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Abstract Background Photodynamic therapy (PDT) efficacy of bismuth sulfide (Bi2S3) semiconductor has been severely restricted by its electron–hole pairs (e−−h+) separation inefficiency and oxygen (O2) deficiency in tumors, which greatly hinders reactive oxygen species (ROS) generation and further clinical application of Bi2S3 nanoparticles (NPs) in biomedicine. Results Herein, novel Bi2S3/titanium carbide (Ti3C2) two-dimensional nano-heterostructures (NHs) are designed to realize multimode PDT of synchronous O2 self-supply and ROS generation combined with highly efficient photothermal tumor elimination for hypoxic tumor therapy. Bi2S3/Ti3C2 NHs were synthesized via the in situ synthesis method starting from Ti3C2 nanosheets (NSs), a classical type of MXene nanostructure. Compared to simple Bi2S3 NPs, Bi2S3/Ti3C2 NHs significantly extend the absorption to the near-infrared (NIR) region and enhance the photocatalytic activity owing to the improved photogenerated carrier separation, where the hole on the valence band (VB) of Bi2S3 can react with water to supply O2 for the electron on the Ti3C2 NSs to generate ·O2 − and ·OH through electron transfer. Furthermore, they also achieve 1O2 generation through energy transfer due to O2 self-supply. After the modification of triphenylphosphium bromide (TPP) on Bi2S3/Ti3C2 NHs, systematic in vitro and in vivo evaluations were conducted, revealing that the synergistic-therapeutic outcome of this nanoplatform enables complete eradication of the U251 tumors without recurrence by NIR laser irradiation, and it can be used for computed tomography (CT) imaging because of the strong X-ray attenuation ability. Conclusion This work expands the phototherapeutic effect of Bi2S3-based nanoplatforms, providing a new strategy for hypoxic tumor theranostics.

Background: Photodynamic therapy (PDT) efficacy of bismuth sulfide (Bi2S3) semiconductor has been severely restricted by its electron–hole pairs (e−−h+) separation inefficiency and oxygen (O2) deficiency in tumors, which greatly hinders reactive oxygen species (ROS) generation and further clinical application of Bi2S3 nanoparticles (NPs) in biomedicine. Results: Herein, novel Bi2S3/titanium carbide (Ti3C2) two-dimensional nano-heterostructures (NHs) are designed to realize multimode PDT of synchronous O2 self-supply and ROS generation combined with highly efficient photothermal tumor elimination for hypoxic tumor therapy. Bi2S3/Ti3C2 NHs were synthesized via the in situ synthesis method starting from Ti3C2 nanosheets (NSs), a classical type of MXene nanostructure. Compared to simple Bi2S3 NPs, Bi2S3/Ti3C2 NHs significantly extend the absorption to the near-infrared (NIR) region and enhance the photocatalytic activity owing to the improved photogenerated carrier separation, where the hole on the valence band (VB) of Bi2S3 can react with water to supply O2 for the electron on the Ti3C2 NSs to generate ·O2− and ·OH through electron transfer. Furthermore, they also achieve 1O2 generation through energy transfer due to O2 self-supply. After the modification of triphenylphosphium bromide (TPP) on Bi2S3/Ti3C2 NHs, systematic in vitro and in vivo evaluations were conducted, revealing that the synergistic-therapeutic outcome of this nanoplatform enables complete eradication of the U251 tumors without recurrence by NIR laser irradiation, and it can be used for computed tomography (CT) imaging because of the strong X-ray attenuation ability. Conclusion: This work expands the phototherapeutic effect of Bi2S3-based nanoplatforms, providing a new strategy for hypoxic tumor theranostics. [ABSTRACT FROM AUTHOR]

Hypoxia is one of the inherent characteristics of most solid tumors; the oxygen-dependent (O2) nature of photodynamic therapy (PDT) limits its clinical treatment against hypoxia tumors. Therefore, improving the oxygen partial pressure of hypoxic tumors is of great significance to improve the PDT effect. Herein, we synthesized the Ti3C2@Porphyridium nanobiohybrids (MX@Pr) by electrostatic self-assembly of photosynthetic oxygen-producing Porphyridium (Pr) and photosensitizer two-dimensional Ti3C2 (MX). Upon 660 nm laser irradiation, MX@Pr in the tumor region could increase the local oxygen level by in situ oxygen generation via Pr-mediated photosynthesis. The oxygen produced by Pr can receive the energy transferred by the excited photosensitizer MX to produce singlet oxygen (1O2), thus significantly enhancing the PDT efficacy of hypoxic tumors and inhibiting tumor growth. This study provides a PDT composite system, which shows the promising prospect of microbial nanomaterial composite systems in the field of biomedicine. [ABSTRACT FROM AUTHOR]

This manuscript has engineered nanoenzymes (HMPC) integrating iron-based MOFs with Pt NPs, which could catalyze H 2 O 2 into O 2 to alleviate tumor hypoxia for enhanced photodynamic therapy and induce ferroptosis by Fenton reaction. [Display omitted] Photodynamic therapy (PDT), as a promising strategy in cancer treatment that utilizes photosensitizers (PSs) to produce reactive oxygen species, has been widely used for eliminating cancer cells under specific wavelength light irradiation. However, the low aqueous solubility of PSs and special tumor microenvironments (TME), such as high glutathione (GSH) and tumor hypoxia remain challenges towards PDT for hypoxic tumor treatment. To address these problems, we constructed a novel nanoenzyme for enhanced PDT-ferroptosis therapy by integrating small Pt nanoparticles (Pt NPs) and near-infrared photosensitizer CyI into iron-based metal organic frameworks (MOFs). In addition, hyaluronic acid was adhered to the surface of the nanoenzymes to enhance the targeting ability. In this design, MOFs act not only as a delivery vector for PSs, but also a ferroptosis inducer. Pt NPs stabilized by MOFs were functioned as an oxygen (O 2) generator by catalyzing hydrogen peroxide into O 2 to relieve tumor hypoxia and increase singlet oxygen generation. In vitro and in vivo results demonstrated that under laser irradiation, this nanoenzyme could effectively relive the tumor hypoxia and decrease the level of GSH, resulting in enhanced PDT-ferroptosis therapy against hypoxic tumor. The proposed nanoenzymes represent an important advance in altering TME for improved clinical PDT-ferroptosis therapy, as well as their potential as effective theranostic agents for hypoxic tumors. [ABSTRACT FROM AUTHOR]

Almost all eukaryotes need oxygen to maintain regular physiological activities. When the organism is under hypoxic situation for a persistent or periodic, it will induce irreversible physiological disorders and even pathological results. Hypoxia is closely related to the pathogenesis of metabolic diseases, cancer, chronic heart disease and kidney disease, myocardial ischemia, as well as reproductive diseases like preeclampsia and endometriosis. Therefore, monitoring and treatment of hypoxia have important implications for the pathophysiology of human-related diseases. Carbon dots (CDs) are emerging nanomaterials developed after 2004 with excellent performance, and have broad application potential in variousdomains likeoptical, biomedicine, energy. Advanced hypoxia therapeutics should be integrated with monitoring and treatment, and CDs with excellent performance are good potential options when sensing is combined with various therapeutic methods. Some researchers have also begun to carry out research in related fields and achieved some results. This article aims to clarify the various applications of CDs in hypoxia-related fields in recent years, including hypoxia sensing and hypoxia tumor theranostics. Finally, the possible challenges and prospects for the application of CDs in hypoxia-related fields are discussed. Graphical Abstract [ABSTRACT FROM AUTHOR]

Perylene derivatives can be stimulated by the hypoxic tumor microenvironment to generate radical anion that is proposed to arouse electron exchange with oxidizing substance, and in turn, realize reactive oxygen species (ROS) burst. Here, three perylene therapeutic agents, PDI‐NI, PDIB‐NI, and PDIC‐NI, are developed and it is found that the minimum lowest unoccupied molecular orbital (LUMO) energy level makes PDIC‐NI most easily accept electrons from the oxidative respiratory chain to form lots of anions, and the resultant maximum ROS generation, establishing an unambiguous mechanism for the formation of perylene radical anions in the cell, presents solid evidence for LUMO energy level determining endogenous ROS burst. Stirringly, PDIC‐NI‐induced ROS generation arouses enhanced mitochondrial oxidative stress and concurrently activates immunogenic cell death (ICD), which not only efficiently kills lung tumor cells but also reprograms immunosuppressive tumor microenvironment, including the cytokine secretion, dendritic cell maturation, as well as cytotoxic T lymphocytes activation, to inhibit the growth of xenografted and metastasis tumor, presenting a proof‐of‐concept demonstration of perylene that acts as an integrated therapeutic agent to well realize hypoxia‐activated chemotherapy with ICD‐induced immunotherapy on lung cancer. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) eliminates cancer cells by converting endogenous oxygen into reactive oxygen species (ROS). However, its efficacy is significantly hindered by hypoxia in solid tumors. Hence, to engineer filamentous fd phage, a human-friendly bacteria-specific virus is proposed, into a nanozyme-nucleating photosensitizer-loaded tumor-homing nanofiber for enhanced production of ROS in a hypoxic tumor. Specifically, Pt-binding and tumor-homing peptides are genetically displayed on the sidewall and tip of the fd phage, respectively. The Pt-binding peptides induced nucleation and orientation of Pt nanozymes (PtNEs) on the sidewall of the phage. The resultant PtNE-coated tumor-homing phage exhibits significantly enhanced sustained catalytic conversion of hydrogen peroxide in hypoxic tumors into O 2 for producing ROS needed for PDT, compared to non-phage-templated PtNE. Density functional theory (DFT) calculations verify the catalytic mechanism of the phage-templated PtNE. After intravenous injection of the PtNE-coated indocyanine green (ICG)-loaded tumor-homing phages into breast tumor-bearing mice, the nanofibers home to the tumors and effectively inhibit tumor growth by the PtNE-enhanced PDT. The nanofibers can also serve as a tumor-homing imaging probe due to the fluorescence of ICG. This work demonstrates that filamentous phage, engineered to become tumor-homing nanozyme-nucleating tumor-hypoxia-relieving nanofibers, can act as cancer-targeting nanozymes with improved catalytic performance for effective targeted PDT., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Abstract Background Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers. Results The as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment. Conclusions This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment. Graphical Abstract

Hypoxia is a prominent feature of malignant tumors and contributes to tumor proliferation, metastasis, and drug resistance in various solid tumors. Therefore, improving tumor oxygenation is crucial for curing tumors. To date, multiple strategies, including oxygen delivering and producing materials, have been designed to increase the oxygen concentration in hypoxic tumors. However, the unsustainable supply of oxygen is still the main obstacle, resulting in a suboptimal outcome in treating oxygen-deprived tumors. Thus, a sufficient oxygen supply is highly desirable in the treatment of hypoxic tumors. Photosynthesis, as the main source of oxygen in nature through the conversion of light energy into chemical energy and oxygen, has been widely studied in scientific research. Moreover, photosynthetic microorganisms have been increasingly applied in cancer therapy by increasing oxygenation, which improves the therapeutic effect of oxygen-consuming tumor therapeutic tools such as radiotherapy and photodynamic therapy. In this review, we summarize recent advances in the design and manufacture of live bacteria as oxygen shuttles for a new generation of hypoxic tumor treatment strategies. Finally, current challenges and future directions are also discussed for successfully addressing hypoxic tumor issues.

Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor efficacy of PDT is limited due to the hypoxic microenvironment of tumor. In this study, classic PDT agent indocyanine green (ICG) and hypoxia-activated chemotherapeutic drug tirapazamine (TPZ) were loaded on mesoporous polydopamine (PDA) to construct PDA@ICG-TPZ nanoparticles (PIT). Then, PIT was camouflaged with cyclic arginine-glycine-aspartate (cRGD) modified tumor cell membranes to obtain the engineered membrane-coated nanoreactor (cRGD-mPIT). The nanoreactor cRGD-mPIT could achieve the dual-targeting ability via tumor cell membrane mediated homologous targeting and cRGD mediated active targeting. With the enhanced tumor-targeting and penetrating delivery system, PIT could efficiently accumulate in hypoxic tumor cells and the loaded drugs were quickly released in response to near-infrared (NIR) laser. The nanoreactor might produce cytotoxic ROS under NIR and further enhance hypoxia within tumor to activate TPZ, which efficiently inhibited hypoxic tumor by synergistic photodynamic-chemotherapy. Mechanically, hypoxia-inhibitory factor-1α (HIF-1α) was down-regulated by the synergistic therapy. Accordingly, the cRGD-mPIT nanoreactor with sustainable and cascade anti-tumor effects and satisfied biosafety might be a promising strategy in hypoxic tumor therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Zinc oxide nanoparticles (ZnO NPs) are important semiconductor materials with interesting photo-responsive properties. During the past, ZnO-based NPs have received considerable attention for photodynamic therapy (PDT) due to their biocompatibility and excellent potential of generating tumor-killing reactive oxygen species (ROS) through gentle photodynamic activation. This article provides a comprehensive review of the recent developments and improvements in optical properties of ZnO NPs as photosensitizers for PDT. The optical properties of ZnO-based photosensitizers are significantly dependent on their charge separation, absorption potential, band gap engineering, and surface area, which can be adjusted/tuned by doping, compositing, and morphology control. Here, we first summarize the recent progress in the charge separation capability, absorption potential, band gap engineering, and surface area of nanosized ZnO-based photosensitizers. Then, morphology control that is closely related to their synthesis method is discussed. Following on, the state-of-art for the ZnO-based NPs in the treatment of hypoxic tumors is comprehensively reviewed. Finally, we provide some outlooks on common targeted therapy methods for more effective tumor killing, including the attachment of small molecules, antibodies, ligands molecules, and receptors to NPs which further improve their selective distribution and targeting, hence improving the therapeutic effectiveness. The current review may provide useful guidance for the researchers who are interested in this promising dynamic cancer treatment technology. [ABSTRACT FROM AUTHOR]

With the development of redox-related therapy modalities in cancer therapy, photodynamic therapy (PDT) has gradually become the most widely used type in the clinic. However, the hypoxic tumor microenvironment restricted the curative effect of PDT. Here, a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy was designed to alleviate tumor hypoxia on the basis of PDT. Specifically, the oxygen producer MnO 2 , oxygen consumption inhibitor atovaquone (ATO) and photosensitizer hypericin (HY) were loaded in SHRN. MnO 2 reacted with excess H 2 O 2 in the tumor microenvironment to increase oxygen generation, while ATO inhibited electron transfer in the aerobic respiratory chain to decrease oxygen consumption. Then, HY utilized this sufficient oxygen to produce ROS under irradiation to enhance the PDT effect. In vitro and in vivo assays confirmed that SHRN exhibits powerful and overall antitumor PDT effects. This formulation may provide an alternative strategy for the development of PDT effects in hypoxic tumor microenvironments. We constructed a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy to alleviate tumor hypoxia on the basis of photodynamic therapy (PDT). This work uniquely aimed at not only increased O 2 generation in hypoxic tumor microenvironment but also reduced O 2 consumption. Moreover, we designed a nanodrug delivery system to enhance the tumor permeability of SHRN. In vitro and in vivo assays all confirmed that SHRN exhibited powerful and overall antitumor effects. This formulation may provide an alternative strategy for the development of the PDT effect in hypoxic solid tumor. [Display omitted] [ABSTRACT FROM AUTHOR]

Despite the clinical potential, photodynamic therapy (PDT) relying on singlet oxygen (1O2) generation is severely limited by tumor hypoxia and endosomal entrapment. Herein, a proton‐driven transformable 1O2‐nanotrap (ANBDP NPs) with endosomal escape capability is presented to improve hypoxic tumor PDT. In the acidic endosomal environment, the protonated 1O2‐nanotrap ruptures endosomal membranes via a "proton‐sponge" like effect and undergoes a drastic morphology‐and‐size change from nanocubes (≈94.1 nm in length) to nanospheres (≈12.3 nm in diameter). Simultaneously, anthracenyl boron dipyrromethene‐derived photosensitizer (ANBDP) in nanospheres transforms to its protonated form (ANBDPH) and switches off its charge‐transfer state to achieve amplified 1O2 photogeneration capability. Upon 730 nm photoirradiation, ANBDPH prominently produces 1O2 and traps generated‐1O2 in the anthracene group to form endoperoxide (ANOBDPH). Benefitting from the hypoxia‐tolerant 1O2‐release property of ANOBDPH in the dark, the 1O2‐nanotrap brings about sustained therapeutic effect without further continuous irradiation, thereby achieving remarkable antitumor performance. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a promising cancer treatment, but limited oxygen supply in tumors (hypoxia) can hinder its effectiveness. This is because traditional PDT relies on Type-II reactions that require oxygen. Type-I photosensitizers (PSs) offer a promising approach to overcome the limitations of tumor photodynamic therapy (PDT) in hypoxic environments. To leverage the advantages of Type-I PDT, the design and evaluation of a series of Type-I PSs for developing pure Type-1 PSs, by incorporating benzene, thiophene, or bithiophene into the donor-acceptor molecular skeleton are reported. Among them, CTTI (with bithiophene) shows the best performance, generating the most superoxide radical (O 2 •- ) upon light irradiation. Importantly, CTTI exclusively produced superoxide radicals, avoiding the less effective Type-II pathway. This efficiency is due to CTTI's energy gap and low reduction potential, which favor electron transfer to oxygen for O 2 •- generation. Finally, CTTI NPs are successfully fabricated by encapsulating CTTI into liposomes, and validated to be effective in killing tumor cells, even under hypoxic conditions, making them promising hypoxia-tolerant tumor phototheranostic agents in both in vitro and in vivo applications., (© 2024 Wiley‐VCH GmbH.)

Background: Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers. Results: The as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment. Conclusions: This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment. [ABSTRACT FROM AUTHOR]

Neoadjuvant targeting of tumor angiogenesis has been developed and approved for the treatment of malignant tumors. However, vascular disruption leads to tumor hypoxia, which exacerbates the treatment process and causes drug resistance. In addition, successful delivery of therapeutic agents and efficacy of radiotherapy require normal vascular networks and sufficient oxygen, which complete tumor vasculopathy hinders their efficacy. In view of this controversy, an optimal dose of FDA-approved anti-angiogenic agents and combination with other therapies, such as immunotherapy and the use of nanocarrier-mediated targeted therapy, could improve therapeutic regimens, reduce the need for administration of high doses of chemotherapeutic agents and subsequently reduce side effects. Here, we review the mechanism of anti-angiogenic agents, highlight the challenges of existing therapies, and present how the combination of immunotherapies and nanomedicine could improve angiogenesis-based tumor treatment. • Angiogenesis supports tumor progression, and mAbs and TKIs are approved to target angiogenesis • Disrupting the vascular network leads to hypoxia and interferes with existing therapies • Low-dose antiangiogenic agents promote vascular normalization and improve subsequent therapies • Nano-immunotherapy improves the normalization of tumor blood vessels and outcomes [ABSTRACT FROM AUTHOR]

In cancer, the use of microbots based on anaerobic bacteria as specific transporters targeting tumor tissues has been explored since most solid tumors exhibit hypoxic regions. The aim of this study was to develop and characterize magnetic microbots based on Bifidobacteria and iron oxide fluorescent magnetic nanoparticles complexed with chitosan and a hypoxia inducible plasmid. In addition, the efficiency of the microbots for gene delivery to solid tumors was evaluated in an in vivo model by florescence and luminescence. To elaborate microbots, iron oxide fluorescent magnetic nanoparticles complexed with chitosan and a hypoxia-inducible plasmid called nanocomplex (NCs) with a size of 302 nm and a ζ potential of +16 mV were obtained and loaded onto Bifidobacteria membranes. Microbots with a diameter between 1–2 µm were characterized by atomic force microscopy (AFM) and scanning electron microscopy (SEM). Microbots were injected intravenously through the tail vein to tumor-bearing mice, and then a magnet was placed to focus them to the tumor area. Forty-eight hours after injection, the biodistribution was determined by florescence and luminescence. The greatest luminescence and fluorescence emitted were found in tumor tissue compared with the normal organs. We created a vector that can be directed by a magnet and deliver genes whose expression is regulated by hypoxic microenvironment of tumor. [ABSTRACT FROM AUTHOR]

Tumor hypoxia has been considered to induce tumor cell resistance to radiotherapy and anticancer chemotherapy, as well as predisposing for increased tumor metastases. Therefore, strategies for the eradication of the hypoxic tumor are highly desirable. Photodynamic therapy (PDT) is a new technique that can be used to treat tumors using laser irradiation to photochemically activate a photosensitizer. Compared to traditional radiotherapy and chemotherapy, photodynamic therapy has many advantages, such as good selectivity, low toxicity, and less trauma and resistance. However, PDT is oxygen-dependent, and the lack of oxygen in hypoxic tumors renders photodynamic therapy ineffective. Cyanobacteria, the earliest photosynthetic oxygen-generating organisms, can utilize water as an electron donor to reduce CO2 into organic carbon compounds along with continuously releasing oxygen under sunlight. Inspired by this, herein, cyanobacteria were used as a living carrier of photosensitizer conjugated upconversion nanoparticles (UCNP) to construct a self-supplying oxygen PDT system. Improvement in the PDT efficiency for hypoxic tumors can be achieved as a result of in situ oxygen production by cyanobacteria under near-infrared (NIR) light using UCNP as a light harvesting antenna. A successful demonstration of this concept would be of great significance and could open the door to a new generation of carrier systems in the field of hypoxia-targeted drug transport platforms. [ABSTRACT FROM AUTHOR]

Due to the "Achilles' heels" of hypoxia, complicated location in solid tumor, small molecular photosensitizers with second near-infrared window (NIR-II) fluorescence, type-I photodynamic therapy (PDT), and photothermal therapy (PTT) have attracted great attention. However, these photosensitizers are still few but yet challenging. Herein, an "all in one" NIR-II acceptor-donor-acceptor fused-ring photosensitizer, Y6-Th, is presented for the in-depth diagnosis and efficient treatment of cancer. Benefiting from the strong intramolecular charge transfer, promoted highly efficient intersystem crossing, largely p-conjugated fused-ring structure, and reduced planarity, the fabricated nanoparticles (Y6-Th nanoparticles) can emit NIR-II fluorescence with the peak located at 1020 nm, exclusively generate O2•- for type-I PDT, and display excellent PTT performance under an 808 nm laser stimulation. These characteristics make Y6-Th a distinguished NIR-wavelength-triggered phototheranostic agent, which can effectively therapy the hypoxic tumor using NIR-II-fluorescence-guided type-I PDT/PTT. This work provides a valuable guideline for fabricating high-performing NIR-II emissive superoxide radical photogenerators., (© 2024 Wiley‐VCH GmbH.)

The hypoxic tumor microenvironment is characterized by disordered vasculature and rapid proliferation of tumors, resulting from tumor invasion, progression and metastasis. The hypoxic conditions restrict efficiency of tumor therapies, such as chemotherapy, radiotherapy, phototherapy and immunotherapy, leading to serious results of tumor recurrence and high mortality. Recently, research has concentrated on developing functional nanomaterials to treat hypoxic tumors. In this review, we categorize such nanomaterials into (i) nanomaterials that elevate oxygen levels in tumors for enhanced oxygen-dependent tumor therapy and (ii) nanomaterials with diminished oxygen dependence for hypoxic tumor therapy. To elevate oxygen levels in tumors, oxygen-carrying nanomaterials, oxygen-generating nanomaterials and oxygen-economizing nanomaterials can be used. To diminish oxygen dependence of nanomaterials for hypoxic tumor therapy, therapeutic gas-generating nanomaterials and radical-generating nanomaterials can be used. The biocompatibility and therapeutic efficacy of these nanomaterials are discussed. [ABSTRACT FROM AUTHOR]

Tumor hypoxia severely impedes the therapeutic efficacy of type II photodynamic therapy (PDT) depending on singlet oxygen (1O2) generation. To combat hypoxic tumors, herein, a new approach is devised to boost superoxide radical (O2•−) photogeneration for type I PDT. Heavy atoms are introduced onto aza‐BODIPY molecules (iodine substituted butoxy‐aza‐BODIPY, IBAB) to promote their intersystem‐crossing (ISC) ability. Meanwhile, methoxy‐poly(ethylene glycol)‐b‐poly(2‐(diisopropylamino) ethyl methacrylate) (mPEG‐PPDA) with enhanced electron‐donating efficiency is employed as a coating matrix to encapsulate IBAB, thereby obtaining amphiphilic aza‐BODIPY nanoplatforms (PPIAB NPs). Under irradiation, triplet‐state IBAB in PPIAB NPs is efficiently generated from singlet state favored by the elevated ISC ability. The electron‐rich environment provided by mPEG‐PPDA can donate triplet‐state IBAB with one electron to form charge‐separated‐state IBAB, which in turn transfers electron to O2 for O2•− production. Significantly, owing to recyclable O2 generated by disproportionation or Harber–Weiss/Fenton reaction, prominent O2•− is generated by PPIAB NPs even in a severe hypoxic environment (2% O2), enabling superior therapeutic efficacy (96.2% tumor‐inhibition rate) over NPs not following this strategy. Thus, the proof‐of‐concept design of ISC‐enhanced and electron‐rich polymer encapsulating PPIAB NPs illuminates the path to preparing O2•− photogenerator for hypoxic cancer treatment. [ABSTRACT FROM AUTHOR]

Combined therapy using photothermal and photodynamic treatments together with chemotherapeutic agents is considered one of the most synergistic treatment protocols to ablate hypoxic tumors. Herein, we sought to fabricate an in situ-injectable PEG hydrogel system having such multifunctional effects. This PEG hydrogel was prepared with (i) nabTM-technique-based paclitaxel (PTX)-bound albumin nanoparticles with chlorin-e6 (Ce6)-conjugated bovine serum albumin (BSA-Ce6) and indocyanine green (ICG), named ICG/PTX/BSA-Ce6-NPs (~175 nm), and (ii) an albumin-stabilized perfluorocarbon (PFC) nano-emulsion (BSA-PFC-NEs; ~320 nm). This multifunctional PEG hydrogel induced moderate and severe hyperthermia (41−42 °C and >48 °C, respectively) at the target site under two different 808 nm laser irradiation protocols, and also induced efficient singlet oxygen (1O2) generation under 660 nm laser irradiation supplemented by oxygen produced by ultrasound-triggered PFC. Due to such multifunctionality, our PEG hydrogel formula displayed significantly enhanced killing of three-dimensional 4T1 cell spheroids and also suppressed the growth of xenografted 4T1 cell tumors in mice (tumor volume: 47.7 ± 11.6 and 63.4 ± 13.0 mm3 for photothermal and photodynamic treatment, respectively, vs. PBS group (805.9 ± 138.5 mm3), presumably based on sufficient generation of moderate heat as well as 1O2/O2 even under hypoxic conditions. Our PEG hydrogel formula also showed excellent hyperthermal efficacy (>50 °C), ablating the 4T1 tumors when the irradiation duration was extended and output intensity was increased. We expect that our multifunctional PEG hydrogel formula will become a prototype for ablation of otherwise poorly responsive hypoxic tumors.

The utilization of alkyl radicals (•R) for hypoxic tumor therapy has great prospects due to its O 2 -independence and high reactivity. However, correlational initiators for in vivo activation remain scarce. Here, we report that ultrasound excitation of oleic acid-capped BaTiO 3 (OA@BaTiO 3 ) can result in an •R cascade and hence a means to conquer hypoxic tumors. Mechanistic studies find that the •R signal disappears when OA@BaTiO 3 undergoes acid washing post-treatment, which is a common procedure for removing the unwanted byproduct BaCO 3 . Combined with the infrared spectrum analysis, acid treatment was proven to weaken the peaks at 2840-2970 cm -1 characteristic of -CH 2 - and terminal -CH 3 stretching vibration of OA. There is compelling evidence that high temperature thermal oxidation of OA involves the generation of •R. Thus, acid washing is considered to remove the loosely bound yet catalytically active OA. And piezoelectric BaTiO 3 , a potential electron-hole redox catalyst, can sensitize these OA molecules and disintegrate them to •R. This unexpected discovery provides us with a distinctive mentality to seek diverse •R initiators for tumor ablation, as well as an additional perspective on the postprocessing of synthetic materials.

Porphyrin photosensitizers are the classic drugs in clinical photodynamic therapy (PDT), but the hypoxia of tumor environment and the rapid oxygen consumption of PDT severely weaken their therapeutic effect. A recently reported water-dependent reversible photoacidity therapy (W-RPAT) is O 2 -independence, providing a solution for the treatment of hypoxic tumors. In this work, TPP-O-PEG5, a porphyrin derivative with binary properties of PDT and W-RPAT, is designed and synthesized for the first time. The nanoparticles (NPs) of TPP-O-PEG5 encapsulated with DSPE-mPEG2000, an amphiphilic polymer approved by Food and Drug Administration, can simultaneously produce reactive oxygen species and H + under irradiation of a 660 nm laser, and revert the H + back under darkness, presenting strong phototoxicity to multiple tumor cell lines with no obvious difference between the IC50 values tested under normoxic (≈20% O 2 ) and hypoxic (<0.5% O 2 ) conditions. Excitingly, in vivo experiments show that the therapeutic effect of TPP-O-PEG5 NPs on large hypoxic tumors is better than that of NPe6, a clinical porphin PDT drug. This work provides a novel strategy for porphyrin photosensitizers to break through the limitation of hypoxic environment, and significantly improve the phototherapeutic effect on hypoxic tumors., (© 2024 Wiley‐VCH GmbH.)

In cancer, the use of microbots based on anaerobic bacteria as specific transporters targeting tumor tissues has been explored since most solid tumors exhibit hypoxic regions. The aim of this study was to develop and characterize magnetic microbots based on Bifidobacteria and iron oxide fluorescent magnetic nanoparticles complexed with chitosan and a hypoxia inducible plasmid. In addition, the efficiency of the microbots for gene delivery to solid tumors was evaluated in an in vivo model by florescence and luminescence. To elaborate microbots, iron oxide fluorescent magnetic nanoparticles complexed with chitosan and a hypoxia-inducible plasmid called nanocomplex (NCs) with a size of 302 nm and a ζ potential of +16 mV were obtained and loaded onto Bifidobacteria membranes. Microbots with a diameter between 1–2 µm were characterized by atomic force microscopy (AFM) and scanning electron microscopy (SEM). Microbots were injected intravenously through the tail vein to tumor-bearing mice, and then a magnet was placed to focus them to the tumor area. Forty-eight hours after injection, the biodistribution was determined by florescence and luminescence. The greatest luminescence and fluorescence emitted were found in tumor tissue compared with the normal organs. We created a vector that can be directed by a magnet and deliver genes whose expression is regulated by hypoxic microenvironment of tumor.

Photodynamic therapy (PDT), as a local cancer treatment strategy, manifests great promise compared to chemotherapy and radiotherapy. However, the drawbacks of conventional organic photosensitizers such as hydrophobicity, deficient stability, and poor tumor selectivity have immensely restricted the PDT functionality. Alternatively, nanomaterials with exceptional physicochemical features have emerged to circumvent these shortcomings. Herein, rational architectures of nanoparticles to address the anti-tumor efficiency of PDT via the cancer-targeting property, oxygen furnishing, and combined therapeutic/diagnostic strategies have been discussed. [ABSTRACT FROM AUTHOR]

Background: Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions., Methods: To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a controlled reduction in systemic glucose by combining dietary carbohydrate restriction, using a ketogenic diet, with gluconeogenesis inhibition, using metformin, on two mouse models of triple-negative breast cancer (TNBC)., Results: We confirmed that MET - 1 breast cancer cells require abnormally high glucose concentrations to survive in a hypoxic environment in vitro. Then, we showed that, compared to a ketogenic diet or metformin alone, animals treated with the combination regimen showed significantly lower tumor burden, higher tumor latency and slower tumor growth. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse model by 31 days, which is approximately equivalent to 3 human years., Conclusion: This is the first preclinical study to demonstrate that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types, one that can also augment existing treatment options to improve patient outcomes., Competing Interests: Competing interests Authors declare no competing interests

Carbonic anhydrase IX is overexpressed in many solid tumors including hypoxic tumors and is a potential target for cancer therapy and diagnosis. Reported imaging agents targeting CA-IX are successful mostly in clear cell renal carcinoma as SKRC-52 and no candidate was approved yet in clinical trials for imaging of CA-IX. To validate CA-IX as a valid target for imaging of hypoxic tumor, we designed and synthesized novel [ 18 F]-PET tracer ( 1 ) based on acetazolamide which is one of the well-known CA-IX inhibitors and performed imaging study in CA-IX expressing hypoxic tumor model as 4T1 and HT-29 in vivo models other than SKRC-52. [ 18 F]-acetazolamide ( 1 ) was found to be insufficient for the specific accumulation in CA-IX expressing tumor. This study might be useful to understand in vivo behavior of acetazolamide PET tracer and can contribute to the development of successful PET imaging agents targeting CA-IX in future. Additional study is needed to understand the mechanism of poor targeting of CA-IX, as if CA-IX is not reliable as a sole target for imaging of CA-IX expressing hypoxic solid tumors. [ABSTRACT FROM AUTHOR]

Microbubbles are proposed as a potentially novel method for oxygen delivery in vivo in initial studies. The lack of commercial microbubbles for oxygen delivery in preclinical research prompted us to fabricate an oxygen-loaded lipid microbubble. We aimed to extend the innovative strategy to modulate the tumor hypoxic microenvironment, using microbubbles intravenously as an oxygen carrier for the controllable tumor-specific delivery of oxygen by ultrasound (US). In our experiment, an oxygen-loaded lipid-coated microbubble (OLM) with mixed gas (O2/C3 F8, 5:1 v/v) was fabricated and exhibited a higher rate of oxygen release to a desaturated solution through burst by US than that in the absence of US. Although in in vivo studies, OLMs could be imaged and triggered by US to elevate the pO2 level in the breast VX2 tumor dramatically within a matter of minutes. The added presence of US-activated OLMs elicited a nearly six-fold increase in pO2 levels within 1 min compared with that of the pre-injection. Owing to the high oxygen payload, great acoustic stability and acoustic properties, OLMs may be proposed as an ideal radio-sensitizer. We conclude that oxygen release mediated by ultrasound-targeted microbubble destruction is feasible and shows potential in image-guided, site-specific cancer radiotherapy. [ABSTRACT FROM AUTHOR]

Hypoxia, an outstanding characteristic of various solid tumors, has been considered a critical factor of aggressive tumor phenotypes, poor clinical prognosis, and increased expression of the multidrug-resistant gene. Therefore, it is critical to develop a drug delivery system to enhance the delivery effect of the antitumor drug in the hypoxic tumor. We constructed two types of tumor targeting micelles based on chitosan and evaluated their properties in targeting hypoxic tumors. Chitosan-based micelles consisted of a hydrophobic group octyl group, a hydrophilic polyethylene glycol, tumor targeting ligands glucosamine or folic acid, and a transmembrane peptide 9-d-arginine. The molecular structure, morphology, size distribution, zeta potential, and biosafety of two micelles were characterized. Oil-soluble CdSe quantum dots were used as a fluorescent probe to evaluate the hypoxic tumor cell targeting properties of the micelles. Moreover, HepG2 human hepatocellular carcinoma cells and HeLa human cervical carcinoma cells were used asin vitromodels. We demonstrated that, under hypoxic conditions, two chitosan micelles showed better targeting ability to HepG2 and HeLa cells, which enhanced the effect of antitumor drugs by specifically targeting transport in hypoxic tumors. Therefore, chitosan micelles may be a potential drug delivery system that can be used to deliver antitumor drugs to hypoxic tumors. [ABSTRACT FROM PUBLISHER]

To develop a radiopharmaceutical localizing in tumor hypoxic tissues, secnidazole (SECN) was labeled with I. The labeled product was prepared with the radiochemical yield higher than 96% when performing the reaction at 45°C for 30 min. The electrophilic radioiodination of SECN was done using different oxidizing agents. Iodogen appeared to be more effective than chloramine-T (CAT) and N-bromosuccinimide (NBS). I-SECN was tested in vivo with a tumor model prepared by the intramuscular injection of Ehrlich cell line into the thigh muscle of mice. I-SECN showed high accumulation in tumor hypoxic tissue (3.6% of injected dose per gram of organ at 2 h post injection). The target/nontarget (T/NT) ratio was high (T/NT = 6 at 24 h post injection). Thus, radioiodinated SECN shows promise as a selective imaging agent for diagnosis of tumor hypoxia. [ABSTRACT FROM AUTHOR]

The low oxygen concentration limits the therapeutic efficacy of photodynamic therapy in treating cancer cells in hypoxia, since the cytotoxic 1 O 2 can't be effectively generated in this condition. To overcome this, we load photosensitizer into perfluorocarbon nanodroplet, which has a high oxygen capacity to enrich O 2 for photodynamic consumption. Under the well-controlled hypoxic condition, we test its efficacy both in vitro and in vivo . This method can be successfully used for destroying cancer cells in hypoxic condition. [ABSTRACT FROM AUTHOR]

[Display omitted] • This study proves that a photosensitizer (PS) with photoinduced ICT and electron donor containing hydrophilic fragment would have water-dependent reversible photoacidity (W-RPA) property; • A novel PS (BN-PEG5) with a binary property of PDT and W-RPAT is constructed and shows significant therapeutic effects towards various tumor cells whatever in normoxia or hypoxia; • The IC50 values of BN-PEG5 to these cells in hypoxia are comparable with the data of commercial PDT drug HpD in normoxia, indicating the advantage of combined PDT and W-RPAT in hypoxic tumors treatment. Photodynamic therapy (PDT) has been applied in the clinical treatment of various tumors. However, the high oxygen dependency of PDT still remains as the major obstacle which undermines its therapeutic efficacy, especially for hypoxic tumors. Recently, we reported a water-dependent reversible photoacidity (W-RPA) mechanism, which is oxygen-independent and has great potential for tumor treatment. Here we find that a previously studied cyclopentanone photosensitizer (B-PEG5) for PDT also has W-RPA characteristic. However, its absorption mainly occurs in blue-green region, limiting the depth of phototherapy. Based on the structure of B-PEG5 , a cyclopentylmalononitrile dye (BN-PEG5) with enhanced absorption in red region is designed and synthesized. Under irradiation of a 635 nm laser, BN-PEG5 can not only produce ROS, but also generate H+. Owing to its binary properties of PDT and W-RPA therapy, BN-PEG5 shows strong phototoxicity to multiple tumor cell lines (4T1, HeLa and MDA-MB-231) either in normoxic condition (∼20% O 2) or extreme hypoxic condition (<0.5% O 2). Furthermore, the IC50 values of BN-PEG5 to these cells in hypoxia (1.39 μM–2.18 μM) are comparable with the data of commercial drug HpD in normoxia (1.80 μM–2.65 μM), which indicates the advantages of combined PDT and W-RPA therapy in hypoxic tumor treatment. [ABSTRACT FROM AUTHOR]

Introduction: Several isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) are connected with tumorigenesis. Hypoxic tumors overexpress CA IX and XII as a consequence of HIF activation cascade, being involved in pH regulation, metabolism, and metastases formation. Other isoforms (CA I, II, III, IV) were also reported to be present in some tumors., Areas Covered: Some CA isoforms are biomarkers for disease progression or response to therapy. Inhibitors, antibodies, and other procedures for targeting these enzymes for the treatment of tumors/metastases are discussed. Sulfonamides and coumarins represent the most investigated classes of inhibitors, but carboxylates, selenium, and tellurium-containing inhibitors were also investigated. Hybrid drugs of CA inhibitors with other antitumor agents for multitargeted therapy were reported., Expert Opinion: Targeting CAs present in solid or hematological tumors with selective, targeted inhibitors is a validated approach, which has been consolidated in the last years. A host of new preclinical data and several clinical trials of antibodies and small-molecule inhibitors are ongoing, which connected with the large number of new chemotypes/procedures discovered to be effective, may lead to a breakthrough in this therapeutic area. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2018 to 2023.