Hypoxia-activated Prodrug Tirapazamine Research Articles

Peptide-IR820 Conjugate: A Promising Strategy for Efficient Vascular Disruption and Hypoxia Induction in Melanoma.

Photothermal therapy (PTT) has emerged as a noninvasive and precise cancer treatment modality known for its high selectivity and lack of drug resistance. However, the clinical translation of many PTT agents is hindered by the limited biodegradability of inorganic nanoparticles and the instability of organic dyes. In this study, a peptide conjugate, IR820-Cys-Trp-Glu-Trp-Thr-Trp-Tyr (IR820-C), was designed to self-assemble into nanoparticles for both potent PTT and vascular disruption in melanoma treatment. When co-assembled with the poorly soluble vascular disrupting agent (VDA) combretastatin A4 (CA4), the resulting nanoparticles (IR820-C@CA4 NPs) accumulate efficiently in tumors, activate systemic antitumor immune responses, and effectively ablate melanoma with a single treatment and near-infrared irradiation, as confirmed by our in vivo experiments. Furthermore, by exploiting the resulting tumor hypoxia, we subsequently administered the hypoxia-activated prodrug tirapazamine (TPZ) to capitalize on the created microenvironment, thereby boosting therapeutic efficacy and antimetastatic potential. This study showcases the potential of short-peptide-based nanocarriers for the design and development of stable and efficient photothermal platforms. The multifaceted therapeutic strategy, which merges photothermal ablation with vascular disruption and hypoxia-activated chemotherapy, holds great promise for advancing the efficacy and scope of cancer treatment modalities.

Glutathione-Responsive Polymersome with Continuous Glutathione Depletion for Enhanced Photodynamic Therapy and Hypoxia-Activated Chemotherapy.

The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both in vitro and in vivo results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.

Sorafenib-Encapsulated Liposomes to Activate Hypoxia-Sensitive Tirapazamine for Synergistic Chemotherapy of Hepatocellular Carcinoma.

Combination therapy with the synergistic effect is an effective way in cancer chemotherapy. Herein, an antiangiogenic sorafenib (SOR) and hypoxia-activated prodrug tirapazamine (TPZ)-coencapsulated liposome (LipTPZ/SOR) is prepared for chemotherapy of hepatocellular carcinoma (HCC). SOR is a multi-target tyrosine kinase inhibitor that can inhibit tumor cell proliferation and angiogenesis. The antiangiogenesis effect of SOR can reduce oxygen supply and aggravate tumor hypoxia, which is able to activate hypoxia-sensitive prodrug TPZ, exhibiting the synergistic antitumor effect. LipTPZ/SOR at different molar ratios of TPZ and SOR can significantly inhibit the proliferation of hepatocellular carcinoma cells. The mole ratio of TPZ and SOR was optimized to 2:1, which exhibited the best synergetic antitumor effect. The synergistic antitumor mechanism of SOR and TPZ was also investigated in vivo. After treated with SOR, the number of vessels was decreased, and the degree of hypoxia was aggravated in tumor tissues. What is more, in the presence of SOR, TPZ could be activated to inhibit tumor growth. The combination of TPZ and SOR exhibited an excellent synergistic antitumor effect. This research not only provides an innovative strategy to aggravate tumor hypoxia to promote TPZ activation but also paints a blueprint about a new nanochemotherapy regimen for the synergistic chemotherapy of HCC, which has excellent biosafety and bright clinical application prospects.

Hypoxia-activated cascade nanovaccine for synergistic chemoembolization-immune therapy of hepatocellular carcinoma

In this work, a promising treatment strategy for triggering robust antitumor immune responses in transarterial chemoembolization of hepatocellular carcinoma (HCC) is presented. The zeolitic imidazolate framework nanoparticles loaded with hypoxia-activated prodrug tirapazamine and immune adjuvant resiquimod facilitated in situ generation of nanovaccine via a facile approach. The nanovaccine can strengthen the ability of killing the liver cancer cells under hypoxic environment, while was capable of improving immunogenic tumor microenvironment and triggering strong antitumor immune responses by increasing the primary and distant intratumoral infiltration of immune cells such as cytotoxic T cells. Moreover, a porous microcarrier, approved by FDA as pharmaceutical excipient, was designed to achieve safe and effective delivery of the nanovaccine via transarterial therapy in rabbit orthotopic VX2 liver cancer model. The microcarrier exhibited the characteristics of excellent drug loading and occlusion of peripheral artery. The collaborative delivery of the microcarrier and nanovaccine demonstrated an exciting inhibitory effect on solid tumors and tumor metastases, which provided a great potential as novel combination therapy for HCC interventional therapy.

Hypoxia and Singlet Oxygen Dual-Responsive Micelles for Photodynamic and Chemotherapy Therapy Featured with Enhanced Cellular Uptake and Triggered Cargo Delivery.

Combination therapy provides better outcomes than a single therapy and becomes an efficient strategy for cancer treatment. In this study, we designed a hypoxia- and singlet oxygen-responsive polymeric micelles which contain azo and nitroimidazole groups for enhanced cellular uptake, repaid cargo release, and codelivery of photosensitizer Ce6 and hypoxia-activated prodrug tirapazamine TPZ (DHM-Ce6@TPZ), which could be used for combining Ce6-mediated photodynamic therapy (PDT) and PDT-activated chemotherapy to enhance the therapy effect of cancer. The hypoxia- and singlet oxygen-responsive polymeric micelles DHM-Ce6@TPZ were prepared by film hydration method. The morphology, physicochemical properties, stimuli responsiveness, in vitro singlet oxygen production, cellular uptake, and cell viability were evaluated. In addition, the in vivo therapeutic effects of the micelles were verified using a tumor xenograft mice model. The resulting dual-responsive micelles not only increased the concentration of intracellular photosensitizer and TPZ, but also facilitated photosensitizer and TPZ release for enhanced integration of photodynamic and chemotherapy therapy. As a photosensitizer, Ce6 induced PDT by generating toxic singlet reactive oxygen species (ROS), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy, thereby evoking a synergistic photodynamic and chemotherapy therapeutic effect. The cascade synergistic therapeutic effect of DHM-Ce6@TPZ was effectively evaluated both in vitro and in vivo to inhibit tumor growth in a breast cancer mice model. The designed multifunctional micellar nano platform could be a convenient and powerful vehicle for the efficient co-delivery of photosensitizers and chemical drugs for enhanced synergistic photodynamic and chemotherapy therapeutic effect of cancer.

Photoresponsive metal-organic framework with combined photodynamic therapy and hypoxia-activated chemotherapy for the targeted treatment of rheumatoid arthritis

Activated M1-type macrophages, which produce inflammatory factors that exacerbate rheumatoid arthritis (RA), represent crucial target cells for inhibiting the disease process. In this study, we developed a novel photoresponsive targeted drug delivery system (TPNPs-HA) that can effectively deliver the hypoxia-activated prodrug tirapazamine (TPZ) specifically to activated macrophages. After administration, this metal-organic framework, PCN-224, constructed uing the photosensitizer porphyrin, exhibits the ability to generate excessive toxic reactive oxygen species (ROS) when exposed to near-infrared light. Additionally, the oxygen-consumed hypoxic environment further activates the chemotherapeutic effect of TPZ, thus creating a synergistic combination of photodynamic therapy (PDT) and hypoxia-activated chemotherapy (HaCT) to promote the elimination of activated M1-type macrophages. The results highlight the significantly potential of this photoresponsive nano-delivery system in providing substantial relief for RA. Furthermore, these findings support its effectiveness in inhibiting the disease process of RA, thereby offering new possibilities for the development of precise and accurate strategies for RA.

Bioengineered "Molecular Glue"-Mediated Tumor-Specific Cascade Nanoreactors with Self-Destruction Ability for Enhanced Precise Starvation/Chemosynergistic Tumor Therapy.

The ordered and directed functionalization of targeting elements on the surface of nanomaterials for precise tumor therapy remains a challenge. To address the above problem, herein, we adopted a materials-based synthetic biotechnology strategy to fabricate a bioengineered fusion protein of materials-binding peptides and targeting elements, which can serve as a "molecular glue" to achieve a directional and organized assembly of targeting biological macromolecules on the surface of nanocarriers. The hypoxia microenvironment of solid tumors inspired the rapid development of starvation/chemosynergistic therapy; however, the unsatisfied spatiotemporal specific performance hindered its further development in precise tumor therapy. As a proof of concept, a bioengineered fusion protein containing a dendritic mesoporous silicon (DMSN)-binding peptide, and a tumor-targeted and acidity-decomposable ferritin heavy chain 1 (FTH1), was constructed by fusion expression and further assembled on the surface of DMSN companying with the insertion of hypoxia-activated prodrug tirapazamine (TPZ) and glucose oxidase (GOX) to establish a nanoreactor for precise starvation/chemosynergistic tumor therapy. In this context, the as-prepared therapeutic nanoreactors revealed obvious tumor-specific accumulation and an endocytosis effect. Next, the acidic tumor microenvironment triggered the structural collapse of FTH1 and the subsequent release of GOX and TPZ, in which GOX-mediated catalysis cut off the nutrition supply to realize starvation therapy based on the consumption of endogenous glucose and further provided an exacerbated hypoxia environment for TPZ in situ activation to initiate tumor chemotherapy. More significantly, the presence of "molecular glue" elevated the tumor-targeting capacity of nanoreactors and further enhanced the starvation/chemosynergistic therapeutic effect remarkably, suggesting that such a strategy provided a solution for the functionality of nanomaterials and facilitated the design of novel targeting nanomedicines. Overall, this study highlights materials-binding peptides as a new type of "molecular glue" and opens new avenues for designing and exploring active biological materials for biological functions and applications.

Integrating Pillar[5]arene and BODIPY for a Supramolecular Nanoplatform To Achieve Synergistic Photodynamic Therapy and Chemotherapy.

BODIPY photosensitizers have been integrated with a hypoxia-activated prodrug to achieve synergistic photodynamic therapy (PDT) and chemotherapy. A novel BODIPY derivative BDP-CN was designed and synthesized. It had two cyano groups to make it complex well with a water-soluble pillar[5]arene. Their association constant was calculated to be (6.8±0.9)×106 M-1 . After self-assembly in water, regular spherical nanocarriers can be formed; these were used to encapsulate the hypoxia-activated prodrug tirapazamine (TPZ). BDP-CN displayed excellent photodynamic activity to complete PDT. In this process, O2 can be continuously consumed to activate TPZ to allow it to be converted to a benzotriazinyl (BTZ) radical with high cytotoxicity to complete chemotherapy. As a result, the formed nanoparticles showed excellent synergistic photodynamic therapy and chemotherapy efficacy. The synergistic therapy mechanism is discussed in detail.

Controllable hypoxia-activated chemotherapy as a dual enhancer for synergistic cancer photodynamic immunotherapy

The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates 1O2 for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors.

Application of tumor pH/hypoxia-responsive nanoparticles for combined photodynamic therapy and hypoxia-activated chemotherapy.

Introduction: Cancer selectivity, including targeted internalization and accelerated drug release in tumor cells, remains a major challenge for designing novel stimuli-responsive nanocarriers to promote therapeutic efficacy. The hypoxic microenvironment created by photodynamic therapy (PDT) is believed to play a critical role in chemoresistance. Methods: We construct dual-responsive carriers (DANPCT) that encapsulate the photosensitizer chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) to enable efficient PDT and PDT-boosted hypoxia-activated chemotherapy. Results and discussion: Due to TAT masking, DANPCT prolonged payload circulation in the bloodstream, and selective tumor cell uptake occurred via acidity-triggered TAT presentation. PDT was performed with a spatially controlled 660-nm laser to enable precise cell killing and exacerbate hypoxia. Hypoxia-responsive conversion of the hydrophobic NI moiety led to the disassembly of DANPCT, facilitating TPZ release. TPZ was reduced to cytotoxic radicals under hypoxic conditions, contributing to the chemotherapeutic cascade. This work offers a sophisticated strategy for programmed chemo-PDT.

A Multifunctional Nano-Delivery System Against Rheumatoid Arthritis by Combined Phototherapy, Hypoxia-Activated Chemotherapy, and RNA Interference.

Effective therapy for rheumatoid arthritis (RA) keeps a challenge due to the complex pathogenesis of RA. It is not enough to completely inhibit the process of RA with any single therapy method. The purpose of the research is to compensate for the insufficiency of monotherapy using multiple treatment regimens with different mechanisms. In this study, we developed a new method to synthesize mesoporous silica nanoparticles hybridized with photosensitizer PCPDTBT (HNs). Branched polyethyleneimine-folic acid (PEI-FA) could be coated on the surface of HNs through electrostatic interactions. It simultaneously blocked the hypoxia-activated prodrug tirapazamine loaded into the mesopores and binded with Mcl-1 siRNA (siMcl-1) that interfered with the expression of the anti-apoptotic protein Mcl-1. Released from the co-delivery nanoparticles (PFHNs/TM) Tirapazamine and siMcl-1 upon exposure to acidic conditions of endosomes/lysosomes in activated macrophages. Under NIR irradiation, photothermal therapy and photodynamic therapy derived from PCPDTBT, hypoxia-activated chemotherapy derived from tirapazamine, and RNAi derived from siMcl-1 were used for the combined treatment for RA by killing activated macrophages. PEI-FA-coated PFHNs/TM exhibited activated macrophage-targeting characteristics, thereby enhancing the in vitro and in vivo NIR-induced combined treatment of RA. The prepared PFHNs/TM have high blood compatibility (far below 5% of hemolysis) and ideal in vitro phototherapy effect while controlling the TPZ release and binding siMcl-1. We prove that PEI-FA-coated PFHNs/TM not only protect the bound siRNA but also are selectively uptaked by activated macrophages through FA receptor-ligand-mediated endocytosis, and effectively silence the target anti-apoptotic protein by siMcl-1 transfection. In vivo, PFHNs/TM have also been revealed to be selectively enriched at the inflammatory site of RA, exhibiting NIR-induced anti-RA efficacy. Overall, these FA-functionalized, pH-responsive PFHNs/TM represent a promising platform for the co-delivery of chemical drugs and nucleic acids for the treatment of RA cooperating with NIR-induced phototherapy.

Biomimetic cell membrane-coated glucose/oxygen-exhausting nanoreactor for remodeling tumor microenvironment in targeted hypoxic tumor therapy

Hypoxia is a common feature within many types of solid tumors, which is closely associated with limited efficacy for tumor therapies. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in tumor-targeting and penetrating drug delivery systems in urgent need. Here, glucose oxidase (GOX) and hypoxia-activated prodrug tirapazamine (TPZ) are loaded into photothermal conversion agent polydopamine (PDA) as the glucose/oxygen-exhausting nanoreactor named PGT. We further construct a tumor cell membrane-coated nanovesicle for the targeted delivery of PGT. This biomimetic nanovesicle exhibits significantly improved tumor-targeting and tumor-penetrating abilities. After internalization by the tumor cells, the loaded drug is quickly released in response to near-infrared (NIR) laser. The PGT nanoreactor can exhaust glucose and oxygen, and further enhance hypoxia within tumor, which efficiently inhibits hypoxic tumor by combining starvation therapy and hypoxia-activated chemotherapy. Mechanically, it is revealed that the nanoreactor significantly increases hypoxia level and downregulates the expression of hypoxia-inhibitory factor-1α (HIF-1α), thereby promoting T cell activation and macrophage polarization to remodel tumor immunosuppressive microenvironment. Therefore, this tumor microenvironment-regulable nanoreactor with sustainable and cascade targeted starvation-chemotherapy provides a novel insight into the treatment of hypoxic tumor.

In vitro breast cancer model with patient-specific morphological features for personalized medicine

In vitro cancer models that can simulate patient-specific drug responses for personalized medicine have attracted significant attention. However, the technologies used to produce such models can only recapitulate the morphological heterogeneity of human cancer tissue. Here, we developed a novel 3D technique to bioprint an in vitro breast cancer model with patient-specific morphological features. This model can precisely mimic the cellular microstructures of heterogeneous cancer tissues and produce drug responses similar to those of human cancers. We established a bioprinting process for generating cancer cell aggregates with ductal and solid tissue microstructures that reflected the morphology of breast cancer tissues, and applied it to develop breast cancer models. The genotypic and phenotypic characteristics of the ductal and solid cancer aggregates bioprinted with human breast cancer cells (MCF7, SKBR3, MDA-MB-231) were respectively similar to those of early and advanced cancers. The bioprinted solid cancer cell aggregates showed significantly higher hypoxia (>8 times) and mesenchymal (>2–4 times) marker expressions, invasion activity (>15 times), and drug resistance than the bioprinted ductal aggregates. Co-printing the ductal and solid aggregates produced heterogeneous breast cancer tissue models that recapitulated three different stages of breast cancer tissue morphology. The bioprinted cancer tissue models representing advanced cancer were more and less resistant, respectively, to the anthracycline antibiotic doxorubicin and the hypoxia-activated prodrug tirapazamine; these were analogous to the results in human cancer. The present findings showed that cancer cell aggregates can mimic the pathological micromorphology of human breast cancer tissue and they can be bioprinted to produce breast cancer tissue in vitro that can morphologically represent the clinical stage of cancer in individual patients.

Folate receptor-targeting semiconducting polymer dots hybrid mesoporous silica nanoparticles against rheumatoid arthritis through synergistic photothermal therapy, photodynamic therapy, and chemotherapy

With ideal optical properties, semiconducting polymer quantum dots (SPs) have become a research focus in recent years; a considerable number of studies have been devoted to the application of SPs in non-invasive and biosafety phototherapy with near-infrared (NIR) lasers. Nevertheless, the relatively poor stability of SPs in vitro and in vivo remains problematic. PCPDTBT was chosen to synthesize photothermal therapy (PTT) and photodynamic therapy (PDT) dual-model SPs, considering its low band gap and desirable absorption in the NIR window. For the first time, cetrimonium bromide was used as a stabilizer to guarantee the in vitro stability of SPs, and as a template to prepare SP hybrid mesoporous silica nanoparticles (SMs) to achieve long-term stability in vivo. The mesoporous structure of SMs was used as a reservoir for the hypoxia-activated prodrug Tirapazamine (TPZ). SMs were decorated with polyethylene glycol-folic acid (SMPFs) to specifically target activated macrophages in rheumatoid arthritis (RA). Upon an 808 nm NIR irradiation, the SMPFs generate intracellular hyperthermia and excessive singlet oxygen. Local hypoxia caused by molecular oxygen consumption simultaneously activates the cytotoxicity of TPZ, which effectively kills activated macrophages and inhibits the progression of arthritis. This triple PTT-PDT-chemo synergistic treatment suggests that SMPFs realize the in vivo application of SPs and may be a potential nano-vehicle for RA therapy with negligible side-toxicity.

Enzyme/GSH dual-responsive biodegradable nanohybrid for spatiotemporally specific photodynamic and hypoxia-augmented therapy against tumors

Photodynamic therapy (PDT) efficacy has been severely limited by the hypoxia in tumor microenvironment. A multitherapy modality was developed, integrating the advantages of each therapy and a nanocarrier: PDT and PDT-induced hypoxia-activated chemotherapy. Following PDT-induced hypoxia augmented in the periphery of the tumors, chemotherapy was locally activated. To this end, new indocyanine green (IR820) and a hypoxia-activated prodrug tirapazamine (TPZ) were loaded in glutathione (GSH) decomposable mesoporous organic silica nanoparticles (GMONs), tethered by hyaluronic acid (HA). This nanohybrid showed a tendency to accumulate and be retained in tumors, due to passive and active targeting. The IR820 produced singlet oxygen (1O2) under near-infrared (NIR) laser irradiation and concomitantly tumorous abnormality exacerbated hypoxia. TPZ-mediated hypoxia-activated chemotherapy acted to kill more tumor cells. In vivo results indicated that the tumor inhibition rate of dual-loaded nanohybrids was up to 76% under NIR laser irradiation. The immunofluorescence staining of tumor slices demonstrated that the superficial part of tumors experienced exacerbated hypoxia with laser irradiation, resulting in TPZ exerting powerful chemotherapy effects. This nanohybrid is expected to be valuable as spatiotemporally specific therapy for cancer.

Novel semiconducting nano-agents incorporating tirapazamine for imaging guided synergistic cancer hypoxia activated photo-chemotherapy.

For cancer treatment, the traditional monotherapy has the problems of low drug utilization rate, poor efficacy and easy recurrence of the cancer. Herein, nanoparticles (NPs) based on a novel semiconducting molecule (ITTC) are developed with excellent photostability, high photothermal conversion efficiency and good 1O2 generation ability. The chemotherapy of the hypoxia-activated prodrug tirapazamine (TPZ) was improved accordingly after oxygen consumption by the photodynamic therapy of ITTC NPs. Additionally, the metabolic process of ITTC NPs in vivo could be monitored in real time for fluorescence imaging guided phototherapy, which presented great passive targeting ability to the tumor site. Remarkably, both in vitro and in vivo experiments demonstrated that the combination of ITTC NPs and TPZ presented excellent synergistic tumor ablation through photothermal therapy, photodynamic therapy and hypoxia-activated chemotherapy with great potential for clinical applications in the future.

A light and hypoxia-activated nanodrug for cascade photodynamic-chemo cancer therapy.

Combination therapy provides significantly better outcomes than a single drug treatment and becomes an efficient strategy for cancer therapy at present. Owing to the advantages of improved drug bioavailability, decreased side effects, and drug codelivery properties, polymeric carrier-based nanodrugs show great application potential in combination therapy. In this study, a pH-responsive block polymer consisting of polyethylene glycol (mPEG) and poly(asparagyl diisopropylethylenediamine-co-phenylalanine) (P(Asp(DIP)-co-Phe)) is synthesized for drug delivery. The polymer self-assembles into nanovesicles and simultaneously encapsulates the hydrophilic hypoxia-activated prodrug tirapazamine (TPZ) and the hydrophobic photosensitizer dihydrogen porphin (chlorin e6, Ce6). The formed nanodrug can be triggered by near infrared irradiation to induce photodynamic therapy (PDT), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy. The cascade synergistic therapeutic effect is evaluated both in vitro and in vivo in a breast cancer mice model. This study reveals a potential strategy for efficient cancer therapy by using Ce6 and TPZ co-encapsulated nanovesicles.

Engineering of Upconverted Metal-Organic Frameworks for Near-Infrared Light-Triggered Combinational Photodynamic/Chemo-/Immunotherapy against Hypoxic Tumors.

Metal-organic frameworks (MOFs) have shown great potential as nanophotosensitizers (nPSs) for photodynamic therapy (PDT). The use of such MOFs in PDT, however, is limited by the shallow depth of tissue penetration of short-wavelength light and the oxygen-dependent mechanism that renders it inadequate for hypoxic tumors. Here, to combat such limitations, we rationally designed core-shell upconversion nanoparticle@porphyrinic MOFs (UCSs) for combinational therapy against hypoxic tumors. The UCSs were synthesized in high yield through the conditional surface engineering of UCNPs and subsequent seed-mediated growth strategy. The heterostructure allows efficient energy transfer from the UCNP core to the MOF shell, which enables the near-infrared (NIR) light-triggered production of cytotoxic reactive oxygen species. A hypoxia-activated prodrug tirapazamine (TPZ) was encapsulated in nanopores of the MOF shell of the heterostructures to yield the final construct TPZ/UCSs. We demonstrated that TPZ/UCSs represent a promising system for achieving improved cancer treatment in vitro and in vivo via the combination of NIR light-induced PDT and hypoxia-activated chemotherapy. Furthermore, the integration of the nanoplatform with antiprogrammed death-ligand 1 (α-PD-L1) treatment promotes the abscopal effect to completely inhibit the growth of untreated distant tumors by generating specific tumor infiltration of cytotoxic T cells. Collectively, this work highlights a robust nanoplatform for combining NIR light-triggered PDT and hypoxia-activated chemotherapy with immunotherapy to combat the current limitations of tumor treatment.

Multifunctional Theranostic Liposomes Loaded with a Hypoxia-Activated Prodrug for Cascade-Activated Tumor Selective Combination Therapy.

Photodynamic therapy (PDT) is becoming a promising therapeutic regimen but is limited by the hypoxic microenvironment in solid tumors and the undesirable post-treatment phototoxicity side effects on normal tissues. To overcome these restrictions and enhance the antitumor therapeutic effect, near-infrared (NIR) light-activated, cancer cell-specific, hypoxia prodrug-loaded chlorin e6 liposomes were developed for tumor selective combination therapy guided by multimodal imaging. The photothermal agent indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ) were coencapsulated into the liposomes, followed by modification with cRGD and conjugation with GdIII to form ICG/TPZ@Ce6-GdIII theranostic liposomes (ITC-GdIII TLs). In the ITC-GdIII TLs, both the fluorescence and photodynamic effect of Ce6 were quenched by ICG via fluorescence resonance energy transfer. The ITC-GdIII TLs can effectively reach the tumor site through the enhanced permeability and retention effect as well as the cRGD-mediated active targeting ability. The fluorescence and photodynamic effect of Ce6 can be activated by the photothermal effect of ICG under NIR light. Upon subsequent irradiation with a 660 nm laser, the released Ce6 could kill cancer cells by generating cytotoxic singlet oxygen. Furthermore, the PDT process would induce hypoxia, which in turn activated the antitumor activity of the codelivered hypoxia-activated prodrug TPZ for a combination antitumor effect. The TLs could be utilized for multimodal imaging (fluorescence/photoacoustic/magnetic resonance imaging)-guided cascade-activated tumor inhibition with optimized therapeutic efficiency and minimized side effects, holding great potential for constructing intelligent nanotheranostics.

Janus Gold Triangle-Mesoporous Silica Nanoplatforms for Hypoxia-Activated Radio-Chemo-Photothermal Therapy of Liver Cancer.

Radiation dosage constraints and hypoxia-associated resistance lead to the failure of radiotherapy (RT), especially in hypoxic liver cancer. Therefore, the intricate use of combined strategies for potentiating and complementing RT is especially important. In this work, we fabricated multifunctional Janus-structured gold triangle-mesoporous silica nanoparticles (NPs) as multifunctional platforms to deliver the hypoxia-activated prodrug tirapazamine (TPZ) for extrinsic radiosensitization, local photothermal therapy, and hypoxia-specific chemotherapy. The subsequent conjugation of folic acid-linked poly(ethylene glycol) provided the Janus nanoplatforms with liver cancer targeting and minimized opsonization properties. In vitro and in vivo experiments revealed the combined radiosensitive and photothermal antitumor effects of the Janus nanoplatforms. Importantly, the TPZ-loaded Janus nanoplatforms exhibited pH-responsive release behavior, which effectively improved the cellular internalization and therapeutic efficiency in hypoxic rather than normoxic liver cancer cells. Hypoxia-specific chemotherapy supplemented the ineffectiveness of radio-photothermal therapy in hypoxic tumor tissues, resulting in remarkable tumor growth inhibition without systematic toxicity. Therefore, our Janus nanoplatforms integrated radio-chemo-photothermal therapy in a hypoxia-activated manner, providing an efficient and safe strategy for treating liver cancer.