU L g⁻¹). Our study provides a robust biowindow-responsive hypoxic tumor theranostic agent to break through the limitations of PDT.

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Conceptual insights

In this research, we designed a new reductive surfactant (trithiol-terminated poly-(methacrylic acid), PTMP-PMAA)-assisted one-step method for preparing a BiOI/BiOIO₃ (BB NCs) heterojunction biophotocatalyst. The PTMP-PMAA can reduce partially KIO₃ (raw material) into KI, leading to the generation of BiOI and BiOIO₃ in one nanocomposite with suitable nanosize, aqueous solubility and biocompatibility. Although the use of BiOIO₃ as a photocatalyst already exists resulting from its high separation efficiency of photoinduced charges originating from its unique internal polar field, the introduction of BiOI could further enable it to be activated by laser light in the biowindow. The photoinduced holes/electrons of the BB NCs can generate hydroxyl radicals and singlet oxygen by a type I and O₂ self-supplying type II photodynamic therapy (PDT) process, respectively. Finally, owing to their high atomic number, BB NCs achieved CT-guided tumor therapy with high-performance. This research provides a biowindow-responsive hypoxic tumor theranostic agent and may shed more light on the application of the biophotocatalyst and opens up a new strategy to prepare heterostructure nanocomposites by using the underlying potential of a suitable surfactant.

Introduction

As a noninvasive and highly efficient therapeutic modality for cancers, photodynamic therapy (PDT), which employs cytotoxic singlet oxygen (¹O₂) produced by light-excited organic photosensitizer (PS) molecules and local oxygen through a direct energy transfer (type II PDT), has attracted great attention in the past few decades.^1–4 However, the low accumulation and selectivity of PS in tumors and the dependence on oxygen severely limit the practical efficiency of PDT. Conjugation of PS with nanocarriers has dramatically increased the tumor accumulation and relieved tumor hypoxia benefiting from the enhanced permeability and retention (EPR) effect and in situ oxygen production capacity of the nanoparticles.^4,5 Nevertheless, the possible leakage of most of the delivered organic PS and the complex construction of the nanocomposites still restrict the clinical applications.^6,7

Compared to organic PSs, inorganic photocatalysts with enhanced permeability and retention (EPR) effect such as titanium dioxide, zinc oxide and cerium oxide can convert H₂O and O₂ to cytotoxic reactive oxygen species (ROS) incorporating hydroxyl radicals (˙OH), superoxide radicals (˙O₂⁻) and ¹O₂via an enhanced type-I PDT process dependent on an electron/hydrogen atom transfer and/or type-II PDT process through energy transfer upon illumination with ultraviolet (UV) light,^8–12 making them attractive PDT agents with diminished oxygen dependence in type-II PDT. To solve the limitation of UV light penetration and induce deep PDT, various upconversion-nanoparticle- and ionizing-radiation-based PDT agents have been developed laboriously by multi-step composite processes.^13–15 To minimize batch variation, some narrow-band gap photocatalysts with simplified structures have been developed, which can be activated by light in the biowindow,^16,17 however, they suffer from reduced photoinduced redox capability. In addition, the quantum efficiency, recombination efficacy of photoderivated electron–hole pairs and separation efficiency of photoinduced carriers also greatly affect the efficiency of the PDT agent in producing ROS.^18,19 As a result, a high dose is often used in vivo, which inevitably induces high system toxicity.

BiOIO₃ is a superior wide-band gap photocatalyst due to its high separation efficiency of photoinduced charges originating from its unique heterolayered structure and internal polar field.^20–22 Fabrication of the BiOI/BiOIO₃ heterojunction nanoconstruct could further improve the photocatalytic activity and simultaneously enable it to be activated by visible light. However, its function as a PDT agent for cancer therapy has never been demonstrated, possibly due to the difficulty in the preparation of the BiOI/BiOIO₃ heterojunction nanocomposite with suitable nanosize and aqueous solubility.

Herein, for the first time, we develop a facile one-step hydrothermal method to prepare uniform BiOI/BiOIO₃ p–n heterostructure nanocomposites (BB NCs) (Scheme 1) as a new agent for efficient type-I and O₂ self-supplying type II PDT to overcome tumor hypoxia. The photogenerated electrons (e⁻) and holes (h⁺) can be enhanced by the built-in electric field upon the migration of the photoderived electrons (e⁻) from the conduction band (CB) of BiOI to that of BiOIO₃ under the irradiation of a 650 nm laser, which can effectively react with H₂O₂/H₂O to produce ˙OH, and split H₂O to produce O₂ and subsequently ¹O₂ under both normoxic and hypoxic conditions. Consequently, the BB NCs can be used as a highly efficient theranostic agent to realize hypoxic tumor destruction at a low dose (0.64 mg kg⁻¹) and excellent computed tomography (CT) imaging as a result of the high X-ray attenuation coefficient of BB NCs (∼41.39 HU L g⁻¹).

Scheme 1 Synthesis process and therapeutic mechanism of BB NCs.

Results and discussion

The BB NCs with dimensions suitable for biological applications were fabricated with bismuth(III) nitrate and potassium iodate (KIO₃) as the sources of Bi³⁺ and IO₃⁻, and trithiol-terminated poly-(methacrylic acid) (PTMP-PMAA) (Fig. S1, ESI†) was used as the surfactant to improve the dispersibility and bio-compatibility, in the presence of HNO₃ (Scheme 1) without an additional loading process. The growth of the BiONO₃ precipitate could be finely suppressed by HNO₃, which could determine the size of the BB NCs due to the respective displacement of IO₃⁻ and I⁻ (Fig. S2 (ESI†), PTMP-PMAA intrinsically possesses abundant sulfhydryls, and it can react with IO₃⁻ to form I⁻) and the synergetic effect of the stereo-hindrance of PTMP-PMAA²³ (Fig. S3, ESI†). Consequently, the as-prepared BB NCs exhibit a short rod-like morphology with a diameter of ∼108 nm (Fig. 1a and Fig. S4, ESI†). We also attempted to use other surfactants to prepare BB NCs, but the size, shape, optical absorbance and catalytic properties were not suitable (Fig. S5, ESI†). Energy-dispersive spectrometry (EDS) indicates the existence of Bi, I, C, S and O elements (Fig. S6, ESI†), which are uniformly distributed in the whole nanocomposites (Fig. 1b), suggesting the successful modification of PTMP-PMAA on the BB NCs as further proved by FTIR spectroscopy measurements (Fig. 1c). The characteristic peak of the symmetric and asymmetric stretching bands of carboxylate (–COO–) at 1388 and 1482 cm⁻¹ could be observed in the FTIR spectra of both BB NCs and PTMP-PMAA molecules, while the peak of the carbonyl group (–CO–) is red-shifted from 1693 cm⁻¹ to 1662 cm⁻¹ after the formation of the NCs, suggesting the modification of PTMP-PMAA by coordination interaction.^24,25 Furthermore, the reduction of sulfhydryl could result in the disappearance of the characteristic peak at 2590 cm⁻¹ and the formation of the NCs induced the vibrations of Bi–O (505 cm⁻¹) and I–O (695 and 764 cm⁻¹) bonds, respectively.²⁶

Fig. 1 (a) TEM image and size distribution (inset) of BB NCs. (b) HAADF-STEM image and EDX elemental mapping of Bi, I, O, S and C elements in BB NCs. (c) FT-IR spectra of BB NCs and PTMP-PMAA. (d) XRD spectra of BiOI, BiOIO₃ and BB NCs. (e) XPS spectra of BiOI, BiOIO₃ and BB NCs. (f) HRTEM image of BB NCs. (g) The formation mechanism of BB NCs.

The hydrodynamic size of the BB NC aqueous solution is ∼171 nm and the ξ-potential is −29.9 mV and BB NCs showed reasonable stability in saline, phosphate buffer (PBS), DMEM culture medium and 80% FBS (Fig. S7, ESI†) due to the stereo-hindrance effect of PTMP-PMAA.^27–29 The nature of the heterojunction was proved by the characterization of X-ray diffraction (XRD) spectroscopy (Fig. 1d and Fig. S8, ESI†). Most of the typical peaks of BB NCs are similar to those of BiOIO₃ (ICSD # 262019) except for the appearance of the peaks at 9.658° and 29.645° belonging to the (001) and (102) peaks of BiOI (JCPDS file 10-0445) and the increase in the ratio of (040)/(002) in comparison to that of pure BiOIO₃ (Fig. S8, ESI†),^26,30 which suggest the coexistence of BiOIO₃ and BiOI as further proved by the characteristic peaks of two sets of I 3d for I⁵⁺ and I⁻ in the X-ray photoelectron spectroscopy (XPS) spectrum of BB NCs (Fig. 1e and Fig. S9, ESI†). Obvious shifts in their peak positions relative to those of pure BiOIO₃ and BiOI suggest the formation of BiOIO₃ and BiOI heterojunctions with close interfacial interaction (Fig. S9, ESI†) due to their crystal lattice matching.^26,30 The well-resolved lattice fringes with lattice spacing of 0.302 nm, 0.280 nm and 0.287 nm can be indexed to the spacing of the (102) and (110) crystal planes of BiOI and the (002) crystal plane of BiOIO₃,¹¹ respectively (Fig. 1f), indicating that the main exposed facets of BiOI and BiOIO₃ could be {001} and {010} facets with high reactivity.^26,30,31 As shown in Fig. 1g, the similar atom arrangement between the {010} facets of BiOIO₃ and the {001} facets of BiOI is important for governing the growth of the {001} facets of BiOI along the {010} facets of BiOIO₃. The sharing of oxygen atoms can increase the contacting areas and intimate interface, which greatly enhances the transfer of photogenerated e⁻–h⁺ between the BiOI/BiOIO₃ heterostructures. We used inductively coupled plasma atomic emission spectroscopy (ICP-AES) to detect the precise content of Bi element and the mass content of Bi is ∼46.8%, and the mole ratio of BiOI : BiOIO₃ is about 2.71 (Fig. S10 and S11, ESI†).

The absorption edge of the as-prepared BB NCs was first evaluated by UV-vis diffuse reflectance spectroscopy (DRS) (Fig. 2a). Relative to the spectrum of pure BiOIO₃, the absorption edge of BB NCs has been dramatically extended to the visible region (∼677 nm) as that of pure BiOI. The band gaps of BiOIO₃ and BiOI were calculated to be 3.05 and 1.70 eV, respectively (Fig. 2b) with conduction band-edge potentials of 1.02 and 0.64 eV as calculated by the empirical equation (Fig. 2c and Fig. S12, ESI†), which were consistent with their flat-band potentials obtained by Mott–Schottky (M–S) methods (Fig. S12, ESI†). In addition, we can also deduce that the pure BiOI and BiOIO₃ belong to p-type and n-type semiconductors, respectively (Fig. S12, ESI†). Therefore, BiOI and BiOIO₃ could form a p–n heterojunction with favorable interfacial charge transfer and enhanced carrier separation efficiency as demonstrated by the smaller arc radius in the EIS Nyquist plots of BB NCs (Fig. 2d)³² and its lower photoluminescence (PL) emission peak intensity at 370 nm under the excitation of 245 nm (Fig. 2e).³³ Under 650 nm-light irradiation, photoinduced e⁻ in the CB of BiOI could transfer to the CB of BiOIO₃, while h⁺ clustered in the VB of BiOI. Such transfer of electrons in the BB NCs could decrease the recombination rate and further enhances the number of carriers to activate the reactions. We speculated that H₂O₂ could react with the accumulated photogenerated e⁻ to generate ˙OH,³⁴ and based on their band-edge potential (Fig. 2c), the photogenerated h⁺ could not only directly react with H₂O molecules to form the most toxic ˙OH without the limitation of O₂ but also can catalyze H₂O to produce O₂ and subsequent ¹O₂, resulting in oxygen-independent type I and O₂ self-supplying type II PDT processes. To test the hypothesis, ˙OH probe: hydroxyphenyl fluorescein (HPF) was used. Indeed, the fluorescence intensity of HPF in the aqueous dispersion of BB NCs was significantly strengthened under the irradiation of a 650 nm laser, and was further enhanced by the addition of H₂O₂ (Fig. 2f), demonstrating that photogenerated (e⁻)/(h⁺) can convert H₂O₂/H₂O to ˙OH during the photocatalytic process. Moreover, it was nearly unaffected in hypoxic conditions (Fig. S13, ESI†) as a result of oxygen-independent type I PDT activity of the BB NCs. What's more, the generation of ˙OH was further verified by the degradation of methyl red (MR) and the FL spectra variation of terephthalic acid (Fig. S14, ESI†). Furthermore, ¹O₂ could also be produced because the fluorescence intensity of singlet oxygen sensor green (SOSG) was obviously increased in the dispersions of BB NCs under irradiation (Fig. 2g), and the amount was not affected in the presence of a superoxide anion scavenger (Fig. S15, ESI†). Notably, in the hypoxic conditions, the ¹O₂ could be still generated although the amount was reduced partly. This is caused by the O₂-evolving capability of BB NCs (Fig. 2h), which results in the O₂ self-supplying type II PDT process. More attractively, the high atomic number of the component element of BB NCs (Z_I = 53, Z_Bi = 83) endows it with extraordinary CT imaging ability. The X-ray absorption coefficient of BB NCs can be calculated to be ∼41.39 HU L g⁻¹ based on the concentration-dependent signal enhancement (Fig. 2i), which is dramatically higher than most of the CT agents, such as hollow MoS_x (17.94 HU L g⁻¹),³⁵ clinical iopromide (16.4 HU L g⁻¹),³⁶ WS₂ quantum dots (37.73 HU L g⁻¹)³⁷ and Au@Pt nanodendrites (28.6 HU L g⁻¹).³⁸ (Table 1, ESI†).

Fig. 2 UV-vis DRS (a) and the plotting of (αhν)^1/2vs. photon energy (b) of BiOI, BiOIO₃ and BB NCs. (c) Schematic band diagram of BiOI and BiOIO₃. EIS Nyquist plots (d) and photoluminescence (PL) spectra under the excitation of 245 nm (e) of BiOI, BiOIO₃ and BB NCs. (f) Fluorescence spectra of HPF in BB NCs dispersion (80 μg mL⁻¹) with and without H₂O₂ after irradiation with a 650 nm laser under normoxic and hypoxic conditions. (g) Fluorescence spectra of SOSG in water (control) and BB NC dispersion (80 μg mL⁻¹) after irradiation with a 650 nm laser under normoxic and hypoxic conditions. (h) Variation of O₂ under irradiation with a 650 nm laser towards BB NCs with different concentrations. (i) CT images and Hounsfield unit values of BB NC dispersions with different concentrations.

The excellent photocatalytic activity of BB NCs suggests great potential as a PDT agent for cancer treatment. They could produce ˙OH in HeLa cells during photocatalysis processes because the fluorescence of HPF in BB NCs/laser-treated cells was brighter than that in untreated cells, which was further enhanced in BB NCs/H₂O₂/laser-treated cells, while only H₂O₂/laser-treated cells showed nearly no fluorescence (Fig. 3a and b). Almost consistent changes in the cellular fluorescence can be found for the identical treatment under hypoxic conditions, suggesting the production of ˙OH independent of oxygen. Meanwhile, the intracellular photocatalysis could also produce ¹O₂ even in hypoxic cancer cells as revealed by the fluorescence changes of SOSG in BB NCs/laser-treated cells (Fig. 3c and d). Significantly enhanced fluorescence can be observed under both normoxic and hypoxic conditions, which was caused by O₂ self-supplying via H₂O splitting under irradiation. Besides, ROS probe 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) was also used to evaluate the total variation of intracellular ROS, and the green fluorescence was greatly enhanced in the HeLa cells pre-incubated with BB NCs and irradiated by a 650 nm laser under normoxic and hypoxic conditions due to the oxidation of the probe (Fig. 3e and f), further proving a strong biophotocatalytic ability of the BB NCs to induce intracellular ROS production. There was no obvious fluorescence distinction under normoxic and hypoxic conditions, indicating that the BB NCs can generate ROS without the limitation of hypoxia in cancer cells. Indeed, when the cells were pre-incubated with BB NCs and irradiated with a 650 nm laser, the fluorescence of [Ru(dpp)₃]Cl₂ (RDPP, O₂ probe) within cells was quenched even in hypoxic conditions (Fig. 3g).

Fig. 3 (a) CLSM images of HeLa cells stained by HPF after different treatments under normoxic and hypoxic conditions, and (b) quantitative analysis expressed as mean intensity of HPF. (c) CLSM images of HeLa cells stained by SOSG after different treatments under normoxic and hypoxic conditions, and (d) quantitative analysis expressed as mean intensity of SOSG. (e) CLSM images of HeLa cells stained by DCFH-DA after different treatments under normoxic and hypoxic conditions, and (f) quantitative analysis expressed as mean intensity of DCFH-DA. (g) CLSM images of HeLa cells stained by RDPP after different treatments under normoxic and hypoxic conditions. (*P < 0.05, **P < 0.01, ***P < 0.001), determined by Student's t test.

Its biocompatibility was evaluated by standard MTT assay to observe the viability of HeLa cells and L929 cells incubated with BB NCs for 24 h. No significant toxicity of HeLa cells can be found under normoxic or hypoxic conditions even when the concentration of BB NCs was up to 300 μg mL⁻¹ (Fig. 4a), and the survival rate of L929 cells was also nearly unchanged (Fig. S16, ESI†). The hypoxic condition of HeLa cells were realized through incubating the cells in an enclosed incubator, into which was injected a gas mixture with constant ingredients (2% O₂, 5% CO₂ and 93% N₂), and the hypoxic condition can be demonstrated by the increased expression (Fig. S17, ESI†) of hypoxia-inducible factor (HIF-1α). FITC-labeled BB NCs were used to investigate the endocytosis situation,³⁹ DAPI was used to label the cell nucleus,⁴⁰ and the green fluorescence of FITC was co-localized with lysosome-tracker red, which demonstrates that BB NCs can be internalized by HeLa cells and transported into the lysosome (Fig. 4b). After the BB NCs were delivered to the lysosome, the O₂-independent production of a high concentration of ROS could lead to lysosome impairment and may depolarize the mitochondrial membrane potential (MMP) and even in turn initiate apoptosis in HeLa cells.^41–43 As shown in Fig. 4c, BB NCs can decrease the MMP tested by 5,5′,6,6′-tetrachloro-1,1′,3,3′ tetraethyl-benzimidazolylcarbocyanine iodide (JC-1), which emits red fluorescence at high MMP and green fluorescence upon collapse of the MMP,⁴ which will inhibit the production of adenosine 5′-triphosphate (ATP) (Fig. 4d and Fig. S18, ESI†) because the decrease of MMP could uncouple the cascade reactions in the oxidative phosphorylation chain.^44,45 All these effects induced almost complete cell death at concentrations of BB NCs up to 80 μg mL⁻¹ under irradiation (Fig. 4e), which resulted in strong red fluorescence signals as stained by propidium iodide (Fig. 4f). These results demonstrate a powerful strategy to treat cancer without the limitation of hypoxia.

Fig. 4 (a) Cytotoxicity of BB NCs at 24 h under normoxic or hypoxic conditions detected by HeLa cells. (b) CLSM images of HeLa cells stained by DAPI, lyso-tracker red and BB NCs labeled by FITC. (c) CLSM images of HeLa cells stained by JC-1 after different treatments. (d) ATP content in HeLa cells with different treatments. (e) Survival of HeLa cells with different treatments. (f) CLSM images of HeLa cells stained by calcein-AM and PI after different treatments.

The excellent CT imaging performance in vitro also endows BB NCs with high CT imaging capability in vivo. After intratumoral injection of 0.2 mL of BB NCs (80 μg mL⁻¹), the contrast signal was increased from 43.8 to 96.8 HU (Fig. 5a and Fig. S19, ESI†). To evaluate the therapeutic effect of BB NCs, tumor-bearing mice were divided into four groups: control, laser, BB NCs, and BB NCs/laser. At 24 h post intravenous injection, the tumors were irradiated by a laser (650 nm) for 15 min (0.5 W cm⁻²), and the body weights and tumor volumes were recorded. It is obvious that the tumors in the BB NCs/laser group were absolutely destroyed (Fig. 5b–d), suggesting an excellent PDT efficiency. Haematoxylin and eosin (H&E) staining (Fig. 5e) was also conducted, and more vacuoles, condensed nuclei, changed shape, and incomplete membrane integrity of the cells were observed in the BB NCs/laser group, suggesting severe destruction.^46,47 Also, hypoxia-inducible factor (HIF-1α) staining (Fig. 5e) in BB NCs/laser-treated tumor tissues are largely stained blue, which indicates that BB NCs can produce O₂ within tissues under illumination. Notably, the dose of BB NCs we used is lower than that of most of the photocatalytic nanomaterials (Table 2, ESI†), such as BiOI@Bi₂S₃@BSA (1.6 mg kg⁻¹),¹⁵ Ce(III)-doped LiYF₄@SiO₂@ZnO structure (4 mg kg⁻¹),⁴⁸ Fe@γ-Fe₂O₃@H-TiO₂ nanocomposites (8 mg kg⁻¹),⁴⁹ bismuth ferrite nanoparticles (12 mg kg⁻¹),⁵⁰ and (UCNPs)–platinum(IV) (Pt(IV))–ZnFe₂O₄ (16 mg kg⁻¹),⁵¹ which results in good biocompatibility of the agent. There was no obvious difference in body weight (Fig. 5f) in the different treated groups, pathological changes in the main organs (Fig. 5g) and blood items (Fig. S20, ESI†) although there were evident distributions of BB NCs in the liver and spleen (Fig. S21, ESI†). The content variations of Bi element distributed in the feces and urine at different time points (Fig. S22, ESI†) suggest that the BB NCs were primarily excreted through feces. The blood circulation of Bi was also detected and the blood circulation half-time is about ∼5.61 h (Fig. S23, ESI†).

Fig. 5 (a) In vivo CT images of tumor-bearing mice pre- and post- injection of BB NC solutions. (b) Photographs of mice and tumors after different treatments. (c) Tumor volume variation (n = 10, **p < 0.01), and tumor weight (d) of the tumor section. (e) H&E staining and HIF-1α staining of tumor sections on the 7th day of mice after different treatments. (f) Body weight of mice during treatment. (g) H&E staining of major organs in control and BB NCs/laser groups on the 30th day of mice after different treatments.

Conclusions

In summary, we prepared 650 nm-light driven BiOI/BiOIO₃ heterostructure nanocomposites through a one-step hydrothermal method realized by the assistance of reductive surfactant: PTMP-PMAA, as the –SH of the used surfactant can react with KIO₃ (raw material) to generate KI and then in situ produce BiOI and BiOIO₃ in one nanocomposite. More importantly, we found that the main exposed facets of BiOI and BiOIO₃ are the {001} and {010} facet, respectively, which can enhance the transfer of photogenerated e⁻–h⁺ between the BiOI/BiOIO₃ heterostructures and then increase the PDT efficiency by producing ¹O₂ and ˙OH through O₂ self-supplying type II and O₂-independent type I PDT processes under visible-light-induced H₂O/H₂O₂ splitting irrespective of hypoxia. After the BB NCs were delivered to the lysosome, a high concentration of ROS induced by biophotocatalysis reduced the MMP and in turn inhibited the production of ATP, which promoted the death of HeLa cells, eventually causing the complete destruction of tumor tissue at a relatively low dose (0.64 mg kg⁻¹). In addition, the new agent also shows extraordinary CT imaging properties (X-ray absorption coefficient is ∼41.39 HU L g⁻¹). The results demonstrate the great potential of BB NCs as hypoxic PDT agents for tumor theranostics.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the Joint Sino-German Research Projects (21761132028), the National Natural Science Foundation of China (21675149, 21705146, 21874125, and 21877107), the Key Research Program of Frontier Sciences, CAS (QYZDY-SSW-SLH019), and the Science and Technology Development Program of Jilin Province (20170414037GH, 20170520133JH, 20190201074JC, 20180101015JC), and K. C. Wong Education Foundation.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8nh00440d

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