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Journal of Colloid and Interface Science Jan 2023The hypoxic tumor microenvironment and photodynamic therapy (PDT)-aggravated hypoxia compromise the anticancer efficacy of chemotherapy, immunotherapy, and PDT. Thus,...
The hypoxic tumor microenvironment and photodynamic therapy (PDT)-aggravated hypoxia compromise the anticancer efficacy of chemotherapy, immunotherapy, and PDT. Thus, sophisticated nanomedicines that can activate their anticancer capability in situ in response to specific stimuli need to be developed. This study aimed to construct a hybrid nanomedicine that activated chemotherapy by inducing hypoxia, which synergized with PDT to promote antitumor outcomes, contrary to the strategies focusing on reversing tumor hypoxia. The hybridization of a porphyrin metal-organic framework (MOF) and gold nanoparticles (AuNPs) enhanced the stability of the hybrid nanomedicine against the phosphate in blood, thereby preventing the premature drug release during blood circulation. The surface modification with polyethylene glycol (PEG) markedly increased the tumor accumulation of the hybrid MOF nanomedicine, which encapsulated a hypoxia-activated prodrug (tirapazamine, TPZ), by enhancing its colloidal stability and pharmacokinetics. The loaded TPZ was rapidly released from the nanomedicine in response to the concentrated intracellular phosphate after cellular uptake, and was then converted into a potent anticancer drug in a hypoxic microenvironment exacerbated by continuous O consumption during PDT. In vitro and in vivo experiments demonstrated that the synergistic PDT and hypoxia-activated chemotherapy exhibited enhanced antitumor therapeutic efficiency and superior antimetastatic effect, and effectively ablated the tumor without recurrence. Therefore, the sophisticated nanomedicine reported here, which eliminated cancer cells by inducing a hypoxic tumor microenvironment, showed translational potential in future therapeutic development.
Topics: Humans; Photosensitizing Agents; Nanomedicine; Metal-Organic Frameworks; Gold; Photochemotherapy; Metal Nanoparticles; Neoplasms; Hypoxia; Phosphates; Cell Line, Tumor; Nanoparticles; Tumor Microenvironment
PubMed: 36162395
DOI: 10.1016/j.jcis.2022.09.061 -
Scientific Reports Feb 2021Tumor tissue contains a continuous distribution of static and dynamically changing oxygen environments with levels ranging from physiologically normal oxygen down to...
Tumor tissue contains a continuous distribution of static and dynamically changing oxygen environments with levels ranging from physiologically normal oxygen down to anoxia. However, in vitro studies are often performed under oxygen levels that are far higher than those found in vivo. A number of devices are available to alter the oxygen environment in cell culture, including designs from our laboratory. However, in our devices and most other designs, changing the media in order to feed or dose cells remains a disruptive factor in maintaining a consistent hypoxic environment. This report presents a novel 96-well plate design that recirculates the local oxygen environment to shield cells during media changes and facilitates toxicity studies of cells cultured under varying oxygen levels. The principle behind the design is presented and the response of human pancreatic cancer PANC-1 cells treated with tirapazamine and doxorubicin under eight different static or cycling oxygen levels was measured. As expected, tirapazamine is progressively more toxic as oxygen levels decrease but retains some toxicity as oxygen is cycled between hypoxic and normoxic levels. Doxorubicin sensitivity is largely unaffected by changing oxygen levels. This technology is ideal for assessing the effects of oxygen as a variable in toxicity screens.
Topics: Cell Culture Techniques; Cell Hypoxia; Cell Line, Tumor; Doxorubicin; High-Throughput Screening Assays; Humans; Neoplasms; Oxygen; Pancreatic Neoplasms; Tirapazamine; Toxicity Tests; Triazines; Tumor Microenvironment
PubMed: 33597640
DOI: 10.1038/s41598-021-83579-1 -
Small (Weinheim An Der Bergstrasse,... Aug 2021Tumor vasculature has long been considered as an extremely valuable therapeutic target for cancer therapy, but how to realize controlled and site-specific drug release...
Tumor vasculature has long been considered as an extremely valuable therapeutic target for cancer therapy, but how to realize controlled and site-specific drug release in tumor blood vessels remains a huge challenge. Despite the widespread use of nanomaterials in constructing drug delivery systems, they are suboptimal in principle for meeting this demand due to their easy blood cell adsorption/internalization and short lifetime in the systemic circulation. Here, natural red blood cells (RBCs) are repurposed as a remote-controllable drug vehicle, which retains RBC's morphology and vessel-specific biodistribution pattern, by installing photoactivatable molecular triggers on the RBC membrane via covalent conjugation with a finely tuned modification density. The molecular triggers can burst the RBC vehicle under short and mild laser irradiation, leading to a complete and site-specific release of its payloads. This cell-based vehicle is generalized by loading different therapeutic agents including macromolecular thrombin, a blood clotting-inducing enzyme, and a small-molecule hypoxia-activatable chemodrug, tirapazamine. In vivo results demonstrate that the repurposed "anticancer RBCs" exhibit long-term stability in systemic circulation but, when tumors receive laser irradiation, precisely releases their cargoes in tumor vessels for thrombosis-induced starvation therapy and local deoxygenation-enhanced chemotherapy. This study proposes a general strategy for blood vessel-specific drug delivery.
Topics: Blood Vessels; Drug Liberation; Drug Repositioning; Erythrocytes; Tissue Distribution
PubMed: 34259382
DOI: 10.1002/smll.202100753 -
Pharmaceutics Jan 2022Oxygen dependence and anabatic hypoxia are the major factors responsible for the poor outcome of photodynamic therapy (PDT) against cancer. Combining of PDT and...
Oxygen dependence and anabatic hypoxia are the major factors responsible for the poor outcome of photodynamic therapy (PDT) against cancer. Combining of PDT and hypoxia-activatable bioreductive therapy has achieved remarkably improved antitumor efficacy compared to single PDT modality. However, controllable release and activation of prodrug and safety profiles of nanocarrier are still challenging in the combined PDT/hypoxia-triggered bioreductive therapy. Herein, we developed a near infrared (NIR) light-decomposable nanomicelle, consisting of PEGylated cypate (pCy) and mPEG-polylactic acid (mPEG-PLA) for controllable delivery of hypoxia-activated bioreductive prodrug (tirapazamine, TPZ) (designated TPZ@pCy), for combating metastatic breast cancer via hypoxia-enhanced phototherapies. TPZ@pCy was prepared by facile nanoprecipitation method, with good colloidal stability, excellent photodynamic and photothermal potency, favorable light-decomposability and subsequent release and activation of TPZ under irradiation. In vitro experiments demonstrated that TPZ@pCy could be quickly internalized by breast cancer cells, leading to remarkable synergistic tumor cell-killing potential. Additionally, metastatic breast tumor-xenografted mice with systematic administration of TPZ@pCy showed notable tumor accumulation, promoting tumor ablation and lung metastasis inhibition with negligible toxicity upon NIR light illumination. Collectively, our study demonstrates that this versatile light-decomposable polymeric micelle with simultaneous delivery of photosensitizer and bioreductive agent could inhibit tumor growth as well as lung metastasis, representing a promising strategy for potent hypoxia-enhanced phototherapies for combating metastatic breast cancer.
PubMed: 35213986
DOI: 10.3390/pharmaceutics14020253 -
ACS Applied Materials & Interfaces Sep 2019Radiation dosage constraints and hypoxia-associated resistance lead to the failure of radiotherapy (RT), especially in hypoxic liver cancer. Therefore, the intricate use...
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.
Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Chemoradiotherapy; Drug Delivery Systems; Gold; Humans; Hyperthermia, Induced; Liver Neoplasms, Experimental; Mice; Mice, Nude; Nanoparticles; Phototherapy; Porosity; Prodrugs; Silicon Dioxide; Tirapazamine; Xenograft Model Antitumor Assays
PubMed: 31474108
DOI: 10.1021/acsami.9b12879 -
Biomicrofluidics Sep 2019In anticancer drug development, it is important to simultaneously evaluate both the effect of drugs on cell proliferation and their ability to penetrate tissues. To...
In anticancer drug development, it is important to simultaneously evaluate both the effect of drugs on cell proliferation and their ability to penetrate tissues. To realize such an evaluation process, here, we present a compartmentalized tumor spheroid culture system utilizing a thin membrane with a through-hole to conduct localized anticancer treatment of tumor spheroids and monitor spheroid dimensions as an indicator of cell proliferation. The system is based on a commercialized Boyden chamber plate; a through-hole was bored through a porous membrane of the chamber, and the pre-existing 0.4 m membrane pores were filled with parylene C. A HepG2 spheroid was immobilized onto the through-hole, separating the upper and lower compartments. Fluorescein (to verify the isolation between the compartments) and tirapazamine (TPZ; to treat only the lower part of the spheroid) were added to the upper and lower compartments, respectively. Since the transportation of fluorescein was blocked during treatment, i.e., the upper and lower compartments were isolated, it was confirmed that localized TPZ treatment was successfully conducted using the developed system. The effect of localized TPZ treatment on cell proliferation was estimated by measuring the maximum horizontal cross-sectional areas in the upper and lower parts of the spheroid by microscopic observations. This system can, thus, be used to perform localized anticancer drug treatment of tumor spheroids and evaluate the effect of drugs on cell proliferation.
PubMed: 31893010
DOI: 10.1063/1.5125650 -
Journal of Nanobiotechnology Nov 2022Carbon monoxide (CO) is an important signaling molecule participating in multiple biological functions. Previous studies have confirmed the valuable roles of CO in...
BACKGROUND
Carbon monoxide (CO) is an important signaling molecule participating in multiple biological functions. Previous studies have confirmed the valuable roles of CO in cancer therapies. If the CO concentration and distribution can be controlled in tumors, new cancer therapeutic strategy may be developed to benefit the patient survival.
RESULTS
In this study, a UiO-67 type metal-organic framework (MOF) nanoplatform was produced with cobalt and ruthenium ions incorporated into its structure (Co/Ru-UiO-67). Co/Ru-UiO-67 had a size range of 70-90 nm and maintained the porous structure, with cobalt and ruthenium distributed uniformly inside. Co/Ru-UiO-67 was able to catalyze carbon dioxide into CO upon light irradiation in an efficient manner with a catalysis speed of 5.6 nmol/min per 1 mg Co/Ru-UiO-67. Due to abnormal metabolic properties of tumor cells, tumor microenvironment usually contains abundant amount of CO. Co/Ru-UiO-67 can transform tumor CO into CO at both cellular level and living tissues, which consequently interacts with relevant signaling pathways (e.g. Notch-1, MMPs etc.) to adjust tumor microenvironment. With proper PEGylation (pyrene-polyacrylic acid-polyethylene glycol, Py-PAA-PEG) and attachment of a tumor-homing peptide (F3), functionalized Co/Ru-UiO-67 could accumulate strongly in triple-negative MDA-MB-231 breast tumors, witnessed by positron emission tomography (PET) imaging after the addition of radioactive zirconium-89 (Zr) into Co-UiO-67. When applied in vivo, Co/Ru-UiO-67 could alter the local hypoxic condition of MDA-MB-231 tumors, and work synergistically with tirapazamine (TPZ).
CONCLUSION
This nanoscale UiO-67 MOF platform can further our understanding of CO functions while produce CO in a controllable manner during cancer therapeutic administration.
Topics: Humans; Metal-Organic Frameworks; Carbon Monoxide; Ruthenium; Triple Negative Breast Neoplasms; Carbon Dioxide; Cobalt; Tumor Microenvironment
PubMed: 36424645
DOI: 10.1186/s12951-022-01704-2 -
Biomacromolecules Jul 2019Stimuli-responsive drug delivery has rendered promising utilities in cancer treatment. Nevertheless, cancer selectivity as well as sensitivity still remains critical...
Stimuli-responsive drug delivery has rendered promising utilities in cancer treatment. Nevertheless, cancer selectivity as well as sensitivity still remains critical challenges that would undermine the therapeutic efficacy of chemodrugs and cause undesired systemic toxicity. Herein, a dual hypoxia-responsive drug delivery system was developed to enable photodynamic therapy (PDT)-induced drug release and drug activation intermediated via PDT-induced hypoxia. Particularly, tumor-targeting and hypoxia-dissociable nanoparticles (NPs) were self-assembled from the amphiphilic polyethylenimine-alkyl nitroimidazole [PEI-ANI, (PA)] and hyaluronic acid-chlorin e6 (HA-Ce6) to encapsulate bioreductive chemodrug, tirapazamine (TPZ). After systemic administration, the obtained PA/HA-Ce6@TPZ NPs enabled effective tumor accumulation due to HA-mediated cancer targeting. Upon receptor-mediated endocytosis, light irradiation (660 nm, 10 mW/cm) produced high levels of reactive oxygen species to mediate PDT and generated a severe local hypoxic environment to dissociate the NPs and selectively release TPZ, as a consequence of hypoxia-triggered hydrophobic-to-hydrophilic transformation of ANI. In the meantime, TPZ was activated under hypoxia, finally contributing to a synergistic anticancer treatment between PDT and hypoxia-strengthened bioreductive chemotherapy. This study, therefore, demonstrates a suitable strategy for cancer-selective drug delivery as well as programmed combination therapy.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Drug Delivery Systems; Female; Mice; Mice, Inbred BALB C; Nanomedicine; Nanoparticles; Neoplasms, Experimental; Photochemotherapy; Photosensitizing Agents; Tirapazamine
PubMed: 31125209
DOI: 10.1021/acs.biomac.9b00428 -
International Journal of Nanomedicine 2024Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O consumption...
PURPOSE
Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O consumption during PDT would diminish its therapeutic effect. Herein, we developed a strategy using the combination of PDT and hypoxia-activated bioreductive drug tirapazamine (TPZ).
METHODS
TPZ was linked to DSPE-PEG-NHS forming DSPE-PEG-TPZ to solve leakage of water-soluble TPZ and serve as an antitumor agent and monomer molecule further forming the micellar. Chlorin e6 (Ce6) was loaded in DSPE-PEG-TPZ forming DSPE-PEG-TPZ@Ce6 (DPTC). To further improve tumor infiltration and accumulation, hyaluronic acid was adopted to make DPTC-containing microneedles (DPTC-MNs).
RESULTS
Both in vitro and in vivo studies consistently demonstrated the synergistic antitumor effect of photodynamic therapy and TPZ achieved by DPTC-MNs. With laser irradiation, overexpressions of PDT tolerance factors NQO1 and HIF-1α were inhibited by this PDT process.
CONCLUSION
The synergistic effect of PDT and TPZ significantly improved the performance of DPTC-MNs in the treatment of melanoma and cutaneous squamous cell carcinoma and has good biocompatibility.
Topics: Humans; Photochemotherapy; Carcinoma, Squamous Cell; Skin Neoplasms; Tirapazamine; Hypoxia; Cell Line, Tumor; Photosensitizing Agents; Nanoparticles; Tumor Microenvironment; Organometallic Compounds; Phenanthrolines
PubMed: 38482522
DOI: 10.2147/IJN.S443835 -
Journal of Hepatocellular Carcinoma 2021Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of... (Clinical Trial)
Clinical Trial
BACKGROUND
Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of combining TPZ and TAE in patients with unresectable HCC and determine the optimal dose for Phase II.
METHODS
This was a Phase 1 multicenter, open-label, non-randomized trial with a classic 3+3 dose escalation and an expansion cohort in patients with unresectable HCC, Child Pugh A, ECOG 0 or 1. Two initial cohorts consisted of I.V. administration of Tirapazamine followed by superselective TAE while the remaining three cohorts underwent intraarterial administration of Tirapazamine with superselective TAE. Safety and tolerability were assessed using NCI CTCAE 4.0 with clinical, imaging and laboratory examinations including pharmacokinetic (PK) analysis and an electrocardiogram 1 day pre-dose, at 1, 2, 4, 6, 10, and 24 hours post-TPZ infusion and an additional PK at 15- and 30-minutes post-TPZ. Tumor responses were evaluated using mRECIST criteria.
RESULTS
Twenty-seven patients (mean [range] age of 66.4 [37-79] years) with unresectable HCC were enrolled between July 2015 and January 2018. Two patients were lost to follow-up. Mean tumor size was 6.53 cm ± 2.60 cm with a median of two lesions per patient. Dose limiting toxicity and maximum tolerated dose were not reached. The maximal TPZ dose was 10 mg/m I.V. and 20 mg/m I.A. One adverse event (AE) was reported in all patients with fatigue, decreased appetite or pain being most common. Grade 3-5 AE were hypertension and transient elevation of AST/ALT in 70.4% of patients. No serious AE were drug related. Sixty percent (95% CI=38.7-78.9) achieved complete response (CR), and 84% (95% CI=63.9-95.5) had complete and partial response per mRECIST for target lesions.
DISCUSSION
TAE with TPZ was safe and tolerable with encouraging results justifying pursuit of a Phase II trial.
PubMed: 34041204
DOI: 10.2147/JHC.S304275