Deep Tumor Tissue Research Articles

NIR-II Responsive Molybdenum Dioxide Nanosystem Manipulating Cellular Immunogenicity for Enhanced Tumor Photoimmunotherapy.

Photothermal therapy (PTT) in the second near-infrared (NIR-II) window has emerged as a better candidate for deep-tissue tumor elimination. More interestingly, the photothermal ablated tumor cells also manifest somewhat immunostimulation potency to elicit antitumor immunity, although most dying cells are undergoing apoptosis that is commonly considered as immunologically silent. Here, a NIR-II responsive nanosystem is established for tumor photoimmunotherapy using molybdenum dioxide (MoO2) nanodumbbells as the nanoconverter. Meanwhile, an apoptosis-blocking strategy is proposed to regulate the cell death pattern under NIR-II laser irradiation in order to improve the immunogenic cell death. The nanoformulation can efficiently block caspase 8-dependent apoptotic pathway in photothermal ablated tumor cells and transform into more immunogenic death patterns, thereby activating systemic immunity to inhibit tumor growth and metastasis. In addition, this strategy also helps enhance the body's responses to α-PD-1 immune checkpoint inhibitor, which implies a potential optimal combination for cancer immunotherapy.

Size-changeable nanoprobes for the combined radiotherapy and photodynamic therapy of tumor

Radiation therapy (RT) and photodynamic therapy (PDT) are promising while challenging in treating tumors. The potential radiation resistance of tumor cells and side effects to healthy tissues restrict their clinical treatment efficacy. Effective delivery of therapeutic agents to the deep tumor tissues would be available for tumor-accurate therapy and promising for the tumor therapy. Thus, developing nanoprobes with effectively delivering radiotherapy sensitizers and photosensitizers to the interior of tumors is needed for the accurate combined RT and PDT of tumor. The size-changeable nanoprobes of Gd2O3@BSA-BSA-Ce6 (BGBC) were synthesized with a crosslinking method. Magnetic resonance imaging (MRI) and in vivo near-infrared (NIR) imaging were measured to evaluate the nanoprobes' tumor accumulation and intratumor penetration effect. The tumor suppression effect of combined RT and PDT with these nanoprobes was also studied for the 4T1 bearing Balb/c mice. The nanoprobes BGBC showed high tumor accumulation and disintegrated into small particles responding to the photo-irradiation-produced reactive oxygen species (ROS), allowing for tumor penetration. Abundant radiotherapy sensitizers and photosensitizers were delivered to the deep tumor tissues, which is available for the accurate therapy of tumor. In addition, the BGBC displayed outstanding MRI and fluorescence imaging effects for evaluating the biodistribution and tumor suppression effect of nanoprobes. Consequently, significant tumor suppression effect was obtained based on the accurate tumor treatment with the combined RT and PDT. The designed size-changeable nanoprobes BGBC showed excellent tumor accumulation and deep tumor penetration, resulting in a significant tumor suppression effect based on the combined RT and PDT. This study provides a novel strategy for dual delivery of radiotherapy sensitizers and photosensitizers into the deep tumor tissues and is promising for the accurate theranostics of tumor.

Bacteria in cancer therapy: A new generation of weapons.

Tumors are presently a major threat to human life and health. Malignant tumors are conventionally treated through radiotherapy and chemotherapy. However, traditional therapies yield unsatisfactory results due to high toxicity to the normal cells, inability to treat deep tumor tissues, and the possibility of inducing drug resistance in the tumor cells. This has caused immunotherapy to emerge as an effective and alternate treatment strategy. To overcome the limitations of the conventional treatments as well as to avert the risk of various drug resistance and cytotoxicity, bacterial anti-tumor immunotherapy has raised the interest of researchers. This therapeutic strategy employs bacteria to specifically target and colonize the tumor tissues with preferential accumulation and proliferation. Such bacterial accumulation initiates a series of anti-tumor immune responses, effectively eliminating the tumor cells. This immunotherapy can use the bacteria alone or concomitantly with the other methods. For example, the bacteria can deliver the anti-cancer effect mediators by regulating the expression of the bacterial genes or by synthesizing the bioengineered bacterial complexes. This review will discuss the mechanism of utilizing bacteria in treating tumors, especially in terms of immune mechanisms. This could help in better integrating the bacterial method with other treatment options, thereby, providing a more effective, reliable, and unique treatment therapy for tumors.

A Theranostic Nanocomplex Combining with Magnetic Hyperthermia for Enhanced Accumulation and Efficacy of pH-Triggering Polymeric Cisplatin(IV) Prodrugs.

Although polymeric platinum(IV) (Pt(IV)) prodrugs can reduce the side effects of cisplatin, the efficacy of the prodrug is still limited by its non-targeted distribution, poor penetration in deep tumor tissue, and low cytotoxicity in tumor cells. To improve the clinical potential of polymeric prodrug micelle, we synthesized amphiphilic polymeric Pt(IV) with high Pt content (22.5%), then developed a theranostic nanocomplex by integrating polymeric Pt(IV) with superparamagnetic Mn0.6Zn0.4Fe2O4 via simple self-assembly. Due to the high content of Mn0.6Zn0.4Fe2O4 (41.7% w/w), the theranostic nanocomplex showed high saturation magnetization (103.1 emu g−1) and excellent magnetocaloric effect (404 W g−1), both of them indicating its advantages in efficient magnetic targeting (MT), magnetic hyperthermia (MH), and magnetic resonance imaging (MRI). In vitro, in combination with MH, the theranostic nanocomplex showed as high cytotoxicity as cisplatin because of a significant increase in platinum of cellular uptake. In vivo, the accumulation of theranostic nanocomplex in tumors was increased by MT and confirmed by MRI. Furthermore, MH improved penetration of theranostic nanocomplex in tumors as expanding blackened area in tumors was observed by MRI. Based on these properties, the theranostic nanocomplex, under the assistance of MT and MH, showed the highest tumor growth inhibition rate (88.38%) after different treatments, while the body weight of mice increased slightly, indicating low side effects compared to those of cisplatin. The study provided an advanced theranostic nanocomplex with low toxicity and high efficacy, indicating a great clinical potential of polymeric Pt(IV).

Photo-responsive NIR-II biomimetic nanomedicine for efficient cancer-targeted theranostics

In pancreatic cancer, the special barrier system formed by a large number of stromal cells severely hinders drug penetration in deep tumor tissues, resulting in low treatment efficiency. Cell membrane protein-camouflaged liposomal nanomedicines have cancer cell targeting abilities, whereas near-infrared two-zone (NIR-II) fluorescence imaging can achieve deep tissue penetration due to its long light wavelength (1,000–1,700 nm). To combine the cell membrane-based biomimetic technology with NIR-II fluorescence imaging, we constructed a biomimetic nanomedicine (BLIPO-I/D) by camouflaging indocyanine green-doxorubicin (ICG-DOX) liposomes with SW1990 pancreatic cancer cell membrane. The nanomedicine exhibited light-controlled DOX release and high pancreatic cancer treatment efficiency in vitro and in vivo. BLIPO-I/D showed the ability of targeted delivery of a large number of liposomes to pancreatic tumor tissues through homologous targeting of SW1990 cell membranes, which increased the NIR-II fluorescence imaging intensity. Irradiation of the liposomes taken up by pancreatic tumor tissues with near-infrared light (808 nm) triggered the rapid release of DOX from the liposomes, induced the photothermal and photodynamic effects of ICG, which exerted anti-tumor effects. Therefore, the fabricated biomimetic liposomal nanomedicine BLIPO-I/D is expected to achieve precise theranostics of pancreatic cancer.

Spatiotemporal decomposition methods for nanobubble contrast-enhanced ultrasound

Nanobubble ultrasound contrast agents (NBs) offer enhanced access to deep tumor tissue by extrapolation from vasculature. When combined with targeting moieties, shell-stabilized nanobubbles can outperform other agents used in molecular ultrasound imaging due to their small size. The visualization and decoupling of extravasated and intravascular NBs is critical to furthering nanobubble molecular imaging with ultrasound. Spatiotemporal processing of echo data, usually via singular value decomposition (SVD), enables enhanced decoupling of signals of stationary from moving scatterers and therefore provides a novel tool for analysis of NB extravasation into the parenchyma. Instead of trivial solutions, we have developed non-negative SVD (nnSVD) methods applicable to most commercial scanners without requiring the raw data. Additionally, our formulation allows addition of proper regularizers, such as sparsity, to further expand the decomposition dimensions. We validate these methods in phantom models and present how the suggested decompositions can distinctly decouple flowing from extravasated NBs in in vivo tumour models with enhanced permeability. Our results show the successful tracking of nanobubble accumulation in tumour tissue and can serve as a relative metric for molecular targeting of prostate cancer. Further exploration of these methods could be used to improve long-term imaging and drug delivery capabilities of NBs.

Near-infrared-II photothermal ultra-small carbon dots promoting anticancer efficiency by enhancing tumor penetration

Because of the particular environment of the tumor microenvironment, improving the deep penetration of drugs in tumor sites is a critical problem to improve the therapeutic effect of the tumor. The ultra-small nanoparticles can achieve deep tumor tissue penetration without modification, which shows tremendous significance in tumor therapy. In this work, the ultra-small permeable carbon dots (PCD) have been developed with near-infrared-II (NIR-II) window photothermal irradiation and good biocompatibility. These PCD showed multi-color fluorescence under visible light and photoacoustic signals under an excitation of 808 nm, guiding fluorescence and photoacoustic imaging for location and distribution in vitro and vivo. The PCD could penetrate the deep tissue in tumor spheroids and tissues. Meanwhile, the irradiated depth of the NIR-II window can provide sufficient photothermal energy with the deep penetration of PCD in tumor tissue to cause tumor ablation. Therefore, this PCD can be used as a safe, fluorescent, and photoacoustic imaging agent for guided NIR-II photothermal tumor therapy, which provides a new direction for the use of ultra-small carbon dots in anticancer therapy in the future.

A two-photon metal-organic framework nanoprobe with catalytic hairpin assembly for amplified MicroRNA imaging in living cells and tissues

Monitoring miRNAs can provide critical information for the generation and progress of various cancers. However, the existing DNA amplification strategies-based fluorescent nanoprobes for intracellular miRNAs imaging are often confronted with problems such as shallow light-penetration depth, enzymatic degradation, and low DNA loading efficiency. Herein, we developed a new two-photon nanoprobe (TP-CHA-MOFs) by using MOF as the nanocarrier and hairpins as a two-photon fluorescence signal amplifier for intracellular miRNA imaging. After cell penetration, intracellular phosphate could coordinate with Zr atoms in the MOFs, leading to the release of hairpins from the surfaces of TP-CHA-MOFs. The intracellular miRNA could trigger the formation of the H1-H2 duplex, which led to a turn-on TP fluorescence signal, realizing amplified detection of target miRNA. TP-CHA-MOFs nanoprobe showed high loading capacity of nucleic acid molecules, high biostability toward enzyme, and good biocompatibility. Because of the employment of TP fluorophore, TP-CHA-MOFs achieved sensitive imaging of intracellular miRNA and differentiated tumor cells with different miRNA levels. Moreover, sensitive imaging of miRNA in deep tumor tissues was realized with a penetration depth of 160 µm. The TP-CHA-MOFs nanoprobe is highly promising for future application in medical diagnostics.

Millisecond-Range Time-Resolved Bioimaging Enabled through Ultralong Aqueous Phosphorescence Probes.

Probes featuring room-temperature phosphorescence (RTP) are promising tools for time-resolved imaging. It is worth noting that the time scale of time-resolved bioimaging generally ranges around the microsecond level, because of the short-lived emission. Herein, the first example of millisecond-range time-resolved bioimaging is illustrated, which is enabled through a kind of ultralong aqueous phosphorescence probes (i.e., cyclo-(Arg-Gly-AspD-Tyr-Cys)-conjugated zinc-doped silica nanospheres), with a RTP emission lasting for ≈5 s and a lifetime as long as 743.7 ms. We demonstrate that live cells and deep tumor tissue in mice can be specifically targeted through immune-phosphorescence imaging, with a high signal-to-background ratio (SBR) value of ≈69 for in vitro imaging, and ≈627 for in vivo imaging, respectively. We further show that, compared to that of fluorescence imaging, the SBR enhancement of millisecond-range time-resolved in vivo bioimaging is up to 105 times.

Millisecond‐Range Time‐Resolved Bioimaging Enabled through Ultralong Aqueous Phosphorescence Probes

AbstractProbes featuring room‐temperature phosphorescence (RTP) are promising tools for time‐resolved imaging. It is worth noting that the time scale of time‐resolved bioimaging generally ranges around the microsecond level, because of the short‐lived emission. Herein, the first example of millisecond‐range time‐resolved bioimaging is illustrated, which is enabled through a kind of ultralong aqueous phosphorescence probes (i.e., cyclo‐(Arg‐Gly‐AspD‐Tyr‐Cys)‐conjugated zinc‐doped silica nanospheres), with a RTP emission lasting for ≈5 s and a lifetime as long as 743.7 ms. We demonstrate that live cells and deep tumor tissue in mice can be specifically targeted through immune‐phosphorescence imaging, with a high signal‐to‐background ratio (SBR) value of ≈69 for in vitro imaging, and ≈627 for in vivo imaging, respectively. We further show that, compared to that of fluorescence imaging, the SBR enhancement of millisecond‐range time‐resolved in vivo bioimaging is up to 105 times.

Combinatorial Therapeutic Approaches with Nanomaterial-Based Photodynamic Cancer Therapy.

Photodynamic therapy (PDT), in which a light source is used in combination with a photosensitizer to induce local cell death, has shown great promise in therapeutically targeting primary tumors with negligible toxicity and minimal invasiveness. However, numerous studies have shown that noninvasive PDT alone is not sufficient to completely ablate tumors in deep tissues, due to its inherent shortcomings. Therefore, depending on the characteristics and type of tumor, PDT can be combined with surgery, radiotherapy, immunomodulators, chemotherapy, and/or targeted therapy, preferably in a patient-tailored manner. Nanoparticles are attractive delivery vehicles that can overcome the shortcomings of traditional photosensitizers, as well as enable the codelivery of multiple therapeutic drugs in a spatiotemporally controlled manner. Nanotechnology-based combination strategies have provided inspiration to improve the anticancer effects of PDT. Here, we briefly introduce the mechanism of PDT and summarize the photosensitizers that have been tested preclinically for various cancer types and clinically approved for cancer treatment. Moreover, we discuss the current challenges facing the combination of PDT and multiple cancer treatment options, and we highlight the opportunities of nanoparticle-based PDT in cancer therapies.

A deep tumor penetration nanoplatform for glycolysis inhibition and antimetastasis of breast cancer.

The poor penetration into deep tumor tissues of nanomedicines could not inhibit the production of lactic acid by deep tumor glycolysis, which leads to the accumulation of lactic acid and promotes tumor metastasis. In order to increase tumor penetration, it remains challenging to avoid tumor metastasis by the direct degradation of the extracellular matrix (ECM). Herein, in order to increase tumor penetration, a nano-platform, which can reduce extracellular matrix (ECM) production, and inhibit the glycolysis of deep tumors by releasing ethylenediaminetetraacetic acid (EDTA) is reported. In this design, EDTA and indocyanine green (ICG) are encapsulated in the liposome by a thin-film hydration method, and folic acid (FA) and the polyethyleneimine polymer (FA-PEI) are applied to coat the surface of liposomes through electrostatic interactions, and the FA-EDTA/ICG-Lip nanoparticles are obtained. FA-EDTA/ICG-Lip NPs can release EDTA and ICG in lysosomes (pH 4.5) to reduce ECM production by down-regulating transforming growth factor β (TGF-β) and activating an immune response by inducing tumor cell immunogenic cell death (ICD), respectively. Simultaneously, EDTA inhibits glycolysis of deep tumors by chelating Mg2+. By avoiding tumor metastasis, the strategy of indirectly reducing ECM production is demonstrated to enhance tumor penetration and inhibit deep tumor glycolysis.

Photothermal conversion performance and acid-induced aggregation of PLNP-Bi2S3 composite nanoplatforms.

Poly(sodium 4-styrenesulfonate) (PSS) molecule modified PLNP-Bi2S3 composite nanoplatforms were constructed by using polyvinylpyrrolidone (PVP) modified Bi2S3 nanoparticles (∼4.6 nm) as a photothermal agent and hexadecyl trimethyl ammonium bromide (CTAB) coated Zn2Ga2.98Ge0.75O8:Cr0.023+ (ZGGO:Cr3+@CTAB) persistent luminescence nanoparticles (PLNPs) through electrostatic adsorption. It is found that the above composite nanoplatforms have excellent laser-irradiation thermal stability and good photothermal conversion performance. The measured photothermal conversion efficiency is ∼44%, which is higher than that (∼37%) of the PLNP-GNR (gold nanorod) composite nanoplatforms. Meanwhile, PSS modified PLNP-Bi2S3 composite nanoplatforms exhibited good solution dispersibility in blood and normal tissue environments. While reaching tumor sites, the above composite nanoplatforms can be rapidly accumulated in cancer cells with acidic environments. This pH-responsive acid-induced aggregation can be ascribed to the chemical reaction induced by the protonation of PSS modified PLNP-Bi2S3 composite nanoplatforms with a negatively charged surface in the acidic environments. Our results suggest that PSS modified PLNP-Bi2S3 composite nanoplatforms might be applied to precision diagnosis and therapy of deep-tissue tumors.

Bacterial-Based Cancer Therapy (BBCT): Recent Advances, Current Challenges, and Future Prospects for Cancer Immunotherapy.

Currently approximately 10 million people die each year due to cancer, and cancer is the cause of every sixth death worldwide. Tremendous efforts and progress have been made towards finding a cure for cancer. However, numerous challenges have been faced due to adverse effects of chemotherapy, radiotherapy, and alternative cancer therapies, including toxicity to non-cancerous cells, the inability of drugs to reach deep tumor tissue, and the persistent problem of increasing drug resistance in tumor cells. These challenges have increased the demand for the development of alternative approaches with greater selectivity and effectiveness against tumor cells. Cancer immunotherapy has made significant advancements towards eliminating cancer. Our understanding of cancer-directed immune responses and the mechanisms through which immune cells invade tumors have extensively helped us in the development of new therapies. Among immunotherapies, the application of bacteria and bacterial-based products has promising potential to be used as treatments that combat cancer. Bacterial targeting of tumors has been developed as a unique therapeutic option that meets the ongoing challenges of cancer treatment. In comparison with other cancer therapeutics, bacterial-based therapies have capabilities for suppressing cancer. Bacteria are known to accumulate and proliferate in the tumor microenvironment and initiate antitumor immune responses. We are currently well-informed regarding various methods by which bacteria can be manipulated by simple genetic engineering or synthetic bioengineering to induce the production of anti-cancer drugs. Further, bacterial-based cancer therapy (BBCT) can be either used as a monotherapy or in combination with other anticancer therapies for better clinical outcomes. Here, we review recent advances, current challenges, and prospects of bacteria and bacterial products in the development of BBCTs.

Engineering Bacteria and Bionic Bacterial Derivatives with Nanoparticles for Cancer Therapy.

Natural bacteria are interesting subjects for cancer treatments owing to their unique autonomy-driven and hypoxic target properties. Genetically modified bacteria (such as bacteria with msbB gene and aroA gene modifications) can effectively cross sophisticated physiological barriers and transport antitumor agents into deep tumor tissues, and they have good biosafety. Additionally, bacteria can secrete cytokines (such as interleukin-224, interferon-gamma [IFN-γ], and interleukin-1β) and activate antitumor immune responses in the tumor microenvironment, resulting in tumor inhibition. All of these characteristics can be easily utilized to develop synergistic antitumor strategies by combining bacteria-based agents with other therapeutic approaches. Herein, representative studies of bacteria-instructed multimodal synergistic cancer therapy are introduced (e.g., photothermal therapy, chemoimmunotherapy, photodynamic therapy, and photocontrolled bacterial metabolite therapy), and their key advantages are systematically expounded. The current challenges and future prospects in advancing the development of bacteria-based micro/nanomedicines in the field of synthetic biology research are also emphasized, which will hopefully promote the development of related bacteria-based cancer therapies.

Theranostic Nanoplatform with Sequential SDT and ADV Effects in Response to Well-Programmed LIFU Irradiation for Cervical Cancer.

BackgroundSome patients with cervical cancer have the need to preserve fertility; therefore, a minimally invasive treatment option that can effectively inactivate tumors in these patients is necessary.MethodsIn this paper, we designed and prepared nanoparticles (NPs) carrying IR780 and perfluorohexane (PFH) and characterized their properties. We focused on the promotion of programmed low-intensity focused ultrasound (LIFU) irradiation on the penetration and treatment of cervical cancer. First we used penetration-enhancing LIFU irradiation to promote the penetration of the NPs into 3D multicellular tumor spheroids (MCTSs) and tumors in tumor-bearing nude mice. Then we used re-therapeutic LIFU irradiation to achieve antitumor effects in vitro and in vivo. Photoacoustic (PA) and magnetic resonance (MR) imaging were used to monitor and evaluate the targeting and therapeutic effects of these NPs on tumor tissues.ResultsThe NPs prepared in this paper exhibited high affinity for HeLa cells, and can selectively achieve mitochondrial localization in the cell due to IR780 assistance. The penetration-enhancing LIFU irradiation have the ability to promote the penetration of the NPs into cervical cancer models in vivo and in vitro. Under LIFU irradiation, the cytotoxic reactive oxygen species (ROS) produced by IR780 during the first half of the re-therapeutic LIFU irradiation and the physical acoustic droplet vaporization (ADV) effect after PFH phase transition during the second half of the re-therapeutic LIFU irradiation can achieve synergistic minimally invasive treatment of tumors, which can be visualized and evaluated by PA and MR imaging in vivo.ConclusionWell-programmed LIFU irradiation can promote NP penetration into deep tumor tissue and achieve antitumor effects simultaneously. Linking ROS + ADV effects can induce cell coagulation necrosis and lead to a comprehensive, long-term impact on tumor tissue, providing a conceptual theranostic nanoplatform for cervical cancer.

Acoustic vaporization of internalized superheated perfluorocarbon nanodroplets for imaging and macrophage function modulation

Ultrasound (US) can detect and interact with its contrast agents, allowing perfluorocarbon-based nanodroplets (NDs) or microbubbles (MBs) to detect and treat tumors in deep tissues. Since NDs given IV passively accumulate in tumor macrophages, we aimed to determine whether phagocytosed perfluorobutane (PFB) NDs that boil at -2 °C, can be vaporized in vivo using a clinical scanner. Should that be possible, PFB NDs can then be used to deliver drugs or genes to modulate macrophage function. We formulated stable PFB NDs and validated their internalization into THP-1 macrophages using confocal microscopy. PFB ND loaded macrophages were then infused into nude rats and US imaging (low MI US imaging, 18H6 transducer) of the liver and spleen performed in vivo using a Siemens Sequoia clinical scanner before and after applying MB destruction pulses (at 1.4 MI, 10L4 transducer). PFB ND-loaded macrophages were not visible using low MI imaging, before applying MB destruction pulses. They immediately vaporized into US visible microbubbles when destruction pulses were applied over the liver and remained visible for many minutes after vaporization. Our current focus is to assess ND-loaded macrophage function before and after ND activation to determine the feasibility of modulating immune function. [Study supported by CPRIT RR150010. RFM is a CPRIT Established Investigator. Siemens ACUSON Sequoia Ultrasound System provided as a loan by Siemens Medical Solutions, USA.]

\u201cPetal-like\u201d size-tunable gold wrapped immunoliposome to enhance tumor deep penetration for multimodal guided two-step strategy

BackgroundBreast cancer is the fastest-growing cancer among females and the second leading cause of female death. At present, targeted antibodies combined with hyperthermia locally in tumor has been identified as a potential combination therapy to combat tumors. But in fact, the uniformly deep distribution of photosensitizer in tumor sites is still an urgent problem, which limited the clinical application. We reported an HER2-modified thermosensitive liposome (immunoliposome)-assisted complex by reducing gold nanocluster on the surface (GTSL-CYC-HER2) to obtain a new type of bioplasma resonance structured carrier. The HER2 decoration on the surface enhanced targeting to the breast cancer tumor site and forming irregular, dense, "petal-like" shells of gold nanoclusters. Due to the good photothermal conversion ability under near-infrared light (NIR) irradiation, the thermosensitive liposome released the antitumor Chinese traditional medicine, cyclopamine, accompanied with the degradation of gold clusters into 3–5 nm nanoparticles which can accelerate renal metabolism of the gold clusters. With the help of cyclopamine to degrade the tumor associated matrix, this size-tunable gold wrapped immunoliposome was more likely to penetrate the deeper layers of the tumor, while the presence of gold nanoparticles makes GTSL-CYC-HER2 multimodal imaging feasible.ResultsThe prepared GTSL-CYC-HER2 had a size of 113.5 nm and displayed excellent colloidal stability, photo-thermal conversion ability and NIR-sensitive drug release. These GTSL-CYC-HER2 were taken up selectively by cancer cells in vitro and accumulated at tumour sites in vivo. As for the in vivo experiments, compared to the other groups, under near-infrared laser irradiation, the temperature of GTSL-CYC-HER2 rises rapidly to the phase transition temperature, and released the cyclopamine locally in the tumor. Then, the released cyclopamine destroyed the stroma of the tumor tissue while killing the tumor cells, which in turn increased the penetration of the liposomes in deep tumor tissues. Moreover, the GTSL-CYC-HER2 enhanced the performance of multimodal computed tomography (CT) and photothermal (PT) imaging and enabled chemo-thermal combination therapy.ConclusionsThis optically controlled biodegradable plasmonic resonance structures not only improves the safety of the inorganic carrier application in vivo, but also greatly improves the anti-tumor efficiency through the visibility of in vivo CT and PT imaging, as well as chemotherapy combined with hyperthermia, and provides a synergistic treatment strategy that can broaden the conventional treatment alone.Graphic

Site-Selective Photosynthesis of Ag-AgCl@Au Nanomushrooms for NIR-II Light-Driven O2- and O2•--Evolving Synergistic Photothermal Therapy against Deep Hypoxic Tumors.

Light-driven endogenous water oxidation has been considered as an attractive and desirable way to obtain O2 and reactive oxygen species (ROS) in the hypoxic tumor microenvironment. However, the use of a second near-infrared (NIR-II) light to achieve endogenous H2O oxidation to alleviate tumor hypoxia and realize deep hypoxic tumor phototherapy is still a challenge. Herein, novel plasmonic Ag-AgCl@Au core-shell nanomushrooms (NMs) were synthesized by the selective photodeposition of plasmonic Au at the bulge sites of the Ag-AgCl nanocubes (NCs) under visible light irradiation. Upon NIR-II light irradiation, the resulting Ag-AgCl@Au NMs could oxidize endogenous H2O to produce O2 to alleviate tumor hypoxia. Almost synchronously, O2 could react with electrons on the conduction band of the AgCl core to generate superoxide radicals (O2•-)for photodynamic therapy. Moreover, Ag-AgCl@Au NMs with an excellent photothermal performance could further promote the phototherapy effect. In vitro and in vivo experimental results show that the resulting Ag-AgCl@Au NMs could significantly improve tumor hypoxia and enhance phototherapy against a hypoxic tumor. The present study provides a new strategy to design H2O-activatable, O2- and ROS-evolving NIR II light-response nanoagents for the highly efficient and synergistic treatment of deep O2-deprived tumor tissue.

Mitochondrion-Anchored Photosensitizer with Near Infrared-I Aggregation-Induced Emission for Near Infrared-II Two-Photon Photodynamic Therapy.

Two-photon photodynamic therapy (2P-PDT) that employs photosensitizers (PSs) with 2P absorption is particularly intriguing in cancer treatment, in that 2P excitation enables precise spatial localization and deep tissue penetration. Here, a donor-π-acceptor PS (named TPBPy) with near infrared (NIR) aggregation-induced emission (AIE) is designed and synthesized for imaging-guided 2P-PDT. The maximal photoluminescence (PL) peak of TPBPy is as high as 720nm when it is encapsulated in liposomes. Upon 2P irradiation by a laser in NIR-II window (λ=1000nm), TPBPy exhibits strong NIR-I PL in a multicellular tumor spheroids (MCTSs) model, showing an imaging depth of 210µm that is significantly higher than upon one-photon irradiation. Moreover, TPBPy localizes specifically on mitochondrion, an important organelle in cell oxidative metabolism and apoptosis. When exposed to the NIR-II irradiation, TPBPy can efficiently generate singlet oxygen (1 O2 ) and trigger cell death. The efficacy of TPBPy-mediated 2P-PDT has also been validated using 4T1 tumor mouse model, the growth of which is significantly suppressed upon NIR-II laser irradiation. TPBPy herein serves as an excellent candidate to suppress deep tumor tissues through NIR-II 2P-PDT, and also renders a new paradigm to construct mitochondrion-anchored AIE luminogens for future cancer theranostic applications.