Fighting Hypoxia to Improve PDT

Abstract

Photodynamic therapy (PDT) has drawn great interest in recent years mainly due to its low side effects and few drug resistances. Nevertheless, one of the issues of PDT is the need for oxygen to induce a photodynamic effect. Tumours often have low oxygen concentrations, related to the abnormal structure of the microvessels leading to an ineffective blood distribution. Moreover, PDT consumes O₂. In order to improve the oxygenation of tumour or decrease hypoxia, different strategies are developed and are described in this review: 1) The use of O₂ vehicle; 2) the modification of the tumour microenvironment (TME); 3) combining other therapies with PDT; 4) hypoxia-independent PDT; 5) hypoxia-dependent PDT and 6) fractional PDT.

Keywords: PDT; hypoxia; oxygen.

Figure 1

Schematic illustration for the synthesis of NaGdF4:Yb,Er,Ca@NaYbF4:Ca@NaNdF4:Gd,Ca @mSiO2 NPs. Reprinted from [26] with permission from the American Chemical Society, Copyright 2018.

Figure 2

MCF-7 tumour growth curves of different groups after treatments. * p < 0.05, ** p < 0.01. All injectants were oxygenated before experiments. Adapted from Luo et al. [36].

Figure 3

P-FRT-RBCs showed enhanced PDT effect under hypoxic environments. Comparison of ¹O₂ generation among P-FRT-RBCs, a mixture of RBCs and free P-FRTs, and free P-FRTs, conducted in an Ar-filled cuvette. The cuvette was irradiated by a 671 nm laser (0.1 W∙cm⁻²) for up to 60 min. SOSG was used as an indicator of ¹O₂ production. Adapted from Tang et al. [38].

Figure 4

PDT for hypoxia tumours. (a) Digital photos of U87MG tumour-bearing mice after 14 days of O₂ release and PDT treatments under NIR irradiation. From up to down mice were treated with RBC microcarriers + 980-nm +808-nm laser; Si microcarriers + 980-nm +808-nm laser; RBC + 980-nm +808-nm laser. (b) Tumour growth profiles of the mice bearing U87MG tumour with different treatments. Reprinted from [39] with permission from Elsevier, Ltd, Copyright 2017.

Figure 5

The BP@RB-Hb structure and the process of one-/two photon. Reprinted from [40] with permission from John Wiley and Sons, Copyright 2018.

Figure 6

Tumour volume under hyperoxia and hypoxia. Adapted from Cao et al. [40]

Figure 7

(a) The absorbance changes of DPBF treated with UiO-66@ICG in DMF after 808 nm laser irradiation for different times. (b) Infrared thermal images of pure H₂O and UiO-66@ICG aqueous dispersion (1 mg∙mL⁻¹) after irradiation for 5 min by 808 nm laser (0.06 W∙cm⁻²). (c) O₂ concentration in 20 mL deoxygenated water before and after adding 5 mg of O₂@UiO-66@ICG. (d) O₂ concentration changes in solutions of O₂@UiO-66@ICG under irradiation by 808 nm laser. DO₂: Enhanced O₂ concentration. The O₂ loading capacity per 1 g of ICG@UiO-66 was calculated as follows: the loading capacity of ICG@UiO-66 ¼ (DO₂: Enhanced O₂ concentration)/ (ICG@UiO-66 concentration). The O₂ loading capacity of ICG@UiO-66 was determined to be ~140 mmol∙g⁻¹ or 4.48 mg∙g⁻¹. Reprinted from [45] with permission from Elsevier Ltd, Copyright 2018.

Figure 8

PDT in vitro on MCF-7 cells. (a) Cytotoxicity of different samples in the presence or absence of irradiation (670 nm, 0.48 W∙cm⁻²). (b) Relative activity multiple of caspase-3 protein in MCF-7 cells activated by Lip(ASC) and Lip(ASC/PFH) (20 μg∙mL⁻¹) with or without 670 nm irradiation for 10 min. Adapted from Liu et al. [50].

Figure 9

Time-dependent changes of dissolved O₂ concentrations in deoxygenated pure water without or with addition of O₂-loaded PFC nanoemulsion (PFC@O₂). An US treatment was applied on these solutions within the indicated period. Reprinted from [53] with permission from the American Chemical Society, Copyright 2016.

Figure 10

Tumour growth curves. Complete tumour eradication was found in the combinational PTT/Oxy-PDT treatment group with i.v. injection of PS-PDI-PAnDs plus a 0.5 W∙cm⁻² laser irradiation. Significant tumour growth inhibition was also observed with animals treated with PTT only (i.v. injection of PS-PDI-PAnPs plus a 0.5 W∙cm⁻² laser irradiation) and Oxy-PDT only (i.v. injection of PS-PDI-PAnDs plus a 0.2 W∙cm⁻² laser irradiation), indicating tumour growth inhibition rates of 82.3% and 67.5%, respectively, on day 18. Adapted from Tang et al. [54].

Figure 11

Tumour growth curves of four groups of mice after treatments as indicated. V₀ and V stand for the tumour volumes before and after the treatments, respectively. Adapted from Tao et al. [56].

Figure 12

O₂ concentration changed after the addition of O₂ saturated Ce6-PFOC-PEI-M, Ce6-OC-PEI-M and PBS into deoxygenated water. Adapted from Wang et al. [58].

Figure 13

(a) Tumour growth curves of six groups after various treatments. (b) Weight of tumours 18 d post various treatments. (Values are means±s.d., n = 5, * p < 0.05.). Adapted from Zhang et al. [61].

Figure 14

In vivo biodistribution of NPs. Semiquantitative fluorescence analysis of the radiant efficiency of organs and tumours isolated at 24 h post-injection. Adapted from Hu et al. [63]

Figure 15

Schematic illustration showing a molecular model of the Mn²⁺ ion linking porphyrin ring and two carboxylate radicals of DVDMS molecules (a), the fabrication process of Mn/DVDMS (b), and photothermal/PDT (PTT/PDT) (c). Reprinted from Chu et al. [77] with permission from John Wiley and Sons, Copyright 2018.

Figure 16

Synthetic route of MnO@OA, MnO@NH₂, and IR808@MnO. Reprinted from [89] with permission from John Wiley and Sons, Copyright 2018.

Figure 17

(a) Schematic illustration of the fabrication of FMZ/DC nanocomposites. The diagram is not drawn to scale. (b) Schematic illustration of FMZ/DC with O₂ generation enhancing the chemo-PDT under 660 nm light irradiation. Reprinted from [99] with permission from John Wiley and Sons, Copyright 2018.

Figure 18

Schematic illustration of the decomposition of MnO₂ nanosheets arising from the redox reaction between UCSMs and acidic H₂O₂, which led to the enhanced UCL imaging for diagnosis/monitoring as well as the massive O₂ generation for improving the synergetic PDT/RT effects. Reprinted from [100] with permission from John Wiley and Sons, Copyright 2015.

Figure 19

In vivo PDT in xenograft mice models with SW1990 PC. Survival rates of mice bearing SW1990 tumours after different treatments. (*) p < 0.05, (**) p < 0.01. Group 1-PBS, Group 2-laser, Group 3-ZCM nanocapsule, Group 4-free MBlaser, Group 5-zeolite-MB-laser, and Group 6-ZCM nanocapsule-laser (n = 5 per group). Adapted from Hu et al. [105].

Figure 20

Schematic illustration of the preparation and structure of CAT-THPP-PEG. Hydrodynamic diameters of catalase, BSA-THPP-PEG and CAT-THPP-PEG in water, PBS and FBS. Reprinted [114] with permission from Elsevier Ltd, Copyright 2018.

Figure 21

Schematic of the synthetic procedure and photo-enhanced therapy of the PSPZP NCs. Reprinted from [118] with permission from Elsevier Ltd, Copyright 2018.

Figure 22

Illustrations of O₂ self-enriched PLGA–FA/IR780–H₂O₂ NPs and their application for PTT and enhanced PDT against tumours. Republished from [131] with permission of the Royal Society of Chemistry, Copyright 2018.

Figure 23

(a,b) CCK-8 assay of 4T1 cells after incubating in a normoxia/hypoxia environment and treated by different methods. Adapted from Wu et al. [134]

Figure 24

Tumour volumes evolution in different treatments groups. PDT-OB = O₂ generating optical battery; GPM: Green luminescent material Adapted from Hu et al. [136].

Figure 25

Relative tumour volume after different treatments. Adapted from Liu et al. [137].

Figure 26

(A) In vitro cell viabilities of HeLa cells incubated with cell culture (control), 980 nm light, UCNPs-g-C3N4 with 980 nm laser irradiation, and UCNPs-g-C3N4−CDs@ZIF-8 at varied concentrations with and without 980 nm laser irradiation. Adapted from Yang et al. [141] (B) CLSM images of HeLa cells incubated with different conditions corresponding to the toxicity test in vitro, and all the cells are marked with calcein AM and PI. Reprinted from [141] with permission from the American Chemical Society, Copyright 2017.

Figure 27

(a) Tumour volumes of HeLa-tumour-bearing mice that received different treatments as displayed. (b) Number of tumour-free mice after treatment during the observation. (c) Survival curves of HeLa-tumour bearing mice that received different treatments as displayed. (d) Body weight of HeLa-tumour-bearing mice that received different treatments as indicated. Adapted from Zhang et al. [144].

Figure 28

(A) Structure of HNCs: (I) anisotropic growth of NRs; (II) gold deposition on top of NRs; (III) RGD modification of HNCs; (B) schematic diagram of visible light driven water splitting to generate ROS for PDT treatment. Republished from [145] with permission from the Royal Society of Chemistry, Copyright 2017.

Figure 29

Quantification of the oxyhemoglobin saturation in the tumour from different groups over time. Adapted from Liu et al. [147].

Figure 30

MMP-2-triggered shape remodelling and cell uptake behaviour of Ato-ICG-GNPs. (a) Fluorescence intensity of ICG-BSA (795 nm) in the supernatant. (b) Absorbance of Ato (490 nm) in the supernatant. Adapted from Xia et al. [151].

Figure 31

In vivo therapeutic outcome. (a) Relative tumour growth curves of mice received different treatments within a total of 28 days. Control (0.1 mL per mouse, PBS); Ato (0.1 mL per mouse, containing 330.15 μg∙mL⁻¹ Ato); ICG-BSA (0.1 mL per mouse, containing 37.44 μg∙mL⁻¹ ICG); Ato-ICG-GNPs (0.1 mL per mouse, containing 330.15 μg∙mL⁻¹ Ato and 37.44 μg∙mL⁻¹ ICG). The tumour region was irradiated by a 808 nm laser with a power density of 1 W∙cm⁻² for a duration of 5 min at 4 h post injection. (n = 18 in each group). (b) Survival profiles as represented by the calculated rate of survival. Adapted from Xia et al. [151].

Figure 32

Chemical structures of (a) Ir-P(ph)₃ and (b) Ir-alkyl. Adapted from Lv et al. [153].

Figure 33

Schematic illustration and characterizations of AVT-NPs. The formation of AVT-NP, generation of cytotoxic TPZ radical under hypoxic conditions in cancer cells, and illustration of AVT-NP/TPZ based PDT that induces a local hypoxic environment and promoted angiogenesis for targeted drug delivery and synergistic chemo-photo therapy. Reprinted from [157] with permission from Elsevier Ltd, Copyright 2017.

Figure 34

(a): Survival of 4T1 cells after photo-thermal treatment: Viability of cells treated with different formulations under an 808 nm laser for 3 min with a sequence of 10 s irradiation and 10 s break. (b): Toxicity of Lip (IR780&TPZ) in 4T1 tumour-bearing mice: Tumour weights in the different groups of mice after the indicated treatments. Adapted from Yang et al. [162].

Figure 35

In vitro cytotoxicity of MCF-7 cancer cells incubated for 24 h with free TPZ, unloaded vesicles, and TPZ-loaded vesicles in the dark (a) and in light (b). Adapted from Wang et al. [164].

Figure 36

Schematic of the light-activated hypoxia-responsive drug-delivery system. Formation and mechanism of DOX/CP-NI NPs. Reprinted from [165] with permission from John Wiley and Sons, Copyright 2016.

Figure 37

Schematic illustration of the fabrication of the ODC-HPOCs [167].

Figure 38

Structure of AQ4N.

Figure 39

Schematic illustration showing the synthetic procedure of A@UiO-66-H-P NPs and the mechanism of PDT and hypoxia-activated cascade chemotherapy. Reprinted from [175] with permission from John Wiley and Sons, Copyright 2018.

Figure 40

Antivascular and pH-Responsive Cancer PTT/PDT of DAA NPs at the tumour site. Reprinted from [187] with permission from the American Chemical Society, Copyright 2018.

Figure 41

Structure of AZBPS. Adapted from Jung et al. [192].

Figure 42

Schematic illustration of the study rationale and design. Reprinted from [193] with permission from the American Chemical Society, Copyright 2013.

Figure 43

In vivo activation of DiR-hCe6-liposome by NIR laser irradiation and the followed tumour Oxygenation. Semi-quantitative analysis of the percentage of positive hypoxia region before and after laser irradiation. Adapted from Feng et al. [196].

Figure 44

In vivo NIR light activated synergistic cancer phototherapy. Relative tumour volume (V/V₀) changing curves of mice after various different treatments at indicated for 14 days. V and V₀ stood for the tumour volumes after and before the treatment, respectively. Adapted from Feng et al. [196].

Figure 45

Schematic representation of Immuno-PDT concept of the study. Reprinted from [197] with permission from the American Chemical Society, Copyright 2019.

Figure 46

Modulation of photoactivation mechanism of a model PS, mTHPP, by the micelle microenvironment. Electron-rich PDPA micelles led to increased type I reactions producing superoxide radical anions, while electron-deficient PLA micelles generated ¹O₂ as predominant species by type II reactions. Adapted from Ding et al. [199].

Figure 47

Structure of ENBS-B. Adapted from Li et al. [200].

Figure 48

Schematic Illustration of Photo-Induced Radical Generation Mechanism of ENBS-B. Reprinted from [200] with permission from the American Chemical Society, Copyright 2018.

Figure 49

Schematic illustration of synthetic process and therapeutic mechanism of CFNs. Reprinted from [201] with permission from the American Chemical Society, Copyright 2018.

Figure 50

Dose–dependent curves for cell viability of HeLa cells treated with Ru1 and Ru2 using a typical MTT assay under light irradiation (L) or in the dark (D). Cells were irradiated with white light (400–800 nm, 30 mW∙cm⁻², 10 min). Adapted from Lv et al. [202].

Figure 51

Schematic illustration of the synthesis process of FMUP, and the intracellular photon-Fenton reaction of FMUP with intracellular H₂O₂ under the irradiation of 980 nm. Reprinted from [203] with permission from Elsevier Ltd, Copyright 2018.

Figure 52

Chemical structures of complexes Ru (II) complexes. Adapted from Tian et al. [204].

Figure 53

Molecular structures of the osmium-based PSs. Adapted from Lazic et al. [205].

Figure 54

Reversible photoisomerization of the diarylethene core with UV and visible light. Adapted from Babii et al. [206].

Figure 55

In vitro cytotoxic activities of the two GS-^DPRoSw photoforms as measured in the MTT test. Adapted from Babii et al. [206].

Figure 56

Structure of SiNP-PAG9 and PEG-PAG9. Adapted from Fadhel et al. [207].

Figure 57

Molecular structure of [Ru(phthalocyanine)(pz)2{Ru(bpy)2NO}2]6+. Adapted from Heinrich et al. [210].

Figure 58

Multiple synergistic effects between NO and PDT generated from the supramolecular NPs α-CD-Ce6-NO NPs to improve therapeutic efficacy. Reprinted from [212] with permission from Elsevier Ltd, Copyright 2018.

Figure 59

Cytotoxicity of MCF-7 cells incubated with α-CDCe6 NPs, α-CD-Ce6-NO NPs, α-CD-Ce6 NPs with laser, and α-CD-Ce6-NO NPs with laser (660 nm, 0.200 W, 2 min). Adapted from Deng et al. [212].

Figure 60

Chemical structures of Pt-1, Pt-2, and Pt-3. Adapted from Lv et al. [215].

Figure 61

Molecular structure of OR141. Adapted from Pinto et al. [216].

Figure 62

Illustration of enhanced cytotoxicity through photogeneration of ¹O₂ by a mitochondria-targeting DAD molecule. Republished from [217] with permission of the Royal Society of Chemistry, Copyright 2018.

Figure 63

Structure of tribenzoporphyrazine. Adapted from Wieczorek et al. [218].

Figure 64

The structure and mechanism of PAP-FC for combined chemo-PDT. Republished from [223] with permission of the Royal Society of Chemistry, Copyright 2018.

Figure 65

Schematic illustration of Ab-DiBDP NPs for dual hypoxia marker imaging and activatable PDT against tumours. Republished from [225] with permission of the Royal Society of Chemistry, Copyright 2018.

Figure 66

(a) Cell viability of A549 cells incubated with PC70 at gradient concentrations for 3 h and exposed to light irradiation for 10 min at a power density of 17 mW∙cm⁻² and (b) dose- and time-dependent PDT effects of PC70 on the A549 cell viability. Adapted from Guan et al. [228].

Figure 67

¹O₂ generation achieved first by irradiation of bifunctional compound PYR at λ = 650 nm, and subsequently by thermal cycloreversion in the dark. The cycles can be repeated indefinitely. Adapted from Turan et al. [233].