Search

The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia-primarily caused by limited oxygen penetration-has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Many efforts have focused on the cancer stem cell (CSC) targeting nano delivery system, however, the anticancer therapy efficacy is relative low due to the highly drug-resistance and drug efflux. Nucleus-targeted drug delivery is a promising strategy for reverse the drug resistance and drug efflux of CSCs, but in vivo nucleus-targeted drug delivery has been challenging. Herein, we designed a mesoporous silica nanoparticle (MSN)-based nucleus-targeted system, which could directly target the CSCs and further enter the nucleus by the surface modification of anti-CD133 and thermal-triggered exposure of TAT peptides under an alternating magnetic field (AMF). The nucleus-targeted drug release ultimately leads to an exhaustive apoptosis of the CSCs through combined thermotherapy and hypoxia-activated chemotherapy. In vivo, the nucleus-targeted nano delivery system efficiently inhibits the tumor growth without notable side effects during the course of treatment. Molecular mechanism study illustrates that the system effectively eliminates the CSCs by blocking the hypoxia signaling pathway. This designed nucleus-targeted nano delivery system is expected to provide new insights for developing efficient platforms for CSC-targeted cancer therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hypoxia plays vital roles in the development of tumor resistance against typical anticancer therapies and local reoxygenation has proved effective to overcome the hypoxia-induced chemoresistance. Perfluorocarbon (PFC) is an FDA approved oxygen carrier and currently vigorously investigated for oxygen delivery to tumors. This study reports a perfluorocarbon and etoposide (EP) loaded porous hollow Fe 3 O 4 -based theranostic nanoplatform capable of delivering oxygen to solid tumors to enhance their susceptibility against EP. Results show that oxygen could be released at a moderate rate from the porous hollow magnetic Fe 3 O 4 nanoparticles (PHMNPs) over an extended period of time, therefore effectively reducing the hypoxia-induced EP resistance of tumor cells. Moreover, the surface of PHMNPs was modified with lactobionic acid (LA)-containing amphiphilic polymers via hydrophobic interaction, which could provide targeting effect against certain types of tumors. The hydrophilic moiety would be subsequently shed by the intratumoral GSH after cellular internalization and result in the agglomeration of nanocarriers inside tumor cells, consequently impeding the nanoparticle exocytosis to enhance their intracellular retention. The enhanced retention could elevate the intracellular EP level and effectively boost the tumor cell killing effect. In addition to the therapeutic benefits, the Fe 3 O 4 nanocage could also be used for the magnetic resonance imaging of the tumor area. The assorted benefits of the composite nanosystem are anticipated to be advantageous for the treatment of drug-resistant hypoxic tumors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This paper reported on a two-photon excited nanocomposite FCRH to overcome tumor hypoxia for enhanced photodynamic therapy (PDT). Through modified by ruthenium (Ⅱ) complex (Ru(bpy) 3 2+ ) and hyperbranched conjugated copolymer with poly (ethylene glycol) arms (HOP), the water-splitting mediated O 2 generation can be triggered via two-photon irradiation from iron-doped carbon nitride (Fe-C 3 N 4 ) for the first time. While exposured to two-photon laser, Ru(bpy) 3 2+ was activated to generate singlet oxygen ( 1 O 2 ) and Fe-C 3 N 4 was triggered to split water for oxygen supply in the mean time. Owing to the injection of photoinduced electrons from excited Ru(bpy) 3 2+ to Fe-C 3 N 4 , O 2 generation by Fe-C 3 N 4 was significantly accelerated. After accumulation of the nanocomposite by enhanced permeability and retention (EPR) effect, FCRH was demonstrated to alleviate the tumorous hypoxia and consequently enhance the antitumor efficacy of PDT. Furthermore, tumor metabolism evaluations explained the capability of the nanocomposite in reducing intratumoral hypoxia. Our results provide a new diagram for ameliorating the hypoxic tumor microenvironment and accelerating 1 O 2 generation under two-photon excitation, which will find great potential for spatiotemporally controlled tumor treatment in vivo., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors. Our strategy utilizing COX-2 inhibition augmented the anti-angiogenetic induced hypoxia responsive prodrug activation well. Both in vitro and in vivo results proved that DA and TA exhibited specificity towards COX-2 positive (+ve) HeLa and A549 cancer cell lines and activation under hypoxic conditions. Compared with controls (R1, and anticancer drug SN-38), TA displayed prolonged tumor retention and enhanced therapeutic efficacy in xenograft mouse models at a reduced dosage. Our results significantly highlighted the importance of COX-2 blockade mediated anti-angiogenesis in complementing the hypoxia-responsive drug delivery systems (DDSs) and could to beneficial for the rapid development of more efficacious antitumor therapeutics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This study reports a tumor-specific ROS-responsive nanoplatform capable of the combination of nitric oxide (NO)-based gas therapy and sensitized photodynamic therapy (PDT). The nanoplatform is constructed on porous coordination network (PCN), which contains NO donor L-Arg and is concurrently coated with cancer cell membrane (L-Arg@PCN@Mem). Under near infrared light (NIR) irradiation, L-Arg@PCN@Mem produces plenty of reactive oxygen species (ROS) directly for PDT therapy, while a part of ROS take the role of oxidative to converse L-Arg into NO for combined gas therapy. The results indicate that the transformation of ROS to NO can enhance PDT efficacy in hypoxic tumors owing to the ability of NO in freely diffusing into deep hypoxic tumor site. Moreover, homologous targeting function originated from the coating of cancer cells membrane further improves the tumor treatment effect owing to the biotargeting toward homologous tumors. This L-Arg@PCN@Mem nanoplatform provides a new therapy paradigm of overcoming the hypoxia barrier of tumor therapy, and holds great potential for the treatment of tumor and NO-related diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hypoxia tumor microenvironment is a major challenge for photodynamical therapy (PDT), and hypoxia-activated chemotherapy combined PDT could be promising for enhanced anticancer therapy. In this study, we report an innovative 2-nitroimidazole derivative conjugated polyethylene glycol (PEG) amphoteric polymer theranostic liposome encapsulated a photosensitizer Chlorin e6 (Ce6), hypoxia-activated prodrug Tirapazamine (TPZ) and gene probe for synergistic photodynamic-chemotherapy. Ce6-mediated PDT upon irradiation with a laser induces hypoxia, which leads to the disassembly of the liposome and activates the antitumor activity of TPZ for improved cancer cell-killing. The released co-delivered gene probe could effectively detect the oncogenic intracellular biomarker for diagnosis. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional PDT. This work contributes to the design of hypoxia-responsive multifunctional liposome for tumor diagnosis and hypoxia-activated chemotherapy combined PDT for synergetic therapy, which holds great promise for future cancer therapy., (Copyright © 2018. Published by Elsevier Ltd.)

Chemotherapy has become a critical treatment for many cancer types. However, its efficacy is hindered by chemoresistance and limited drug accumulation induced by the hypoxic tumor environment. Therefore, there is an urgent need for useful strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we report the development of a multifunctional liposome simultaneously loading an oxygen carrier (hemoglobin, Hb) and an anti-tumor drug (doxorubicin, DOX) to enhance chemotherapeutic effects against hypoxic tumors. The liposomes, DOX-Hb-lipo (DHL), showed efficient loading of oxygen and site-specific oxygen delivery into tumors, inducing the reversal of tumor hypoxia. Furthermore, the O 2 interference capacity increased the uptake of the drug into hypoxic cancer cells, inducing a remarkably increased toxicity of the drug against cancer cells. Interestingly, the obtained DHL showed a significantly enhanced internalization into cancer cells and accumulation in tumors compared to DL (DOX loaded liposomes without Hb), while the enhanced effect did not occur in normal cells. The specific delivery of DHL into cancer cells should be attributed to the mediation of Hb on the surface of the liposomes. In addition, DHL considerably increased reactive oxygen species (ROS) production in a hypoxic environment and promoted the ROS-mediated cytotoxicity of DOX. Based on the elevated drug accumulation in the tumor sites, increased internalization into cancer cells and enhanced oxygen levels in tumor regions, DHL reversed hypoxia-induced chemoresistance and exhibited stronger antitumor effects. Thus, DHL might be a promising alternative strategy for cancer treatment., (Copyright © 2018. Published by Elsevier Ltd.)

Improving the supply of O 2 and the circulation lifetime of photosensitizers for photodynamic therapy (PDT) in vivo would be a promising approach to eliminate hypoxic tumors. Herein, by taking advantage of the significant gas-adsorption capability of metal-organic frameworks (MOFs), a biomimetic O 2 -evolving photodynamic therapy (PDT) nanoplatform with long circulating properties was fabricated. Zirconium (IV)-based MOF (UiO-66) was used as a vehicle for O 2 storing, then conjugated with indocyanine green (ICG) by coordination reaction, and further coated with red blood cell (RBC) membranes. Upon 808 nm laser irradiation, the initial singlet oxygen ( 1 O 2 ) generated by ICG would decompose RBC membranes. At the same time, The photothermal property of ICG could facilitate the burst release of O 2 from UiO-66. Subsequently, the generated O 2 could significantly improve the PDT effects on hypoxic tumor. Owing to the advantages of long circulation and O 2 self-sufficient, the designed nanotherapeutic agent can improve the efficiency of treatment against hypoxia tumor via PDT. Hence, this study presents a new paradigm for co-delivery of O 2 and photosensitizers, and provides a new avenue to eliminate hypoxic tumors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A combinatorial therapy that utilizes two or more therapeutic modalities is more effective in overcoming the limitations than each individual method used alone. Despite great advances have been achieved, the combination of chemotherapy and photodynamic therapy (PDT) still cannot satisfy the clinic requirements as the antitumor efficacy could be severely affected by tumor-associated hypoxia. Herein, for the first time, we reported a platinum(IV) complex-based polyprodrug that can in situ generate the highly toxic platinum(II) species as chemotherapeutics and simultaneously induce a high level of reactive oxygen species (ROS) in a PDT-like process without the use of photosensitizer and consumption of oxygen. By in situ polymerizing the platinum(IV) complex-based prodrug monomer (PPM) and 2-methacryloyloxy ethyl phosphorylcholine (MPC), nanosized hydrogel-like polyprodrug could be synthesized. Upon being exposed to light, Pt(IV) moieties in this photoactivable polyprodrug were reduced to generate Pt(II) species. At the meantime, a high level of ROS was generated without the presence of endogenous oxygen, which was confirmed by electron spin resonance (ESR) and fluorescence probes. With the unique nanosized architecture and photoresponsive feature, the as-synthesized polyprodrug exhibited the advantages of sustained drug release, long-term circulation, preferable tumor accumulation, and reversing drug resistance by downregulating the expression of multidrug resistance-associated protein 1 (MRP1) in the anticancer treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Treating the hypoxic region of the tumor remains a significant challenge. The goals of this study are to develop an exosome platform that can target regions of tumor hypoxia and that can be monitored in vivo using magnetic particle imaging (MPI). Four types of exosomes (generated under hypoxic or normoxic conditions, and with or without exposure to X-ray radiation) were isolated from MDA-MB-231 human breast cancer cells. Exosomes were labeled by DiO, a fluorescent lipophilic tracer, to quantify their uptake by hypoxic cancer cells. Subsequently, the exosomes were modified to carry SPIO (superparamagnetic iron oxide) nanoparticles and Olaparib (PARP inhibitor). FACS and fluorescence microscopy showed that hypoxic cells preferentially take up exosomes released by hypoxic cells, compared with other exosome formulations. In addition, the distribution of SPIO-labeled exosomes was successively imaged in vivo using MPI. Finally, the therapeutic efficacy of Olaparib-loaded exosomes was demonstrated by increased apoptosis and slower tumor growth in vivo. Our novel theranostic platform could be used as an effective strategy to monitor exosomes in vivo and deliver therapeutics to hypoxic tumors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Nonspecific distribution of photosensitizer and the intrinsic hypoxic condition in the tumor microenvironment are two key factors limiting the efficacy of O 2 -dependent photodynamic therapy (PDT). Herein, a dual-triggered oxygen self-supported nanosystem using black phosphorus nanosheet (BPNS) as both photosensitizer and nanocarrier was developed to enhance PDT for tumors within hypoxic microenvironment. The BPNS platform was functionalized with folate and a blocker DNA duplex of 5'-Cy5-aptamer-heme/3'-heme labeled oligonucleotides. The resulting heme dimer could passivate its peroxidase activity. After specific recognition of aptamer-target, the quenched fluorescence is "turned" on by cellular adenosine triphosphate. The passivated nanosystem then activates the catalytic function towards excessive intracellular H 2 O 2 to generate O 2 essential to sustain BPNS-mediated PDT, leading to 8.7-fold and 7.5-fold increase of PDT efficacy in treating the hypoxic cell and tumor, respectively. Therefore, the dual-triggered oxygen self-supply nanosystem not only exerts tumor microenvironment-associated stimulus for enhanced PDT but also surmounts hypoxia-associated therapy resistance., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aiming at improved therapeutic efficacies, the combination of chemotherapy and radiotherapy (chemo-radiotherapy) has been widely studied and applied in clinic. However, the hostile characteristics of tumor microenvironment such as hypoxia often limit the efficacies in both types of cancer therapies. Herein, catalase (CAT), an antioxidant enzyme, is encapsulated inside liposomes constituted by cisplatin (IV)-prodrug-conjugated phospholipid, forming CAT@Pt (IV)-liposome for enhanced chemo-radiotherapy of cancer. After being loaded inside liposomes, CAT within CAT@Pt (IV)-liposome shows retained and well-protected enzyme activity, and is able to trigger decomposition of H 2 O 2 produced by tumor cells, so as to produce additional oxygen for hypoxia relief. As the result, treatment of CAT@Pt (IV)-liposome induces the highest level of DNA damage in cancer cells after X-ray radiation compared to the control groups. In vivo tumor treatment further demonstrates a remarkably improved therapeutic outcome in chemo-radiotherapy with such CAT@Pt (IV)-liposome nanoparticles. Hence, an exquisite type of liposome-based nanoparticles is developed in this work by integrating cisplatin-based chemotherapy and catalase-induced tumor hypoxia relief together for combined chemo-radiotherapy with great synergistic efficacy, promising for clinical translation in cancer treatment., (Copyright © 2017. Published by Elsevier Ltd.)

Pre-existing hypoxia in tumors can result in an inadequate oxygen supply during photodynamic therapy (PDT), which in turn hampers photodynamic efficacy. To overcome this problem, we developed an orthogonal near-infrared upconversion controlled red blood cell (RBC) microcarriers to selectively deliver O 2 in hypoxia area. Moreover, this RBC microcarriers are able to overcome a series of complex biological barriers which include transporting across the inflamed endothelium, evading mononuclear phagocyte system, reducing reticuloendothelial system uptake. Based on these abilities, RBC microcarriers have efficient tumors accumulation and are capable of delivery a large amount of O 2 for PDT under near-infrared (NIR) irradiation to realize effective solid tumor eradication., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An azobenzene scaffold serves as both a fluorescence quencher and nitrogen mustard deactivator in a mitochondrial targeting unit bearing theranostic drug delivery system (DDS). The DDS exhibited a tissue selectivity for tumors with aggressive phenotypes, and the efficient in vitro and in vivo azoreduction under hypoxia conditions resulted in bright fluorescence at the tumor site as well as the in situ activation of the prodrug. In vivo therapeutic experiments demonstrated a significant reduction in tumor growth versus number of controls and ex vivo tissue analysis confirmed tissue normalization with strongly reduced angiogenic markers and suppressed cell proliferation. Mechanistic insight of the DDS's mode of action was gained by gene and protein expression experiments, aided by a proteomic analysis, revealing the circumvention of cellular drug resistance pathways as well as the normalization of Slit-Robo signaling, and the involvement of granzyme-triggered mitochondria-mediated apoptosis. Overall, the combined high sensitivity and synthetic ease as well as excellent therapeutic response suggests a revival of the azobenzene class of hypoxia activated drugs, especially applied to theranostics, is warranted., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cancer radiotherapy (RT) is a clinically used tumor treatment strategy applicable for a wide range of solid tumors. However, during RT treatment of tumors, only a small portion of applied ionizing irradiation energy is absorbed by the tumor, in which the largely hypoxic microenvironment also limits the anti-tumor efficacy of RT. In this work, we rationally fabricate polyethylene glycol (PEG) stabilized perfluorocarbon (PFC) nano-droplets decorated with TaOx nanoparticles (TaOx@PFC-PEG) as a multifunctional RT sensitizer. The obtained TaOx@PFC-PEG nanoparticles on one hand can absorb X-ray by TaOx to concentrate radiation energy within tumor cells, on the other hand after saturating PFC with oxygen will act as an oxygen reservoir to gradually release oxygen and improve tumor oxygenation. As the result, remarkably enhanced in vivo RT treatment is achieved with TaOx@PFC-PEG nanoparticles in our mouse tumor model experiments. Our work thus presents a new nanotechnology strategy to enhance RT-induced tumor treatment by simultaneously concentrating radiation energy within tumors and improving tumor oxygenation, using one multifunctional agent., (Copyright © 2016 Elsevier Ltd. All rights reserved.)