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1.
    
Photodynamic therapy (PDT) has been applied in cancer treatment by converting O2 into reactive singlet oxygen (1O2) to kill cancer cells. However, the effectiveness of PDT is limited by the fact that tumor hypoxia causes an inadequate O2 supply, and the overexpressed glutathione (GSH) in cancer cells consumes reactive oxygen species. Herein, a multifunctional hybrid system is developed for selective and highly efficient PDT as well as gene‐silencing therapy using a novel GSH‐activatable and O2/Mn2+‐evolving nanocomposite (GAOME NC). This system consists of honeycomb MnO2 (hMnO2) nanocarrier loaded with catalase, Ce6, and DNAzyme with folate label, which can specifically deliver payloads into cancer cells. Once endocytosed, hMnO2 carriers are reduced by the overexpressed GSH to Mn2+ ions, resulting in the reduction of GSH level and disintegration of GAOME NC. The released catalases then trigger the breakdown of endogenous H2O2 to generate O2, which is converted by the excited Ce6 into 1O2. The self‐sufficiency of O2 and consumption of GSH effectively enhance the PDT efficacy. Moreover, DNAzyme is freed for gene silencing in the presence of self‐generated Mn2+ ions as cofactors. The rational synergy of enhanced PDT and gene‐silencing therapy remarkably improve the in vitro and in vivo therapeutic efficacy of cancers.  相似文献   

2.
    
The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO2) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO2) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO2 shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO2 degrades rapidly within the TME, releasing Mn2+ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO2 shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H2O2 and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.  相似文献   

3.
    
Photosensitizers (PSs) are light‐sensitive molecules that are highly hydrophobic, which poses a challenge to their use for targeted photodynamic therapy. Hence, considerable efforts have been made to develop carriers for the delivery of PSs. Herein, a novel design is described of highly biocompatible, fluorescent, folic acid (FA)‐functionalized carbon nanodots (CDs) as carriers for the PS zinc phthalocyanine (ZnPc) to achieve simultaneous biological imaging and targeted photodynamic therapy. FA is modified on PEG‐­passivated CDs (CD‐PEG) for targeted delivery to FA‐positive cancer cells, and ZnPc is loaded onto CD‐PEG‐FA via π–π stacking interactions. CD‐PEG‐FA/ZnPc exhibits excellent targeted delivery of the PS, leading to simultaneous imaging and significant targeted photodynamic therapy after irradiation in vitro and in vivo. The present CD‐based targeted delivery of PSs is anticipated to offer a convenient and effective platform for enhanced photodynamic therapy to treat cancers in the near future.  相似文献   

4.
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5.
    
Most anticancer drugs with broad toxicities are systematically administrated to cancer patients and their distribution in tumors is extremely low owing to hypoxia, which compromises the therapeutic efficacies of these cancer drugs. Consequently, a preponderant proportion of cancer drugs is distributed in off-target-healthy tissues, which often causes severe adverse effects. Precision cancer therapy without overdosing patients with drugs remains one of the most challenging issues in cancer therapy. Here, a novel concept of nanopoxia is presented, which is a tumor-hypoxia-based photodynamic nanoplatform for the release of therapeutic agents to achieve precision cancer therapy. Under tumor hypoxia, exposure of tumors to laser irradiation induces the fracture of polymer outer shell and produces anticancer reactive oxygen species, and switches 2D antimonene (Sb) nanomaterials to cytotoxic trivalent antimony to synergistically kill tumors. In preclinical cancer models, delivery of Sb nanomaterials to mice virtually ablates tumor growth without producing any detectable adverse effects. Mechanistically, the tumor hypoxia-triggered generation of trivalent antimony displays direct damaging effects on cancer cells and suppression of tumor angiogenesis. Together, the study provides a proof-of-concept of hypoxia-based precision cancer therapy by developing a novel nanoplatform that offers multifarious mechanisms of cancer eradication.  相似文献   

6.
    
Myeloid‐derived suppressor cells (MDSCs) are garnering increasing attention given their role in tumor development. Herein, a nano‐enabled strategy is demonstrated for the eradication of tumor‐infiltrated MDSCs by reversing hypoxia. Oxygen‐independent photodynamic bismuth tungstate nanoparticles (Bi2WO6 NPs) are loaded into reactive oxygen species (ROS) responsive platelet membranes (PMs) to form a hybrid (PM‐BiW NPs). P‐Selectin on PMs endows PM‐BiW NPs with selectivity toward cancer cells. Once in the tumor, laser illumination stimulates the Bi2WO6 NPs photothermally and photodynamically, which produces enormous quantities of hydroxyl radicals. These hydroxyl radicals help rupture the PM and mitigate hypoxia with the assistance of ionizing radiation. This effectively remodels the tumor microenvironment toward one disfavoring the recruitment of MDSCs and contributes to better prognosis. To better understand the mechanism, the expression levels of a set of markers are monitored. It is found that the downregulations of hypoxia‐inducible factor‐1α, ectonucleoside triphosphate diphosphohydrolase 2, and adenosine‐5‐phosphoricacid are behind the blocked infiltration of MDSCs. This platform strategy offers a promising approach to overcome the immunosuppression caused by MDSCs through a trimodal therapy integrating the power of photothermal and photodynamic therapy in addition to radiation therapy.  相似文献   

7.
    
Hypoxia, as characterized by the low local oxygen, confers on cancer cells resistance to oxygen‐consuming photodynamic therapy (PDT). The limited success reached by current approaches harnessing reoxygenation to enhance PDT outcome promotes the reconsideration of the design of the therapeutic approach. In this study, a multistage delivery system capable of reversing hypoxia is demonstrated. Unlike previous strategies that only expect to affect the peripheral tumor tissue, the size‐shrinkable system allows those deeply located hypoxia regions to be treated. Specifically, therapeutics, including atovaquone and indocyanine green derivatives that are respectively responsible for oxidative phosphorylation blockage and PDT, are encapsulated in a gelatin nanoparticle, whose structure would rupture to promote deep penetration when facing matrix metallopeptidase 2 enzyme overexpression in tumor tissue. The antihypoxic performance of the platform has been evaluated using a variety of analyses including flow‐cytometry assay, immunofluorescence, and micro‐positron‐emission tomography imaging. Tumor regression in animal models confirms the feasibility and effectiveness of conquering the PDT‐resistance through abrogating the oxygen consumption. It is hopeful that such a strategy could shed light on the development of next‐generation PDT‐adjuvant treatment.  相似文献   

8.
    
Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO2) nanoparticles toward endogenous hydrogen peroxide (H2O2) within the tumor microenvironment to generate O2, multifunctional chlorine e6 (Ce6) loaded MnO2 nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO2‐PEG) are formulated to achieve enhanced tumor‐specific PDT. In vitro studies under an oxygen‐deficient atmosphere uncover that Ce6@MnO2‐PEG nanoparticles could effectively enhance the efficacy of light‐induced PDT due to the increased intracellular O2 level benefited from the reaction between MnO2 and H2O2, the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO2‐PEG nanoparticles upon intravenous injection as revealed by T1‐weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO2‐PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.  相似文献   

9.
    
Tumors have adapted various cellular antidotes and microenvironmental conditions to subsist against photodynamic therapy (PDT) and chemodynamic therapy (CDT). Here, the development of reactive oxygen species (ROS)‐activatable liposomes (RALP) for therapeutic enhancement by simultaneously addressing the critical questions in PDT and CDT is reported. The design of RALP@HOC@Fe3O4 features ROS‐cleavable linker molecules for improved tumor penetration/uptake and ondemand cargo releasing, and integration of Fe3O4 and an oxaliplatin prodrug for smart regulation of hypoxia tumor microenvironment. Glutathione stored by the tumor cells is consumed by the prodrug to produce highly toxic oxaliplatin. Depletion of glutathione not only avoids the undesired annihilation of ROS in PDT, but also modulates the chemical specie equilibria in tumors for H2O2 promotion, leading to greatly relieved tumor hypoxia and PDT enhancement. Synergistically, Fe (II) in the hybrid RALP formulation can be fuelled by H2O2 to generate ?OH in the Fenton reaction, thus elevating CDT efficiency. This work offers a strategy for harnessing smart, responsive, and biocompatible liposomes to enhance PDT and CDT by regulating tumor microenvironment, highlighting a potential clinical translation beneficial to patients with cancer.  相似文献   

10.
    
Photodynamic therapy (PDT) is a promising treatment modality for cancer management. So far, most PDT studies have focused on delivery of photo­sensitizers to tumors. O2, another essential component of PDT, is not artificially delivered but taken from the biological milieu. However, cancer cells demand a large amount of O2 to sustain their growth and that often leads to low O2 levels in tumors. The PDT process may further potentiate the oxygen deficiency, and in turn, adversely affect the PDT efficiency. In the present study, a new technology called red blood cell (RBC)‐facilitated PDT, or RBC‐PDT, is introduced that can potentially solve the issue. As the name tells, RBC‐PDT harnesses erythrocytes, an O2 transporter, as a carrier for photosensitizers. Because photosensitizers are adjacent to a carry‐on O2 source, RBC‐PDT can efficiently produce 1O2 even under low oxygen conditions. The treatment also benefits from the long circulation of RBCs, which ensures a high intraluminal concentration of photosensitizers during PDT and hence maximizes damage to tumor blood vessels. When tested in U87MG subcutaneous tumor models, RBC‐PDT shows impressive tumor suppression (76.7%) that is attributable to the codelivery of O2 and photosensitizers. Overall, RBC‐PDT is expected to find wide applications in modern oncology.  相似文献   

11.
    
Oxygen plays an essential role in the photodynamic therapy (PDT) of cancer. However, hypoxia inside tumors severely attenuates the therapeutic effect of PDT. To address this issue, a novel strategy is reported for cutting off the oxygen consumption pathway by using sub‐50 nm dual‐drug nanoparticles (NPs) to attenuate the hypoxia‐induced resistance to PDT and to enhance PDT efficiency. Specifically, dual‐drug NPs that encapsulate photosensitizer (PS) verteporfin (VER) and oxygen‐regulator atovaquone (ATO) with sub‐50 nm diameters can penetrate deep into the interior regions of tumors and effectively deliver dual‐drug into tumor tissues. Then, ATO released from NPs efficiently reduce in advance cellular oxygen consumption by inhibition of mitochondria respiratory chain and further heighten VER to generate greater amounts of 1O2 in hypoxic tumor. As a result, accompanied with the upregulated oxygen content in tumor cells and laser irradiation, the dual‐drug NPs exhibit powerful and overall antitumor PDT effects both in vitro and in vivo, and even tumor elimination. This study presents a potential appealing clinical strategy in photodynamic eradication of tumors.  相似文献   

12.
    
Photosensitizers (PSs) with effective reactive oxygen species generation ability against hypoxia are of great potential for clinical treatment of malignant tumors. However, complex tumor microenvironment, such as antioxidative responses and immunosuppression, would ineluctably limit the efficiency of photodynamic therapy (PDT). Herein, a molecular-targeting photosensitizer QTANHOH is rationally designed for histone deacetylases (HDACs-targeting photo-immunotherapy application. The PS QTANHOH displays excellent type-I/II PDT performance, exhibiting significant phototoxicity toward cancer cells with half maximal inhibitory concentration (IC50) less than 10 nm in both normoxia and hypoxia conditions under blue laser irradiation. Moreover, the bioactive compound could inhibit HDACs and activate the immune microenvironment to boost PDT efficacy on the immunocompetent BALB/c mice with breast cancer, leading to the eradication of solid tumor and inhibition of metastasis. Notably, the molecular-targeting photosensitizer introduces an alternative strategy to achieve superior phototherapy for cancer therapy.  相似文献   

13.
光动力治疗是一种具有临床前景的新兴癌症治疗方法, 可以特异地在肿瘤部位发挥作用并且对人体的伤害较小, 但是疏水性光敏剂小分子的毒性、肿瘤的乏氧微环境及纳米载药系统的生物降解性等影响了其抗肿瘤疗效和体内代谢清除。本文利用六氯铂酸作为新型氧化剂成功引发吡咯/氨基吡咯的氧化聚合, 实现了其表面氨基功能化; 进一步通过还原剂硼氢化钠还原纳米结构中铂酸阴离子为铂纳米簇, 制得铂纳米簇掺杂的聚吡咯纳米粒子(platinum nanocluster-doped polypyrrole nanoparticles, PtPPy); 最后通过酰胺键偶连光敏剂四(4-羧基苯基)卟吩[meso-tetra (4-carboxyphenyl)porphine, TCPP], 获得递送TCPP的功能性纳米药物(PtPPy@T)。该纳米药物为球型结构, 形态均匀, 粒径为91.93 ± 13.45 nm, zeta电位为-18.39 ± 1.4 mV。实验证明, PtPPy@T可与肿瘤过表达的过氧化氢发生反应, 产生大量的氧气, 改善肿瘤乏氧微环境, 同时为随后的光动力治疗提供充足的反应基板; 使用658 nm激光照射肿瘤组织, 激活PtPPy@T的光动力效应, 催化氧气转化为单线态氧, 从而引发肿瘤细胞的氧化损伤并诱导其凋亡; 实验研究表明该PtPPy@T纳米药物在体内和体外都有较好的肿瘤抑制效果。所有动物实验均经中国医学科学院、北京协和医学院放射医学研究所机构动物护理和使用委员会批准(IRM/2-IACUC-2312-006)。  相似文献   

14.
    
Tumor hypoxia strengthens tumor resistance to different therapies especially oxygen involved strategies, such as photodynamic therapy (PDT). Herein, the thermal responsive phase change materials (PCM) are utilized to coencapsulate ultrasmall manganese dioxide (sMnO2) and organic photosensitizer IR780 to obtain IR780‐sMnO2‐PCM nanoparticles for controlled tumor hypoxia modulation and enhanced phototherapy. The thermal responsive protective PCM layer can not only prevent IR780 from photodegradation, but also immediately release sMnO2 to decompose endogenous H2O2 and generate enough oxygen for PDT under laser irradiation. Owing to the efficient accumulation of IR780‐sMnO2‐PCM nanoparticles in tumor under intravenous injection as revealed by both florescence imaging and photoacoustic imaging, the tumor hypoxia is greatly relieved. Furthermore, in vivo combined photothermal therapy (PTT) and PDT, IR780‐sMnO2‐PCM nanoparticles, compared to IR780‐PCM nanoparticles, exhibit better performance in inhibiting tumor growth. The results highlight the promise of IR780‐sMnO2‐PCM in controlled modulation of tumor hypoxia to overcome current limitations of cancer therapies.  相似文献   

15.
    
Tumor adaptive treatment tolerance associated with chemotherapy originates from low tumor accumulation and adverse effects and remains a formidable challenge for cancer therapy. Herein, human serum albumin (HSA)‐based nanomedicines modified with diazirine and loaded with indocyanine green (ICG) and tirapazamine (TPZ), denoted as ICG/TPZ@HSA dNMs are developed. The obtained ICG/TPZ@HSA dNMs can efficiently eradicate the tumors through a cascade of synergistic events triggered by the sequential irradiation of lasers in the tumor area. Upon a 405 nm laser irradiation, the ICG/TPZ@HSA dNMs are able to form aggregates via crosslinking and thus realized enhanced tumor site accumulation and prolonged retention time. The following irradiation at tumor area with an 808 nm laser‐generated local hyperthermia and reactive oxygen species, which results in efficient tumor ablation and increased local hypoxia in the tumor microenvironment. The resulted local hypoxia further activates the initially nontoxic TPZ to a highly cytotoxic derivative, by which precisely bioactivated chemotherapy is achieved following the phototherapy. Thus, upon the laser irradiations, a cascade of aggregation, phototherapy, and bioactivated chemotherapy is successfully triggered, which achieves efficient precise eradication of tumors without detectable side effects in vivo.  相似文献   

16.
    
Dental caries is a common disease caused by plaque biofilms, which are important pathogenic factors in many diseases. When hosts are overexposed to dietary sugars, pathogens such as Streptococcus mutans (S. mutans) and other cariogenic bacteria, metabolically assemble an extracellular matrix rich in exopolysaccharides to form a disease-causing biofilm, in which the microenvironment is characterized by regional hypoxia, low pH, and nutritional deprivation. Current antimicrobials with inadequate penetration and a lack of pathogens targeting the biofilm do not degrade the protective matrix within the biofilm. In this study, a guanidine and galactose decorated nanophotosensitizer with oxygen self-sufficient capability, p(GF/GEF)-I, is developed to enhance the permeability of biofilms by positively charging the particle surface and easily binding to the bacteria within the membrane through electrostatic interactions. 90% of the biofilm on enamel surface is eliminated after treatment with p(GF/GEF)-I under laser irradiation. Notably, the nanophotosensitizer inhibits the recolonization of dental biofilms by S. mutans, preventing secondary infections. Furthermore, dental caries in a rodent model are reduced with exposure to nanophotosensitizer. p(GF/GEF)-I is a significantly higher efficacy without damaging the surrounding soft tissue. With further development and optimization, p(GF/GEF)-I shows significant potential as a phototherapeutic agent for the treatment of biofilm-induced diseases.  相似文献   

17.
    
Photodynamic therapy (PDT) has received extensive attention as a promising cancer treatment approach. Still, challenges to in vivo photodynamic therapy have existed for decades. First, the “always on” nature of conventional photosensitizers will cause damage to normal tissues thereby limiting the treatment efficiency of PDT. Second, the hypoxic TME protects cancer stem cells (CSCs) deeply harbored in the center of tumors from PDT administration, thus contributing to the recrudescence and metastasis of tumors. Herein, a ROS-triggered self-immolative therapeutic prodrug ( Mu-PS ) is reported, comprising of an activatable photosensitizer, an indomethacin (IMC) part, and a ROS-responsive trigger, for the anti-stemness chemical and photodynamic therapy of tumors. Intriguingly, Mu-PS can target the tumor and selectively release the photosensitizer and IMC upon the activation of TME-related ROS, generating massive phototoxic 1O2 to kill most non-CSCs tumor cells under the action of PDT and block the growth of CSCs by IMC, hence, it multiplies the therapeutic index. Noteworthy, the anti-stemness mechanism of IMC in tumors is confirmed and elucidated for the first time. Overall, this study introduces a self-immolatative prodrug for combined CSCs-involved chemical therapy and activatable PDT for tumors and provides a design paradigm of prodrug for the precise prognosis and treatment of tumors.  相似文献   

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19.
    
Tumor hypoxia and chemoresistance are long‐lasting challenges in clinical cancer treatments resulting in treatment failures and low patient survival rates. Application of phototherapies to treat deep tissue‐buried tumors has been hampered by the lack of near infrared photosensitizers, and consumption of tissue oxygen, worsening the tumor hypoxia problem. Herein, an unprecedented theranostic lanthanum hexaboride‐based nanodrug is engineered to act as bimodal computed tomographic/magnetic resonance imaging contrast agents, absorb long near infrared (NIR) light in the biological window IIb (1500–1700 nm), generate hydroxyl radicals without using oxygen, and destroy drug‐resistant NCI‐H23 lung tumors completely, leading to an amazingly long average half‐life of 180 days, far exceeding than those of doxorubicin‐treated (21 days) and untreated mice groups (13 days). This work pioneers the field of photodynamic therapy in conquering hypoxia and chemodrug resistance problems for NIR‐IIb oxygen‐independent cancer treatments.  相似文献   

20.
    
Conventional oxygen‐dependent photodynamic therapy (PDT) has faced severe challenges because of the non‐specificity of most available photosensitizers (PSs) and the hypoxic nature of tumor tissues. Here, an O2 self‐sufficient cell‐like biomimetic nanoplatform (CAT‐PS‐ZIF@Mem) consisting of the cancer cell membrane (Mem) and a cytoskeleton‐like porous zeolitic imidazolate framework (ZIF‐8) with the embedded catalase (CAT) protein molecules and Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4, defined as PS) is developed. Because of the immunological response and homologous targeting abilities of the cancer cell membrane, CAT‐PS‐ZIF@Mem is selectively accumulated at the tumor site and taken up effectively by tumor cells after intravenous injection. After the intracellular H2O2 penetration into the framework, it is catalyzed by CAT to produce O2 at the hypoxic tumor site, facilitating the generation of toxic 1O2 for highly effective PDT in vivo under near‐infrared irradiation. By integrating the immune escape, cell homologous recognition, and O2 self‐sufficiency, this cell‐like biomimetic nanoplatform demonstrates highly specific and efficient PDT against hypoxic tumor cells with much reduced side‐effect on normal tissues.  相似文献   

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