Relieve Tumor Hypoxia Research Articles

Nanozymes-Engineered Metal-Organic Frameworks for Catalytic Cascades-Enhanced Synergistic Cancer Therapy.

The efficiency of chemical intercommunication between enzymes in natural networks can be significantly enhanced by the organized catalytic cascades. Nevertheless, the exploration of two-or-more-enzymes-engineered nanoreactors for catalytic cascades remains a great challenge in cancer therapy because of the inherent drawbacks of natural enzymes. Here, encouraged by the catalytic activity of the individual nanozyme for benefiting the treatment of solid tumors, we propose an organized in situ catalytic cascades-enhanced synergistic therapeutic strategy driven by dual-nanozymes-engineered porphyrin metal-organic frameworks (PCN). Precisely, catalase-mimicking platinum nanoparticles (Pt NPs) were sandwiched by PCN, followed by embedding glucose oxidase-mimicking ultrasmall gold nanoparticles (Au NPs) within the outer shell, and further coordination with folic acid (P@Pt@P-Au-FA). The Pt NPs effectively enabled tumor hypoxia relief by catalyzing the intratumoral H2O2 to O2 for (1) enhancing the O2-dependent photodynamic therapy and (2) subsequently accelerating the depletion of β-d-glucose by Au NPs for synergistic starving-like therapy with the self-produced H2O2 as the substrate for Pt NPs. Consequently, a remarkably strengthened antitumor efficiency with prevention of tumor recurrence and metastasis was achieved. This work highlights a rationally designed tumor microenvironment-specific nanoreactor for opening improved research in nanozymes and provides a means to design a catalytic cascade model for practical applications.

Stealth surface driven accumulation of “Trojan Horse” for tumor hypoxia relief in combination with targeted cancer therapy

The clearance of tumor-associated immune systems (TAISs) is the key impediment of the drug delivery, which leads to the low drug accumulation (0.7%) in the traditional chemotherapy. To tackle this issue, we constructed biomimetic nanoparticles serving as “Trojan Horse”, which consist of polydopamine (PDA) nanospheres with payloads of catalase (CAT), anticarcinogenic drug doxorubicin (Dox) and surrounding tumor cell membrane. Due to the coating of the homotypic cancer cell membrane, the “Trojan Horse” escaped the clearance of TAISs and heightened tumor-site target delivery. Sequentially, the over-expressive hydrogen peroxide in the tumor microenvironment penetrated the membrane of the “Trojan Horse” and reacted with CAT to generate oxygen, which realized the hypoxia relief. The hypoxia relief removed the immune resistance of tumors via the polarization of tumor-associated macrophages from M2 to M1 and broke the chemoresistance by downregulation of P-glycoprotein. With the oxygen generation, the cell membrane was broken and separated from the Dox-loaded PDA resulting in the immunotherapy by antigen presentation. Finally, the Dox-PDA nanospheres were taken into the tumor cells to achieve the chemo-phototherapy under near-infrared laser irradiation. The “Trojan Horse” showed higher accumulation (15.3%) over the enhanced permeability and retention effect (7.5%) of conventional nanodrugs and led to complete tumor eradication in vivo, which provides a promising treatment paradigm against tumor.

Tumor hypoxia relief overcomes multidrug resistance and immune inhibition for self-enhanced photodynamic therapy

As the self-regulation of tumors in the tumor microenvironment (TME), the hypoxia becomes the limitation again in the last period of oxygen-rich inducing enhanced photodynamic therapy (PDT). In this study, a promising TME-triggered oxygen nanogenerator for self-enhanced PDT primed antitumor immunotherapy was designed via simple and green chemistry methods. Indocyanine green (ICG), as a multi-role photosensitizer, was applied in photothermal therapy (PTT), PDT and diagnostic imaging. Given this, we utilized the heat generated by the ICG and branched gold nanoshells to promote the catalysis of hydrogen peroxide in the TME, which synchronized the oxygen generation and enhanced PDT (called self-enhanced PDT). Furthermore, the relief of tumor hypoxia broke the chemoresistance and promoted the polarization of tumor-associated macrophages from M2 to M1 type, which heightened the efficacy of chemotherapy and immunotherapy. Overall, this work has addressed a long-term issue for the limitation of PDT resulting from hypoxia and provided a close connection among the diversified therapeutic modalities.

Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer

AbstractThe condensed tumor extracellular matrix (ECM) consisting of cross‐linked hyaluronic acid (HA) is one of key factors that results in the aberrant tumor microenvironment (TME) and the resistance to various types of therapies. Herein, hyaluronidase (HAase) is modified by a biocompatible polymer, dextran (DEX), via a pH‐responsive traceless linker. The formulated DEX‐HAase nanoparticles show enhanced enzyme stability, reduced immunogenicity, and prolonged blood half‐life after intravenous injection. With efficient tumor passive accumulation, DEX‐HAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to enhanced penetration of oxygen and other therapeutic agents. The largely relieved tumor hypoxia would promote the therapeutic effect of nanoparticle‐based photodynamic therapy (PDT), accompanied by the reverse of the immunosuppressive TME to boost cancer immunotherapy. Interestingly, the therapeutic responses achieved by the combination of PDT and anti‐programmed death‐ligand 1 (anti‐PD‐L1) checkpoint blockade therapy could be significantly enhanced by pretreatment with DEX‐HAase. In addition to destructing tumors with direct light exposure, a robust abscopal effect is achieved after such treatment, which is promising for tumor metastasis inhibition. The work presents a new type of adjuvant nanomedicine to assist photodynamic‐immunotherapy of cancer, by effective modulation of TME.

A Smart Photosensitizer-Cerium Oxide Nanoprobe for Highly Selective and Efficient Photodynamic Therapy.

Cerium oxide (CeO x) with a reversible surface Ce3+/Ce4+ redox pair has played an important role in catalytic reactions, whereas catalase mimetics of CeO x have attracted little attention in the field of biotherapy. Herein, a smart photosensitizer-cerium oxide nanoprobe was developed to represent a promising paradigm in high-performance photodynamic therapy. The photosensitizer was linked to CeO x nanoparticles through a substrate peptide (EGPLGVRGK) of matrix metalloproteinase-2 (MMP-2). The smart nanoprobe could be converted from the "silent state" before arriving at the cancer cells to the "activated state" within the cells to turn on the fluorescence and 1O2 generation when the peptide linker (EGPLGVRGK) was cut by the cancer biomarker MMP-2. Moreover, CeO x played the role of an excellent catalase-like compound to decompose endogenous hydrogen peroxide to relieve tumor hypoxia. Via the conventional application of CeO x, our study showed innovatively how a smart nanoprobe could relieve tumor hypoxia and achieve a therapeutic effect for highly selective and efficient personalized treatment.

Light-Triggered In Situ Gelation to Enable Robust Photodynamic-Immunotherapy by Repeated Stimulations.

Photodynamic therapy (PDT) has shown the potential of triggering systemic antitumor immune responses. However, while the oxygen-deficient hypoxic tumor microenvironment is a factor that limits the PDT efficacy, the immune responses after conventional PDT usually are not strong enough to eliminate metastatic tumors. Herein, a light-triggered in situ gelation system containing photosensitizer-modified catalase together with poly(ethylene glycol) double acrylate (PEGDA) as the polymeric matrix is designed. Immune adjuvant nanoparticles are further introduced into this system to trigger robust antitumor immune responses after PDT. Following local injection of the mixed precursor solution into tumors and the subsequent light exposure, polymerization of PEGDA can be initiated to induce in situ gelation. Such hybrid hydrogel with long-term tumor retention of various agents and the ability to enable persistent tumor hypoxia relief can enable multiple rounds of PDT, which results in significantly enhanced immune responses by multiround stimulation. Further combination of such gel-based multiround PDT with anticytotoxic T-lymphocyte antigen-4 checkpoint blockade offers not only the abscopal effect to inhibit growth of distant tumors but also effective long-term immune memory protection from rechallenged tumors. Therefore, such a light-triggered in situ gelation system by a single-dose injection can enable greatly enhanced photoimmunotherapy by means of repeated stimulations.

G-Quadruplex/Porphyrin Composite Photosensitizer: A Facile Way to Promote Absorption Redshift and Photodynamic Therapy Efficacy.

Photosensitizer is one of the most important elements of photodynamic therapy (PDT). Herein, we reported a novel strategy to prepare a new series of composite photosensitizers. The composite photosensitizer was prepared by simply mixing DNA G-quadruplexes with a hydrophilic porphyrin (TMPipEOPP)4+·4I-. Compared with the conventional porphyrin photosensitizers, the excitation wavelength of the composite one has been ∼50 nm redshifted (from 650 to 700 nm), which is beneficial to the penetration of the light. Moreover, the composite photosensitizer showed an about 7.4-fold increase of light absorption efficiency, thus greatly enhancing the singlet oxygen (1O2) generation capacity and PDT efficacy. What is more, the introduction of nucleic acids in the composite photosensitizer could also provide some extra charming properties, such as the targeted recognition ability conferred by aptamer and high capability to assemble with various drug carriers. We demonstrated that the composite photosensitizer could be easily assembled with MnO2 nanosheet. The obtained nanodevice integrated the merits of a composite photosensitizer and MnO2 nanosheet, thus showing strong near-infrared absorption, high 1O2 generation efficiency, avoidance of nonideal 1O2 consumption by glutathione, and in situ O2 generation to relieve tumor hypoxia. This nanodevice showed greatly improved PDT efficacy both in vitro and in vivo, presenting a huge potential for applications in clinical therapy for tumors.

An Oxygen Self-sufficient Fluorinated Nanoplatform for Relieved Tumor Hypoxia and Enhanced Photodynamic Therapy of Cancers.

The efficacy of photodynamic therapy (PDT) in the solid tumor is hampered by many challenges, including its oxygen self-consuming nature, insufficient oxygen levels within the hypoxic tumor microenvironment, and limited penetration of photosensitizers within tumors. Herein, we develop the IR780@O2-SFNs/iRGD as an oxygen self-sufficient and tumor-penetrating nanoplatform, which consists of IR780-loaded pH-sensitive fluorocarbon-functionalized nanoparticles (SFNs) and iRGD as a tumor targeting peptide that can penetrate deeper within the tumor. Because of the high oxygen affinity and outstanding permeability of the obtained nanoplatform, oxygen and IR780 which are encapsulated in the same core can play their roles to the utmost, resulting in remarkably accelerated singlet oxygen production, as demonstrated in vitro by the 3D multicellular spheroids and in vivo by tumor tissues. More interestingly, a single-dose intravenous administration of IR780@O2-SFNs/iRGD into mice bearing orthotopic breast cancer could selectively accumulate at the tumor site, highly alleviate the tumor hypoxia, significantly inhibit the primary tumor growth, and reduce the lung and liver metastasis, enabling the improved photodynamic therapeutic performance. Thus, this work paves an effective way to improve PDT efficacy through increasing tumor oxygenation and selective delivery of photosensitizers to the deep and hypoxic tumor.

Perfluorocarbon‐Loaded and Redox‐Activatable Photosensitizing Agent with Oxygen Supply for Enhancement of Fluorescence/Photoacoustic Imaging Guided Tumor Photodynamic Therapy

AbstractThe wide clinical application of photodynamic therapy (PDT) is hampered by poor water solubility, low tumor selectivity, and nonspecific activation of photosensitizers, as well as tumor hypoxia which is common for most solid tumors. To overcome these limitations, tumor‐targeting, redox‐activatable, and oxygen self‐enriched theranostic nanoparticles are developed by synthesizing chlorin e6 (Ce6) conjugated hyaluronic acid (HA) with reducible disulfide bonds (HSC) and encapsulating perfluorohexane (PFH) within the nanoparticles (PFH@HSC). The fluorescence and phototoxicity of PFH@HSC nanoparticles are greatly inhibited by a self‐quenching effect in an aqueous environment. However, after accumulating in tumors through passive and active tumor‐targeting, PFH@HSC appear to be activated from “OFF” to “ON” in photoactivity by the redox‐responsive destruction of the vehicle's structure. In addition, PFH@HSC can load oxygen within lungs during blood circulation, and the oxygen dissolved in PFH is slowly released and diffuses over the entire tumor, finally resulting in remarkable tumor hypoxia relief and enhancement of PDT efficacy by generating more singlet oxygen. Taking advantage of the excellent imaging performance of Ce6, the tumor accumulation of PFH@HSC can be monitored by fluorescent and photoacoustic imaging after intravenous administration into tumor‐bearing mice. This PFH@HSC nanoparticle might have good potential for dual imaging‐guided PDT in hypoxic solid tumor treatment.

Holo-Lactoferrin Modified Liposome for Relieving Tumor Hypoxia and Enhancing Radiochemotherapy of Cancer.

Hypoxic microenvironments in the solid tumor play a negative role in radiotherapy. Holo-lactoferrin (holo-Lf) is a natural protein, which acts as a potential ligand of transferrin receptor (TfR). In this work, an anticancer drug, doxorubicin (Dox)-loaded liposome-holo-Lf nanocomposites, is developed for tumor targeting and imaging guided combined radiochemotherapy. Dox-loaded liposome-holo-Lf (Lf-Liposome-Dox) nanocomposites exhibit significant cellular uptake likely owing to the TfR receptor-mediated targeting accumulation of Lf-Liposome-Dox nanocomposites. Additionally, the nanocomposites exhibit high accumulation in the tumor site after intravenous injection as evidenced from in vivo fluorescence imaging. More importantly, it is found that the holo-Lf has the ability to catalyze the conversion of hydrogen peroxide (H2 O2 ) to oxygen for relieving the tumor hypoxic microenvironment. Photoacoustic imaging further confirms the abundant generation of oxygen in the presence of Lf-Liposome-Dox nanocomposites. Based on these findings, in vivo combined radiochemotherapy is performed using Lf-Liposome-Dox as therapeutic agent, achieving excellent cancer treatment effect. The study further promotes the potential biomedical application of holo-Lf in cancer treatment.

GE11-PDA-Pt@USPIOs nano-formulation for relief of tumor hypoxia and MRI/PAI-guided tumor radio-chemotherapy.

Radio-chemo combination therapy has synergetic therapeutic effects on tumors. However, the tumor microenvironment, e.g. hypoxia and elevated H2S levels, limits its treatment efficacy. In this study, we developed a cisplatin-loaded, poly dopamine-coated and GE11 peptide-conjugated multi-functional theranostic system (GE11-PDA-Pt@USPIOs) based on poly acrylic acid-coated ultra-small superparamagnetic iron oxide nanoparticles (PAA@USPIOs) for modulation of the tumor hypoxic microenvironment and magnetic resonance imaging/photoacoustic imaging (MRI/PAI) guided radio-chemotherapy of tumors. The thick PAA coating on the USPIOs allowed highly efficient cisplatin loading by complexing the carboxylic groups on PAA with activated cisplatin. A subsequent thin layer of polydopamine (PDA) encapsulation following drug loading provided a means of further surface functionalization; it endowed the particles with photo-thermal properties but did not impede release of the drug or iron ions. GE11-PDA-Pt@USPIOs had high specificity for EGFR-positive tumor cells, could catalyze decomposition of H2O2 to oxygen and exhibited radio-chemo synergetic therapeutic effects under hypothermia conditions in vitro. Once administered intravenously, MRI and PA imaging revealed that the probes were able to accumulate in tumors with high efficiency; this relieved the tumor hypoxic conditions, sensitizing the tumors to radiation therapy. As a result, radio-chemo combination therapy significantly inhibited tumor growth. Our study illustrates for the first time that USPIOs can relieve tumor hypoxia and that GE11-PDA-Pt@USPIOs are highly effective for radio-chemotherapy of EGFR-positive tumors.

Collagenase-Encapsulated pH-Responsive Nanoscale Coordination Polymers for Tumor Microenvironment Modulation and Enhanced Photodynamic Nanomedicine.

The abundant tumor extracellular matrix (ECM) could result in insufficient tumor retention and ineffective intratumor penetration of therapeutic agents as well as an acidic and hypoxic tumor microenvironment (TME), leading to unsatisfactory therapeutic outcomes for many types of therapies. Therefore, developing strategies to modulate the TME by selectively degrading the condensed ECM may be helpful to improve existing cancer therapies. Herein, collagenase (CLG)-encapsulated nanoscale coordination polymers (NCPs) are synthesized based on Mn2+ and an acid-sensitive benzoic-imine organic linker and then modified by polyethylene glycol (PEG). Upon intravenous (iv) injection, these CLG@NCP-PEG nanoparticles show efficient accumulation within the tumor, in which CLG would be released because of the collapse of NCP structures within the acidic TME. The released CLG enzyme could then specifically degrade collagens, the major component of ECM, leading to a loosened ECM structure, enhanced tumor perfusion, and relieved hypoxia. As a result, the second wave of nanoparticles, chlorin e6 (Ce6)-loaded liposomes (liposome@Ce6), would exhibit enhanced retention and penetration within the tumor. Such phenomena together with relieved tumor hypoxia could then lead to greatly enhanced photodynamic therapeutic effect of liposome@Ce6 for mice pretreated with CLG@NCP-PEG. Our work thus presents a unique strategy for TME modulation using pH-responsive NCPs as smart enzyme carriers.

Calcium Bisphosphonate Nanoparticles with Chelator-Free Radiolabeling to Deplete Tumor-Associated Macrophages for Enhanced Cancer Radioisotope Therapy.

Tumor-associated macrophages (TAMs) are often related with poor prognosis after radiotherapy. Depleting TAMs may thus be a promising method to improve the radio-therapeutic efficacy. Herein, we report a biocompatible and biodegradable nanoplatform based on calcium bisphosphonate (CaBP-PEG) nanoparticles for chelator-free radiolabeling chemistry, effective in vivo depletion of TAMs, and imaging-guided enhanced cancer radioisotope therapy (RIT). It is found that CaBP-PEG nanoparticles prepared via a mineralization method with poly(ethylene glycol) (PEG) coating could be labeled with various radioisotopes upon simple mixing, including gamma-emitting 99mTc for single-photon-emission computed tomography (SPECT) imaging, as well as beta-emitting 32P as a therapeutic radioisotope for RIT. Upon intravenous injection, CaBP(99mTc)-PEG nanoparticles exhibit efficient tumor homing, as evidenced by SPECT imaging. Owning to the function of bisphosphonates as clinical drugs to deplete TAMs, suppressed angiogenesis, normalized tumor vasculatures, enhanced intratumoral perfusion, and relieved tumor hypoxia are observed after TAM depletion induced by CaBP-PEG. Such modulated tumor microenvironment appears to be highly favorable for cancer RIT using CaBP(32P)-PEG as the radio-therapeutic agent, which offers excellent synergistic therapeutic effect in inhibiting the tumor growth. With great biocompatibility and multifunctionalities, such CaBP-PEG nanoparticles constituted by Ca2+ and a clinical drug would be rather attractive for clinical translation.

Perfluorocarbon Nanoparticles Mediated Platelet Blocking Disrupt Vascular Barriers to Improve the Efficacy of Oxygen-Sensitive Antitumor Drugs.

Currently, limited tumor drug permeation and poor oxygen perfusion are two major bottlenecks that significantly impair the efficacy of existing antitumor drugs, especially oxygen-sensitive antitumor drugs. One vital cause of these major bottlenecks is the abnormal tumor vessel barrier. To the best knowledge of the authors, platelets play a vital role in the maintenance of an abnormal tumor blood barrier through platelet-tumor interaction. Thus, platelet inhibition may present a new way to enhance drug delivery. In this study, it is originally discovered that perfluorotributylamine-based albumin nanoparticles (PFTBA@HSA) possess excellent platelet inhibiting abilities, which then selectively disrupt the tumor vessel barrier, resulting in a remarkably enhanced intratumoral drug accumulation. Interestingly enough, the tumor hypoxia is also obviously relieved by enhanced oxygen carrier red blood cell distribution and PFTBA@HSA infiltration in the tumors. Finally, the efficacy of oxygen-sensitive antitumor drugs is significantly amplified by PFTBA@HSA owing to enhanced drug permeation and relieved tumor hypoxia. Therefore, for the first time, it is demonstrated that PFTBA@HSA could be used as an effective way to improve the efficacy of existing tumor therapies by disrupting tumor vessel barriers through targeted platelet inhibition.

NIR-II light activated photodynamic therapy with protein-capped gold nanoclusters

The use of near-infrared (NIR) light for photodynamic therapy (PDT) is a promising strategy to circumvent the limitations of current PDT, in which visible light with limited tissue penetration depth is usually used. In the present study, alkyl thiolated gold nanoclusters (AuNCs) were co-modified with human serum albumin (HSA) and catalase (CAT), and then employed as a multifunctional, optical, theranostic nano-agent. In the AuNC@HSA/CAT system, the AuNCs were able to produce singlet oxygen under excitation by a 1,064-nm laser, which locates in the second NIR window (NIR-II), and featured much lower tissue absorption and scattering, enabling NIR-II-triggered PDT. The HSA coating greatly improved the physiological stability of the nanoparticles, which showed efficient tumor retention after intravenous injection, as revealed by detecting the AuNC fluorescence. Moreover, the presence of CAT in the nanoparticles triggered decomposition of tumor endogenous H2O2 to generate oxygen, thereby enhancing the efficacy of PDT by relieving tumor hypoxia. Compared with conventional PDT using visible light, NIR-II-triggered PDT exhibits remarkably increased tissue penetration. Thus, we developed a new type of photosensitizing nano-agent that simultaneously enables in vivo fluorescence imaging, tumor hypoxia relief, and NIR-II light-induced in vivo PDT in the treatment of cancer.

Self-Supplied Tumor Oxygenation through Separated Liposomal Delivery of H2O2 and Catalase for Enhanced Radio-Immunotherapy of Cancer.

The recent years have witnessed the blooming of cancer immunotherapy, as well as their combinational use together with other existing cancer treatment techniques including radiotherapy. However, hypoxia is one of several causes of the immunosuppressive tumor microenvironment (TME). Herein, we develop an innovative strategy to relieve tumor hypoxia by delivering exogenous H2O2 into tumors and the subsequent catalase-triggered H2O2 decomposition. In our experiment, H2O2 and catalase are separately loaded within stealthy liposomes. After intravenous (iv) preinjection of CAT@liposome, another dose of H2O2@liposome is injected 4 h later. The sustainably released H2O2 could be decomposed by CAT@liposome, resulting in a long lasting effect in tumor oxygenation enhancement. As the result, the combination treatment by CAT@liposome plus H2O2@liposome offers remarkably enhanced therapeutic effects in cancer radiotherapy as observed in a mouse tumor model as well as a more clinically relevant patient-derived xenograft tumor model. Moreover, the relieved tumor hypoxia would reverse the immunosuppressive TME to favor antitumor immunities, further enhancing the combined radio-immunotherapy with cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade. This work presents a simple yet effective strategy to promote tumor oxygenation via sequential delivering catalase and exogenous H2O2 into tumors using well-established liposomal carriers, showing great potential for clinical translation in radio-immunotherapy of cancer.

Covalent Organic Polymers Based on Fluorinated Porphyrin as Oxygen Nanoshuttles for Tumor Hypoxia Relief and Enhanced Photodynamic Therapy

AbstractEffective and sustained tumor oxygenation has found practical significance in benefiting the treatment of solid tumors. In this study, fluorinated covalent organic polymers (COPs) are prepared by cross‐linking the photosensitizer meso‐5, 10, 15, 20‐tetra (4‐hydroxylphenyl) porphyrin (THPP) with perfluorosebacic acid (PFSEA) and poly(ethylene glycol) (PEG) via a one‐pot esterification, to enable simultaneous tumor oxygenation and photodynamic treatment. Due to the presence of PFSEA, the obtained THPPpf–PEG shows efficient loading of perfluoro‐15‐crown‐5‐ether (PFCE), a type of perfluocarbon, and thereby molecular oxygen, both of which would significantly enhance the photodynamic effect of THPP. After chelating THPP with a radio‐isotope, 99mTc, both THPPpf–PEG and PFCE‐loaded THPPpf–PEG (PFCE@THPPpf–PEG) can be vividly visualized under the single‐photon emission computed tomography (SPECT) imaging, which uncovers efficient tumor accumulation of those COPs' post intravenous injection. Owing to the oxygen delivery ability of PFCE, efficient tumor oxygenation is observed for mice post injection of PFCE@THPPpf–PEG, which further leads to greatly enhanced photodynamic treatment of tumors. This study presents a unique type of multifunctional fluorinated COPs with well‐defined composition, long blood circulation time, and sustained tumor oxygenation ability, showing great promises for potential clinical translation in photodynamic treatment of tumors.

Photosensitizer-crosslinked in-situ polymerization on catalase for tumor hypoxia modulation & enhanced photodynamic therapy

Tumor hypoxia is known to be one of critical factors that aggravate the tumor resistance to photodynamic therapy (PDT) in which oxygen is essential for tumor destruction. Herein, catalase, an enzyme to trigger hydrogen peroxide (H2O2) decomposition, is modified by in-situ free radical polymerization, using meso-tetra(p-hydroxyphenyl) porphine (THPP) as the cross-linker to enable condensed grafting of short polyethylene glycol (PEG) chains on the protein surface as a permeable brush-like safeguard. The formulated catalase-entrapped nanocapsules (CAT-THPP-PEG) with enhanced enzyme stability can be labeled with 99mTc4+, a radioisotope ion that is chelated by the porphyrin structure of THPP, to allow in vivo single-photon emission computed tomography (SPECT) imaging. It is found that such CAT-THPP-PEG nanoparticles exhibit efficient tumor passive retention after intravenous injection, and are able to greatly relieve tumor hypoxia by triggering the decomposition of tumor endogenous H2O2 into oxygen. With THPP functioning as a photosensitizer, in vivo PDT is further conducted, achieving a remarkable antitumor therapeutic effect. This work presents an enzyme modification strategy by in-situ polymerization with photosensitizer as the cross-linker to develop multifunctional nano-theranostics with strengthened enzymatic stability, efficient tumor passive homing, SPECT imaging capability, enhanced PDT efficacy as well as decreased immunogenicity, promising for clinical translation.

Iridium nanocrystals encapsulated liposomes as near-infrared light controllable nanozymes for enhanced cancer radiotherapy

Owing to the existence of severe tumor hypoxia and limited X-ray absorption of solid tumors, the therapeutic efficacy of radiotherapy is far from satisfactory. Herein, ultrasmall iridium nanocrystals (IrNCs) with homogeneous size distribution are successfully synthesized. The obtained IrNCs show catalase-like catalytic activity towards hydrogen peroxide (H2O2) with great temperatures/pH stability. As free IrNCs are prone to be toxified by thiol-containing biomolecules, we encapsulate as-prepared IrNCs within stealth liposomal carriers, obtaining Ir@liposome with well-protected catalytic activity in physiological conditions. By utilizing its efficient photothermal conversion ability, such Ir@liposome shows effective near-infrared-(NIR)-responsive catalytic activity towards H2O2 decomposition. As revealed by in vivo photoacoustic imaging, our Ir@liposome exhibits efficient passive tumor accumulation upon intravenous injection, and could efficiently decompose the tumor endogenous H2O2 into O2, particularly upon exposure to the NIR laser. As the results of relieved tumor hypoxia after such treatment and the radiosensitization capability of Ir as a high-Z element, greatly enhanced radio-therapeutic efficacy with Ir@liposome is then achieved. This work thus presents a unique type of NIR light controllable theranostic nanozyme based on noble metal nanocrystals as a nanoscale radiosensitizer with great performance in enhancing cancer radiotherapy.

A Bioenvironment-Responsive Versatile Nanoplatform Enabling Rapid Clearance and Effective Tumor Homing for Oxygen-Enhanced Radiotherapy

Nanoradiosensitizer-augmented cancer radiotherapy (RT) has been widely investigated, whereas the desirable nanoradiosensitizer with the characteristics of rapid clearance, effective tumor homing, and tumor hypoxia relief is still lacking. Herein, bismuth sulfide–albumin composite nanospheres followed by catalase conjugation (denoted as BSNSs-CAT) have been well constructed as a bioenvironment-responsive nanoradiosensitizer platform. The BSNSs-CAT phagocytosed by normal cells demonstrate architectural disintegration into small ones in response to physiological pH, achieving small size-favored rapid clearance, which largely mitigates the concern of long-term toxicity of BSNSs-CAT in normal tissues. More importantly, benefiting from their large size-favored enhanced permeability and retention effect, BSNSs-CAT accumulate efficiently in tumors and remain architecturally stable in a mildly acidic tumor microenvironment (TME), which strongly favors a response with H2O2 overproduced TME. As a result, the produce...