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Purpose To investigate the temporal and spatial infiltration of TRAMP-C1 tumors by myeloid-derived suppressor cells (MDSCs) after high-dose radiation therapy (RT), and to explore their effect on tumor growth. Methods and Materials TRAMP-C1 intramuscularly tumors were irradiated with a single dose of 8 Gy or 25 Gy. The dynamics of infiltrated MDSCs and their intratumoral spatial distribution were assessed by immunohistochemistry and flow cytometry. Cytokine levels in the blood and tumor were analyzed by multiplex immunoassay. Mice were injected with anti-Gr-1 antibody to determine whether MDSCs affect tumor growth after RT. Results CD11b+Gr-1+ MDSCs infiltrated TRAMP-C1 tumors irradiated with 25 Gy, but not 8 Gy, within 4 hours and recruitment persisted for at least 2 weeks. Both CD11b+Ly6G+Ly6C+ polymorphonuclear-MDSCs (PMN-MDSCs) and CD11b+Ly6G-Ly6Chi monocytic-MDSCs (M-MDSCs) were involved. Tumor RT also increased the representation of both MDSC subpopulations in the spleen and peripheral blood. Levels of multiple cytokines were increased in the tumors at 2 weeks, including GM-CSF, G-CSF, CCL-3, CCL-5, CXCL-5, IL-6, IL-17α, and VEGF-a; while G-CSF, IL-6, and TNF-α levels increased in the blood. PMN-MDSCs aggregated in the central necrotic region of the irradiated tumors over time, where they were associated with avascular hypoxia (CD31-PIMO+). MDSCs expressed the proangiogenic factor, matrix metalloproteinase-9, and, within the necrotic area, high levels of arginase-1 and indoleamine 2,3-dioxygenase. Depletion of PMN-MDSCs by Gr-1 antibody increased the efficacy of high-dose RT. Conclusions PMN-MDSCs infiltrate TRAMP-C1 tumors after high-dose RT. Their spatial distribution suggests they are involved in the evolution of an intratumoral state of necrosis associated with avascular hypoxia, and their phenotype is consistent with them being immunosuppressive. They appear to promote tumor growth after RT, making them a prime therapeutic target for therapeutic intervention. Assessment of MDSCs and cytokine levels in blood could be an index of the need for such an intervention.

Compact nanohybrids can potentially unite various therapeutic features and reduce side effects for precise cancer therapy. However, the poor accumulation and limited tumor penetration of drugs at the tumor impede the manifestation of nanomedicine. We developed a rabies virus glycoprotein (RVG)-amplified hierarchical targeted hybrid that acts as a stealthy and magnetolytic carrier that transports dual tumor-penetrating agents incorporating two drugs (boron-doped graphene quantum dots (B-GQDs)/doxorubicin and pH-responsive dendrimers (pH-Den)/palbociclib). The developed RVG-decorated hybrids (RVG-hybrids) enhance the accumulation of drugs at tumor by partially bypassing the BBB via spinal cord transportation and pH-induced aggregation of hierarchical targeting. The penetrated delivery of dual pH-Den and B-GQD drugs to deep tumors is actuated by magnetoelectric effect, which are able to generate electrons to achieve electrostatic repulsion and disassemble the hybrids into components of a few nanometers in size. The synergy of magnetoelectric drug penetration and chemotherapy was achieved by delivery of the B-GQDs and pH-Den to orthotopic tumors, which prolonged the host survival time. This RVG-amplified dual hierarchical delivery integrated with controlled and penetrated release from this hybrid improve the distribution of the therapeutic agents at the brain tumor for synergistic therapy, exhibiting potential for clinic use.

Background There are limited effective drugs that can reach the brain to target brain tumors, in particular glioblastoma, which is one of the most difficult cancers to be cured from. Because the overexpression of the sigma-2 receptor is frequently reported in glioma clinical samples and associated with poor prognosis and malignancy, we herein studied the anti-tumor effect of the sigma-2 receptor agonist PB221 (4-cyclohexyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperidine) on an anaplastic astrocytoma tumor model based on previous encouraging results in pancreatic cancer and neuroblastoma SK-N-SH cells. Methods The expression of the sigma-2 receptor, transmembrane protein 97 (TMEM97), in ALTS1C1 and UN-KC6141 cell lines was measured by RT-PCR and quantitative RT-PCR. The binding of sigma-2 receptor fluorescent ligands PB385 (6-[5-[3-(4-cyclohexylpiperazin-1-yl)propyl]-5,6,7,8-tetrahydronaphthalen-5-yloxy]-N-(7-nitro-2,1,3-benzoxadiazol-4-yl)hexanamine) and NO1 (2-{6-[2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one-5-yloxy]hexyl}-5-(dimethylamino)isoindoline-1,3-dione) was examined by flow cytometry and the fluorescent plate reader. The antitumor activity of PB221 was initially examined in the murine brain tumor cell line ALTS1C1 and then in the murine pancreatic cell line UN-KC6141. The potential therapeutic efficacy of PB221 for murine brain tumors was examined by in vitro migration and invasion assays and in vivo ectopic and orthotopic ALTS1C1 tumor models. Results: The IC50 of PB221 for ALTS1C1 and UN-KC6141 cell lines was 10.61 ± 0.96 and 13.13 ± 1.15 μM, respectively. A low dose of PB221 (1 μM) significantly repressed the migration and invasion of ALTS1C1 cells, and a high dose of PB221 (20 μM) resulted in the apoptotic cell death of ALTS1C1 cells. These effects were reduced by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine, suggesting mitochondrial oxidative stress is involved. The in vivo study revealed that PB221 effectively retarded tumor growth to 36% of the control tumor volume in the ectopic intramuscular tumor model and increased the overall survival time by 20% (from 26 to 31 days) in the orthotopic intracerebral tumor model. Conclusions This study demonstrates that the sigma-2 receptor agonist PB221 has the potential to be an alternative chemotherapeutic drug for brain tumors with comparable side effects as the current standard-of-care drug, temozolomide. Electronic supplementary material The online version of this article (10.1186/s12885-019-5700-7) contains supplementary material, which is available to authorized users.

International audience; Extracellular nucleotides are important mediators of cell activation and trigger multiple responses via membrane receptors known as purinergic receptors (P2). P2X receptors are ligand-gated ion channels, activated by extracellular ATP. P2X4 is one of the most sensitive purinergic receptors, that is typically expressed by neurons, microglia, and some epithelial and endothelial cells. P2X4 mediates neuropathic pain via brain-derived neurotrophic factor and is also involved in inflammation in response to high ATP release. It is therefore involved in multiple inflammatory pathologies as well as neurodegenerative diseases. We have produced monoclonal antibodies (mAb) directed against this important human P2X4 receptor. Focusing on two mAbs, we showed that they also recognize mouse and rat P2X4. We demonstrated that these mAbs can be used in flow cytometry, immunoprecipitation and immunohistochemistry, but not in Western blot assays, indicating that they target conformational epitopes. We also characterised the expression of P2X4 receptor on mouse and human peripheral blood lymphocytes (PBL). We showed that P2X4 is expressed at the surface of several leukocyte cell types, with the highest expression level on eosinophils, making them potentially sensitive to adenosine triphosphate (ATP). P2X4 is expressed by leucocytes, in human and mouse, with a significant gender difference, males having higher surface expression levels than females. Our findings reveal that PBL express significant levels of P2X4 receptor, and suggest an important role of this receptor in leukocyte activation by ATP, particularly in P2X4high expressing eosinophils.

Dual-targeted delivery of drugs and energy by nanohybrids can potentially alleviate side effects and improve the unique features required for precision medicine. To realize this aim, however, the hybrids which are often rapidly removed from circulation and the piled up tumors periphery near the blood vessels must address the difficulties in low blood half-lives and tumor penetration. In this study, a sponge-inspired carbon composites-supported red blood cell (RBC) membrane that doubles as a stealth agent and photolytic carrier that transports tumor-penetrative agents (graphene quantum dots and docetaxel (GQD-D)) and heat with irradiation was developed. The RBC-membrane enveloped nanosponge (RBC@NS) integrated to a targeted protein that accumulates in tumor spheroids via high lateral bilayer fluidity exhibits an 8-fold increase in accumulation compared to the NS. Penetrative delivery of GQDs to tumor sites is actuated by near-infrared irradiation through a one-atom-thick structure, facilitating penetration and drug delivery deep into the tumor tissue. The synergy of chemotherapy and photolytic effects was delivered by the theranostic GQDs deep into tumors, which effectively damaged and inhibited the tumor in 21 days when treated with a single irradiation. This targeted RBC@GQD-D/NS with the capabilities of enhanced tumor targeting, NIR-induced drug penetration into tumors, and thermal ablation for photolytic therapy promotes tumor suppression and exhibits potential for other biomedical applications.

Designing a single multifunctional nanoparticle that can simultaneously impart both diagnostic and therapeutic functions is considered to be a long-lasting hurdle for biomedical researchers. Conventionally, a multifunctional nanoparticle can be constructed by integrating organic dyes/magnetic nanoparticles to impart diagnostic functions and anticancer drugs/photosensitizers to achieve therapeutic outcomes. These multicomponents systems usually suffer from severe photobleaching problems and cannot be activated by near-infrared (NIR) light. Here, it is demonstrated that all-in-one lanthanide-doped mesoporous silica frameworks (EuGdOx@MSF) loaded with an anticancer drug, doxorubicin (DOX) can facilitate simultaneous bimodal magnetic resonance (MR) imaging with approximately twofold higher T1-MR contrast as compared to the commercial Gd(III)-DTPA complex and fluorescence imaging with excellent photostability. Upon a very low dose (130 mW cm−2) of NIR light (980 nm) irradiation, the EuGdOx@MSF not only can sensitize formation of singlet oxygen (1O2) by itself but also can phototrigger the release of the DOX payload effectively to exert combined chemo-photodynamic therapeutic (PDT) effects and destroy solid tumors in mice completely. It is also discovered for the first time that the EuGdOx@MSF-mediated PDT effect can suppress the level of the key drug resistant protein, i.e., p-glycoprotein (p-gp) and help alleviate the drug resistant problem commonly associated with many cancers.

Cancer is one of the major life-threatening diseases among human beings. Developing a simple, cost-effective and biocompatible approach to treat cancers using ultra-low doses of light is a grand challenge in clinical cancer treatments. In this study, we report for the first time that nano-sized graphene oxide (GO) exhibits single-photon excitation wavelength dependent photoluminescence in the visible and short near-infrared (NIR) region, suitable for in vivo multi-color fluorescence imaging. We also demonstrate in both in vitro and in vivo experiments to show that nano GO can sensitize the formation of singlet oxygen to exert combined nanomaterial-mediated photodynamic therapeutic (NmPDT) and photothermal therapy (NmPTT) effects on the destruction of B16F0 melanoma tumors in mice using ultra-low doses (∼0.36 W/cm 2 ) of NIR (980 nm) light. The average half-life span of the mice treated by the GO-PEG-folate-mediated NmPDT effects is beyond 30 days, which is ∼1.8 times longer than the mice treated with doxorubicin (17 days). Overall, the current study points out a successful example of using GO-PEG-folate nanocomposite as a theranostic nanomedicine to exert simultaneously in vivo fluorescent imaging as well as combined NmPDT and NmPTT effects for clinical cancer treatments.

Rationale: Cisplatin (CDDP) is a broad-spectrum anticancer drug but chemoresistance to CDDP impedes its wide use for cancer therapy. Autophagy is an event occurring in the cytoplasm and cytoplasmic LC3 puncta formation is a hallmark of autophagy. Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we aimed to evaluate whether combined use of GO with CDDP (GO/CDDP) overcomes chemoresistance in different cancer cells and uncover the underlying mechanism. Methods: We treated different cancer cells with GO/CDDP and evaluated the cytotoxicity, death mechanism, autophagy induction and nuclear entry of CDDP. We further knocked down genes essential for autophagic flux and deciphered which step is critical to nuclear import and cell death. Finally, we performed immunoprecipitation, mass spectrometry and immunofluorescence labeling to evaluate the association of LC3 and CDDP. Results: We uncovered that combination of GO and CDDP (GO/CDDP) promoted the killing of not only CT26 cells, but also ovarian, cervical and prostate cancer cells. In the highly chemosensitized Skov-3 cells, GO/CDDP significantly enhanced concurrent nuclear import of CDDP and autophagy marker LC3 and elevated cell necrosis, which required autophagy initiation and progression but did not necessitate late autophagy events (e.g., autophagosome completion and autolysosome formation). The GO/CDDP-elicited nuclear trafficking and cell death also required importin α/β, and LC3 also co-migrated with CDDP and histone H1/H4 into the nucleus. In particular, GO/CDDP triggered histone H4 acetylation in the nucleus, which could decondense the chromosome and enable CDDP to more effectively access chromosomal DNA to trigger cell death. Conclusion: These findings shed light on the mechanisms of GO/CDDP-induced chemosensitization and implicate the potential applications of GO/CDDP to treat multiple cancers.

Cancer is one of the major diseases leading to human deaths. Complete destruction of deep tissue-buried tumors using non-invasive therapies is a grand challenge in clinical cancer treatments. Many therapeutic modalities were developed to tackle this problem, but only partial tumor suppression or delay growths were usually achieved. In this study, we report for the first time that complete destruction of deep tissue-buried tumors can be achieved by combination of gold nanoechinus (Au NEs)-mediated photodynamic therapy (PDT) and gene silencing under ultra-low doses of near infra-red (NIR) light irradiation (915 nm, 340 mW/cm(2); 1064 nm, 420 mW/cm(2)) in the first and second biological windows. The average lifespan of the mice treated by the above combined therapy is beyond 40 days, which are ∼ 2.6 times longer than that (15 days) observed from the anticancer drug doxorubicin-treated group. The current study points out a new direction for the therapeutic design to treat deeply seated tumors in future cancer treatments.

The nucleus is one of the most important cellular organelles and molecular anticancer drugs, such as cisplatin and doxorubicin, that target DNA inside the nucleus, are proving to be more effective at killing cancer cells than those targeting at cytoplasm. Nucleus-targeting nanomaterials are very rare. It is a grand challenge to design highly efficient nucleus-targeting multifunctional nanomaterials that are able to perform simultaneous bioimaging and therapy for the destruction of cancer cells. Here, unique nucleus-targeting gold nanoclusters (TAT peptide–Au NCs) are designed to perform simultaneous in vitro and in vivo fluorescence imaging, gene delivery, and near-infrared (NIR) light activated photodynamic therapy for effective cancer cell killing. Confocal laser scanning microscopy observations reveal that TAT peptide–Au NCs are distributed throughout the cytoplasm region with a significant fraction entering into the nucleus. The TAT peptide–Au NCs can also act as DNA nanocargoes to achieve very high gene transfection efficiencies (≈81%) in HeLa cells and in zebrafish. Furthermore, TAT peptide–Au NCs are also able to sensitize formation of singlet oxygen (1O2) without the co-presence of organic photosensitizers for the destruction of cancer cells upon NIR light photoexcitation.

Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we demonstrated that both GO and the chemotherapy drug cisplatin (CDDP) induced autophagy but elicited low degrees of CT26 cell death. Strikingly, GO combined with CDDP (GO/CDDP) potentiated the CT26 cell killing via necrosis. GO/CDDP not only elicited autophagy, but induced the nuclear import of CDDP and the autophagy marker LC3. The nuclear LC3 did not co-localize with p62 or Lamp-2, neither did blocking autolysosome formation significantly hinder the nuclear import of LC3/CDDP and necrosis, indicating that autophagosome and autolysosome formation was dispensable. Conversely, suppressing phagophore formation and importin-α/β significantly alleviated the nuclear import of LC3/CDDP and necrosis. These data suggested that GO/CDDP diverted the LC3 flux in the early phase of autophagy, resulting in LC3 trafficking towards the nucleus in an importin-α/β-dependent manner, which concurred with the CDDP nuclear import and necrosis. Intratumoral injection of GO/CDDP into mice bearing CT26 colon tumors potentiated immune cell infiltration and promoted cell death, autophagy and HMGB1 release, thereby synergistically augmenting the antitumor effects. Altogether, we unveiled a mechanism concerning how nanomaterials chemosensitize cancer cells and demonstrated the potentials of GO as a chemosensitizer.

Recently, living cells with tumor-homing properties have provided an exciting opportunity to achieve optimal delivery of nanotherapeutic agents. However, premature payload leakage may impair the host cells, often leading to inadequate in vivo investigations or therapeutic efficacy. Therefore, a nanoplatform that provides a high drug-loading capacity and the precise control of drug release is required. In the present study, a robust one-step synthesis of a doxorubicin (DOX)-loaded gold nanorod/albumin core-shell nanoplatform (NR@DOX:SA) was designed for effective macrophage-mediated delivery to demonstrate how nanoparticle-loaded macrophages improve photothermal/chemodrug distribution and retention ability to achieve enhanced antitumor effects. The serum albumin shell of these nanoagents served as a drug reservoir to delay the intracellular DOX release and drug-related toxicity that impairs the host cell carriers. Near-infrared laser irradiation enabled on-demand payload release to destroy neighboring tumor cells. A series of in vivo quantitative analyses demonstrated that the nanoengineered macrophages delivered the nanodrugs through tumor-tropic migration to tumor tissues, resulting in the twice homogenous and efficient photothermal activations of drug release to treat prostate cancer. By contrast, localized pristine NR@DOX:SAs exhibit limited photothermal drug delivery that further reduces their retention ability and therapeutic efficacy after second combinational treatment, leading to a failure of cancer therapy. Moreover, the resultant unhealable wounds impair quality of life. Free DOX has rapid clearance and therefore exhibits limited antitumor effects. Our findings suggest that in comparison with pristine nanoparticles or free DOX, the nanoengineered macrophages effectively demonstrate the importance and effect of homogeneous drug distribution and retention ability in cancer therapy.

Hepatitis C virus (HCV)-induced hepatic stress is associated with increased oxidative DNA damage and has been implicated in hepatic inflammation. However, HCV infection and replication are uneven and vary among individual hepatocytes. To investigate the effect of the viral load on host DNA damage, we used an Enhanced Yellow Fluorescent Protein gene (EYFP)-tagged HCV virus to distinguish between HCV intracellular high viral load (HVL) cells and low viral load (LVL) cells. The cell sorting efficiency was confirmed by the high expression of the HCV polyprotein. We found DNA damage γ-H2AX foci in the HVL population. Comet assays demonstrated that HVL was related to the extent of the DNA strand breaks. Surprisingly, the DNA qPCR arrays and western blotting showed that the damage-related genes GPX2, MRE11, phospho-ATM, and OGG1 were significantly up-regulated in LVL cells but inversely down-regulated or consistently expressed in HVL cells. The colony survival assay to examine the repair abilities of these cells in response to irradiation showed that the LVL cells were more resistant to irradiation and had an increased ability to repair radiation-induced damage. This study found that intracellular viral loads drove cellular DNA damage levels but suppressed damage-related gene expression. However, the increase in damage-related gene expression in the LVL cells may be affected by ROS from the HVL cells. These findings provide new insights into the distinct DNA damage and repair responses resulting from different viral loads in HCV-infected cells.

The gadolinium-doped iron oxide nanoparticles (GdIONP) with greater specific power adsorption rate (SAR) than Fe3O4 was developed and its potential application in tumour therapy and particle tracking were demonstrated in transgenic adenocarcinoma of the mouse prostate C1 (TRAMP-C1) tumours. The GdIONPs accumulated in tumour region during the treatment could be clearly tracked and quantified by T2-weighted MR imaging. The therapeutic effects of GdIONP-mediated hyperthermia alone or in combination with radiotherapy (RT) were also evaluated. A significant increase in the tumour growth time was observed following the treatment of thermotherapy (TT) only group (2.5 days), radiation therapy only group (4.5 days), and the combined radio-thermotherapy group (10 days). Immunohistochemical staining revealed a reduced hypoxia region with vascular disruption and extensive tumour necrosis following the combined radio-thermotherapy. These results indicate that GdIONP-mediated hyperthermia can improve the efficacy of RT by its dual functions in high temperature (temperature greater than 45 °C)-mediated thermal ablation and mild-temperature hyperthermia (MTH) (temperature between 39 and 42 °C)-mediated reoxygenation.

Gold nanoechinus can sensitize the formation of singlet oxygen in the first and the second near-infra red (NIR) biological windows and exert in vivo dual modal photodynamic and photothermal therapeutic effects (PDT and PTT) to destruct the tumors completely. This is the first literature example of the destruction of tumors in NIR window II induced by dual modal nanomaterial-mediated photodynamic and photothermal therapy (NmPDT & NmPTT).

Purpose: To examine whether brain tumors grown in pre-irradiated (PreIR) thigh have a similar tumor bed effect (TBE) as in PreIR brain tissue.Material and methods: Tumor growth delay and immunohistochemical (IHC) staining for CD31, an endothelial surface marker, and PIMO, a hypoxia marker, were used to study the TBE of a murine astrocytoma, ALTS1C1, or a stromal-derived factor-1 (SDF-1) gene-silenced astrocytoma, ALTS1C1-SDFkd, growing in different PreIR stroma beds.Results: ALTS1C1 tumors growing in both PreIR brain and PreIR thigh had reduced microvascular density (MVD) and more chronic hypoxia, but tumor growth delay was only seen in PreIR brain tissue. In contrast, ALTS1C1-SDFkd tumors showed tumor growth delay in PreIR thigh, with little effect in PreIR brain tissue.Conclusions: This study cautions that both the tumor and the nature of the PreIR stromal bed are important when using pre-irradiation as a model of recurrent brain tumors after radiation therapy.

Upon excitation with near-infrared light (980 nm), PEGylated W18 O49 nanowires can sensitize the formation of singlet oxygen and thus reactive oxygen species (ROS). The resulting photodynamic therapy (PDT) effect can cause the destruction of tumors in the absence of organic photosensitizers. PEG=poly(ethylene glycol), PTT=photothermal therapy.

The purpose of this preclinical study was to perform a longitudinal investigation of the function and morphology of the vasculatures of primary and recurrent tumors, because recurrent tumors have lower curability. Thus, elucidating differences in the features of the vasculatures of primary and recurrent tumors could help to improve tumor therapies. The transgenic adenocarcinoma of the mouse prostate tumors were transplanted in nonirradiated and with 25 Gy of preirradiation normal tissues to produce the primary and recurrent tumor models, respectively. The perfusion and branching index of tumor vasculatures were characterized to reveal the function and morphology information, respectively. The blood vessels were more dilated and continuous in recurrent tumors than in primary tumors. During tumor progression, the perfusion increased in primary tumors but did not change significantly in recurrent tumors. The tumor perfusion was lower in recurrent tumors than in primary tumors, whereas branching index in 2-D ultrasound images did not differ between the two tumor models. Furthermore, the introducing 3-D volumetric power Doppler image may have the potential for accurately revealing the morphologic features within tumors. The results of this study suggest that power Doppler imaging is an easily applied and rapid method for noninvasively assessing the vascular features of primary and recurrent tumors and for exploring differences between their vasculature pathways.

Delivery of drug and energy within responsive carriers that effectively target and accumulate in cancer cells promises to mitigate side effects and to enhance the uniquely therapeutic efficacy demanded for personalized medicine. To achieve this goal, however, these carriers, which are usually piled up at the periphery of tumors near the blood vessel, must simultaneously overcome the challenges associated with low tumor penetration and the transport of sufficient cargos to deep tumors to eradicate whole cancer cells. Here, we report a sponge-like carbon material on graphene nanosheet (graphene nanosponge)-supported lipid bilayers (lipo-GNS) that doubles as a photothermal agent and a high cargo payload platform and releases a burst of drug/energy (docetaxel (DTX) and gasified perfluorohexane (PFH)) and intense heat upon near-infrared irradiation. Ultrasmall lipo-GNS (40 nm) modified with a tumor-targeting protein that penetrates tumor spheroids through transcytosis exhibited a 200-fold increase in accumulation relative to a 270 nm variant of the lipo-GNS. Furthermore, a combination of therapeutic agents (DTX and PFH) delivered by lipo-GNS into tumors was gasified and released into tumor spheroids and successfully ruptured and suppressed xenograft tumors in 16 days without distal harm when subjected to a single 10 min near-infrared laser treatment. Moreover, no tumor recurrence was observed over 60 days post-treatment. This sophisticated lipo-GNS is an excellent delivery platform for penetrated, photoresponsive, and combined gasification/chemo-thermotherapy to facilitate tumor treatment and for use in other biological applications.

Chemotherapy is typically used to treat malignant brain tumors, especially for the tumors in surgically inaccessible areas. However, owing to the existence of blood-brain barrier (BBB), the tumor accumulation and therapeutic efficacy of clinical therapeutics is still of great concerns. To this end, we present herein a prominent therapeutic strategy adopting adipose-derived stem cells (ADSCs) capable of carrying nanotherapeutic payloads selectively toward brain tumors for thermo/chemotherapy. The nanoparticle (NP) payload was obtained from co-assembly of poly(γ-glutamic acid-co-distearyl γ-glutamate) with poly(lactic-co-glycolic acid), paclitaxel (PTX), and oleic acid-coated superparamagnetic iron oxide NPs in aqueous solution. The particle size and drug loading content were ca 110 nm and 8.4 wt%, respectively. After being engulfed by ADSCs, the nanotherapeutics was found rather harmless to cellular hosts at a PTX concentration of 30 μM over 48 h in the absence of pertinent stimulus. Nevertheless, the ADSC-based approach combined with high frequency magnetic field exhibits a sound therapeutic performance with a 4-fold increase in therapeutic index on brain astrocytoma (ALTS1C1)-bearing mice (C57BL/6 J) as compared to the typical chemotherapy using a current first-line chemodrug, temozolomide. Immunohistochemical examination of brain tumor sections confirms the successful cellular transport and pronounced cytotoxic action of therapeutics against tumor cells in vivo. This work demonstrates the promise of ADSC-mediated chemo/thermal therapy against brain tumors.

Radiotherapy is crucial and substantially contributes to multimodal cancer treatment. The combination of conventional fractionation radiotherapy (CFRT) and systemic therapy has been established as the standard treatment for many cancer types. With advances in linear accelerators and image-guided techniques, high-dose fractionation radiotherapy (HFRT) is increasingly introduced in cancer centers. Clinicians are currently integrating HFRT into multimodality treatment. The shift from CFRT to HFRT reveals different effects on the tumor microenvironment and responses, particularly the immune response. Furthermore, the combination of HFRT and drugs yields different results in different types of tumors or using different treatment schemes. We have reviewed clinical trials and preclinical evidence on the combination of HFRT with drugs, such as chemotherapy, targeted therapy, and immune therapy. Notably, HFRT apparently enhances tumor cell killing and antigen presentation, thus providing opportunities and challenges in treating cancer.

Purpose: Tumor heterogeneity is a major obstacle to therapy, and thus, how to achieve the maximal therapeutic gain in tumor suppression is an important issue. To accomplish this goal, assessing changes in tumor behaviors before treatment is helpful for physicians to adjust treatment schedules. In this study, the authors longitudinally and spatially investigated tumor perfusion and vascular density by power Dopplerimaging and immunohistochemical analysis, respectively. Moreover, the authors developed a method to describe quantitatively the spatial distribution of the vasculature within the central and peripheral regions of tumors. Methods: Tumor perfusion was estimated by power Dopplerimages at an operating frequency of 25 MHz. To avoid the attenuation effect of such high-frequency ultrasound, murine tumors were subcutaneously transplanted into the thighs of mice and then monitored for 11 days. The tumors were removed at various time intervals for immunohistochemical analysis of their vascular density using CD31 staining. The spatial characteristics of the tumor vasculature were quantified by aγ value, which characterizes the rate at which vascular signals increase with the fractional sizes of the peripheral area within the tumor. Results: During tumor progression, the volume of tumor perfusion in the power Dopplerimages was strongly correlated with the vascular density determined by immunohistochemical analysis. In addition, theγ value significantly decreased with increased tumor size in the power Dopplerimages but not in the immunohistochemical analysis. Conclusions: Although the tumor perfusion and vascular density estimates showed good temporal correlations during tumor progression, they did not show good spatial correlations due to tumor perfusion patterns changing from homogeneous to heterogeneous. In contrast to the perfusion patterns, the vascular density of the tumor remained uniformly distributed. In the present study, no necrosis regions were found in the tumor experiments. Furthermore, the measurement ofγ value is a simple method for assessing the vasculatures of spatial distribution within tumors.

A recombinant annexin A5 with the N-terminal extension of six histidine residues was labeled with (99m)Tc(I)-tricarbonyl ion to produce the (99m)Tc-labeled annexin A5, referred to (99m)Tc(I)-his(6)-annexin A5. We have explored the agent as an effective imaging probe for in vivo detecting the apoptosis of internal tissue subjected with high radiation doses in a γ-irradiated mouse model.[(99m)Tc(CO)(3)(OH(2))(3)](+) was prepared and taken to directly label his(6)-annexin A5. The radiochemical purity of (99m)Tc(I)-his(6)-annexin A5 after size-exclusion separation was measured by HPLC. The binding affinity of (99m)Tc(I)-his(6)-annexin A5 to apoptotic cells was assessed using 20 Gy-irradiated Jurkat T cells. The effectiveness of (99m)Tc(I)-his(6)-annexin A5 as an imaging probe to detect the internal tissue apoptosis was assessed by biodistribution study and nanoSPECT/CT using the animal model of C57BL/6J mice conducted with 10 Gy γ irradiation.The radiochemical purity of (99m)Tc(I)-his(6)-annexin A5 could attain ≥95%. The binding affinity of (99m)Tc(I)-his(6)-annexin A5 to the 20 Gy-irradiated Jurkat cells was found to be ca. 20-fold higher than that to the sham-irradiated cells. In the animal imaging study, the splenic uptake of (99m)Tc(I)-his(6)-annexin A5 for the 10 Gy-irradiated mice showed from ca. 3-fold to 5-fold higher than those of the sham-irradiated mice from 45 to 165 min postinjection. The corresponding intestinal uptake showed from ca. 2-fold to 3-fold higher during the same period of time postinjection. The biodistribution study demonstrated the organ uptakes comparable with the imaging results. The apoptotic extents of the spleen and the intestine from the SPECT/CT imaging were correlated with an immunohistochemical staining assay for caspase 3 active form fragment.This work is the first study to demonstrate that (99m)Tc(I)-his(6)-annexin A5 is a potential clinical imaging agent for detecting radiation-induced tissue apoptosis in an animal model.

Polymeric vesicles produced by spontaneous self-association of poly(acrylic acid-co-distearin acrylate) (poly(AAc-co-DSA)) with varying ratios of AAc and DSA units in aqueous solution of pH 5.0 exhibit the pH-regulated drug release behavior. Through the electrostatic interaction with ionized AAc residues, doxorubicin (DOX) molecules can be highly accommodated onto either the inner or outer surfaces of vesicles when the pH is adjusted from 5.0 to 7.4. The extent of DOX encapsulation is dependent largely on the structural transition of vesicles in response to the pH change. While the pH-evolved drug release profile varies to some extent with the distribution of DOX molecules within vesicles, the drug release from vesicles is accelerated significantly via the disruption of the electrostatic interaction of DOX species with ionized AAc moieties at pH 5.0. The DOX-loaded polymeric vesicles show promoted cellular uptake and cytotoxicity comparable to free DOX for HeLa cells. This indicates that they are probably taken up by the cells via the lipid raft-mediated endocytosis.

Antiangiogenesis is an appealing anticancer approach but requires continued presence of the antiangiogenic agents, which can be remedied by gene therapy. Baculovirus is an emerging gene delivery vector but only mediates transient expression (

To investigate the effects of ataxia telangiectasia mutated (ATM)-regulated reactive oxygen species (ROS) and cell death pathways on the response of U87MG glioma cells to ionising radiation (IR) and oxidative stress.ATM expression was blocked in U87MG glioma cells using a small interfering RNA (siRNA) technique. Cell survival, sub-lethal damage (SLD), and potential lethal damage (PLD) repair following IR were assessed by clonogenic assay while changes in intracellular ROS, the apoptosis, and autophagy were followed by flow cytometry and Western blotting.Blocking ATM expression in U87MG cells increased intracellular ROS levels and sensitivity to the cytotoxic effects of IR and oxygen stress; effects that could be partly counteracted by the antioxidant N-acetylcysteine (NAC). Knock down of ATM rendered cells unable to repair sub-lethal or potentially lethal damage and DNA double strand breaks (DSB) after IR exposure; something that NAC could not counteract. ATM did control the pathways a cell used to die following IR and this did seem to be ROS-dependent.ATM is involved in redox control but ROS elevations following ATM knock down seem more involved in the decision as to what cell death pathway is utilised after IR than DSB repair and radiosensitivity.

HeLa cells were incubated with neutron capture nuclei (boron-10 and gadolinium)-containing carbon nanoparticles, followed by irradiation of slow thermal neutron beam. Under a neutron flux of 6 x 10(11) n/cm(2) (or 10 min irradiation at a neutron flux of 1 x 10(9) n/cm(2) s), the percentages of acute cell death at 8 h after irradiation are 52, 55, and 28% for HeLa cells fed with BCo@CNPs, GdCo@CNPs, and Co@CNPs, respectively. The proliferation capability of the survived HeLa cells was also found to be significantly suppressed. At 48 h after neutron irradiation, the cell viability further decreases to 35 +/- 5% as compared to the control set receiving the same amount of neutron irradiation dose but in the absence of carbon nanoparticles. This work demonstrates "proof-of-concept" examples of neutron capture therapy using (10)B-, (157)Gd-, and (59)Co-containing carbon nanoparticles for effective destruction of cancer cells. It will also be reported the preparation and surface functionalization of boron or gadolinium doped core-shell cobalt/carbon nanoparticles (BCo@CNPs, GdCo@CNPs and Co@CNPs) using a modified DC pulsed arc discharge method, and their characterization by various spectroscopic measurements, including TEM, XRD, SQUID, FT-IR, etc. Tumor cell targeting ability was introduced by surface modification of these carbon nanoparticles with folate moieties.

Purpose: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. Methods and Materials: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. Results: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNA expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1–2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. Conclusions: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo .

Purpose To investigate whether changes in the volume transfer coefficient (K trans ) in a growing tumor could be used as a surrogate marker for predicting tumor responses to radiation therapy (RT) and chemotherapy (CT). Methods and Materials Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was consecutively performed on tumor-bearing mice, and temporal and spatial changes of K trans values were measured along with tumor growth. Tumor responses to RT and CT were studied before and after observed changes in K trans values with time. Results Dynamic changes with an initial increase and subsequent decline in K trans values were found to be associated with tumor growth. When each tumor was divided into core and peripheral regions, the K trans decline was greater in core, although neither vascular structure or necrosis could be linked to this spatial difference. Tumor responses to RT were worse if applied after the decline of K trans , and there was less drug distribution and cell death in the tumor core after CT. Conclusion The K trans value in growing tumors, reflecting the changes of tumor microenvironment and vascular function, is strongly associated with tumor responses to RT and CT and could be a potential surrogate marker for predicting the tumor response to these treatments.

Photodynamic therapy (PDT) is a powerful technique photochemically tailored for activating apoptosis of malignant cells. Although PDT has shown promise in several clinical applications, malignant cells in hypoxic regions are often resistant to PDT due to the transport limitation of therapeutics and the oxygen-dependent nature of PDT. Herein, we present an innovative strategy for overcoming the limits of PDT in tumor hypoxia using bone marrow-derived monocytes as cellular vehicles for co-transport of oxygen and red light activatable photosensitizer, chlorin e6 (Ce6). Superparamagnetic iron oxide nanoparticle/Ce6/oxygen-loaded polymer bubbles were prepared and internalized into tumortropic monocytes. These functional bubbles were found harmless to cellular hosts without external triggers. Nevertheless, the therapeutic monocytes exhibited a superior performance in inhibiting tumor growth on Tramp-C1 tumor-bearing mice (C57BL/6J) upon the treatments of tumors with high frequency magnetic field and red light laser (660 nm). Histological examinations of the tumor sections confirmed the successful cellular transport of therapeutic payloads to tumor hypoxia and the pronounced antitumor effect elicited by combined hyperthermia/photodynamic therapy along with the additional oxygen supply. This work demonstrates that this oxygen/therapeutic co-delivery via tumortropic monocytes toward tumor hypoxia is promising for improving PDT efficacy.

Designing various inorganic nanomaterials that are cost effective, water soluble, optically photostable, highly fluorescent and biocompatible for bioimaging applications is a challenging task. Similar to semiconducting quantum dots (QDs), silicon QDs are another alternative and are highly fluorescent, but non-water soluble. Several surface modification strategies were adopted to make them water soluble. However, the photoluminescence of Si QDs was seriously quenched in the aqueous environment. In this report, highly luminescent, water-dispersible, blue- and green-emitting Si QDs were prepared with good photostability. In vitro studies in monocytes reveal that Si QDs exhibit good biocompatibility and excellent distribution throughout the cytoplasm region, along with the significant fraction translocated into the nucleus. The in vivo zebrafish studies also reveal that Si QDs can be evenly distributed in the yolk-sac region. Overall, our results demonstrate the applicability of water-soluble and highly fluorescent Si QDs as excellent in vitro and in vivo bioimaging probes.

Overcoming limitations often experienced in nanomedicine delivery toward hypoxia regions of malignant tumors remains a great challenge. In this study, a promising modality for active hypoxia drug delivery was developed by adopting tumortropic monocytes/macrophages as a cellular vehicle for co-delivery of echogenic polymer/C5F12 bubbles and doxorubicin-loaded polymer vesicles. Through the remote-controlled focused ultrasound (FUS)-triggered drug liberation, therapeutic monocytes show prominent capability of inducing apoptosis of cancer cells. The in vivo and ex vivo fluorescence imaging shows appreciable accumulation of cell-mediated therapeutics in tumor as compared to the nanoparticle counterpart residing mostly in liver. Inhibition of tumor recurrence with γ-ray pre-irradiated Tramp-C1-bearing mice receiving therapeutic monocytes intravenously alongside the FUS activation at tumor site was significantly observed. Immunohistochemical examination of tumor sections confirms successful cellular transport of therapeutic payloads to hypoxic regions and pronounced cytotoxic action against hypoxic cells. Following the intravenous administration, the cellular-mediated therapeutics can penetrate easily to a depth beyond 150 μm from the nearest blood vessels within pre-irradiated tumor while nanoparticles are severely limited to a depth of ca 10-15 μm. This work demonstrates the great promise of cellular delivery to carry therapeutic payloads for improving chemotherapy in hypoxia by combining external trigger for drug release.

Bone marrow and intestinal damage limits the efficacy of radiotherapy for cancer and can result in death if the whole body is exposed to too high a dose, as might be the case in a nuclear accident or terrorist incident. Identification of an effective nontoxic biological radioprotector is therefore a matter of some urgency. In this study, we show that an orally administered hot-water extract from a Chinese herbal medicine, Cordyceps sinensis (CS), protects mice from bone marrow and intestinal injuries after total-body irradiation (TBI). CS increased the median time to death from 13 to 20 days after 8 Gy TBI and from 9 to 18 days after 10 Gy TBI. Although CS-treated mice receiving 10 Gy TBI survived intestinal injury, most died from bone marrow failure, as shown by severe marrow hypoplasia in mice dying between 18 and 24 days. At lower TBI doses of 5.5 and 6.5 Gy, CS protected against bone marrow death, an effect that was confirmed by the finding that white blood cell counts recovered more rapidly. In vitro, CS reduced the levels of free radical species (ROS) within cells, and this is one likely mechanism for the radioprotective effects of CS, although probably not the only one.

The aim of this study was to investigate means of increasing the efficiency with which cancer cell death following local radiation therapy (RT) is translated into the generation of tumor immunity since, if this were to be achieved, it would be expected to enhance the rates of disease-free recurrence and survival. Our investigations centered around the use of interleukin-3 (IL-3), expressed intratumorally using an inducible adenoviral vector, to alter the immunogenicity of established murine TRAMP-C1 prostate cancer receiving a course of fractionated local RT (7 Gy per fraction per day for 5 days). Because high systemic levels of IL-3 can be associated with toxicity, a tetracycline-regulated gene delivery system was employed. The results show that while intratumoral IL-3 expression or RT alone caused a modest delay in TRAMP-C1 tumor growth, the combination was synergistic with 50% of mice being cured and developing a long-term, tumor-specific state of immunity. Immunological analyses performed on splenic lymphocytes demonstrated that, compared to RT or IL-3 alone, combined treatment significantly increased the number of tumor-specific IFN-gamma-secreting and cytotoxic T cells. The study demonstrates that tetracycline-regulated IL-3 gene expression within tumors can enhance the immune response to prostate cancer and this can augment the efficacy of a course of RT without additional side effects.

DNA immunizations with the major structural protein VP1 of coxsackievirus B3 (CVB3) have been previously found to protect mice from a lethal challenge with CVB3. The function of this vaccination procedure is mainly based on accelerated antibody induction with an early cytokine expression and increased virus-specific cytotoxic activity of spleen cells causing decreased myocyte destruction and reduced viral replication. Here, we report that the co-expression of the immune-stimulatory interleukin-2 (IL-2) can increase the efficacy of the inoculated DNA vaccine depending on the route of administration and the mouse strain used.

McBride, W. H., Chiang, C-S., Olson, J. L., Wang, C-C., Hong, J-H., Pajonk, F., Dougherty, G. J., Iwamoto, K. S., Pervan, M. and Liao, Y-P. A Sense of Danger from Radiation. Radiat. Res. 162, 1–19 (2004). Tissue damage caused by exposure to pathogens, chemicals and physical agents such as ionizing radiation triggers production of generic “danger” signals that mobilize the innate and acquired immune system to deal with the intrusion and effect tissue repair with the goal of maintaining the integrity of the tissue and the body. Ionizing radiation appears to do the same, but less is known about the role of “danger” signals in tissue responses to this agent. This review deals with the nature of putative “danger” signals that may be generated by exposure to ionizing radiation and their significance. There are a number of potential consequences of “danger” signaling in response to radiation exposure. “Danger” signals could mediate the pathogenesis of, or recovery from, radiation damage. They could alte...

Many reports have shown that hypoxia and gliosis could promote tumor cells by shielding from the immune response and relapsing, but their roles on brain tumor therapies are still unclear. Using an invasive murine astrocytoma tumor model, ALTS1C1, we found that tumor invasion front is associated with a specific hypoxia region, naming tumor peripheral hypoxia, contributes to brain tumor therapy resistant and may be responsible for tumor recurrence after the therapy. Using this tumor model, we found that the overgrowing tumor caused the shortage of vessels and resulted in the hypoxia in the early stage of tumor progression, which is conventionally called chronic hypoxia or avascular hypoxia. When tumor continues to grow, a rim of hypoxia area was formed at tumor edge and subsequently activated nearby astrocytes. At the same time, the outward reactive astrocytes enhanced tumor invasion into normal parenchyma tissues. As a result, a specific hypoxia was produced in tumor peripheral, which has relative high microvascular density (MVD) and is associated with highly reactive astrocytosis. We explored the role of this region on the response to therapies. By quantitative counting the apoptotic tumor cells across the tumor cross-section following radiation- or chemo-therapy, we found that cells at the active astrocytic region (the peripheral region) are more resistant than cells in tumor core. These results indicate that the peripheral hypoxia, not the chronic hypoxia, is the main cause of the failure of brain tumor therapy. Most importantly, we found that the formation of tumor peripheral hypoxia might be associated with the activation of astrocytes. Therefore, tactics that can suppress astrocytosis and prevent the formation of peripheral hypoxia may be alternative approaches for complementing the shortage of traditional brain tumor therapy. Citation Format: Chiu-Min Lin, Chi-Shiun Chiang. Critical role of spatial location of hypoxia and its association with astrocytes in the resistance of brain tumor to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2976. doi:10.1158/1538-7445.AM2017-2976

Tumor-associated macrophages are one of the most abundant infiltrating cells in solid tumors. These cells are originated from the bone marrow and circulating in peripheral blood. Through the specific chemoattractant released by the tumor cells or stromal cells, bone marrow-derived monocytes (BMDMs) are able to accumulate at the tumor site by their corresponding receptors. In this study, we utilized the characteristics of tumor-tropism of BMDMs on a nanoparticle-based drug delivery system. We hypothesized that the cellular membrane of BMDMs can provide nanoparticle protection from the mononuclear phagocyte system and the chemokine receptor on the membrane can enhance the tumor-tropism of the nanoparticles. To prove the hypothesis, the cellular membrane was extracted from BMDMs and then coated on the drug-loaded nanoparticles. We also found that the expression of chemokine receptor CXCR4 on the bone BMDMs can be induced following the stimulation of tumor conditioned medium. The tumor targeting effect of the monocyte membrane-coated nanoparticles is diminished against SDF-1 knockdown tumor cells. These results indicate that the SDF-1/CXCR4 axis is contributed to the tumor-tropism of the monocyte membrane-coated nanoparticles toward astrocytoma cell line, ALTS1C1, and this effect can be boosted by the stimulation of tumor conditioned medium. In conclusion, we established a nanoparticle-based drug delivery platform against brain tumor with the cellular membrane coating technology and maximized the effect of tumor-targeting by tumor conditioned medium stimulation. Citation Format: Yi-Nan Li, Chien-Wen Chang, Chi-Shiun Chiang. SDF-1/CXCR4 axis-mediated tumor-tropism of monocyte membrane-coated nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2196. doi:10.1158/1538-7445.AM2017-2196

Glioblastoma multiforme (GBM) is a very common type of "incurable" malignant brain tumor. Although many treatment options are currently available, most of them eventually fail due to its recurrence. Boron neutron capture therapy (BNCT) emerges as an alternative noninvasive therapeutic treatment modality. The major challenge in treating GBMs using BNCT is to achieve selective imaging, targeting, and sufficient accumulation of boron-containing drug at the tumor site so that effective destruction of tumor cells can be achieved without harming the normal brain cells. To tackle this challenge, this study demonstrates for the first time that an unprecedented 10 B-enriched (96% 10 B enrichment) boron nanoparticle nanomedicine (10 BSGRF NPs) surface-modified with a Fluorescein isothiocyanate (FITC)-labeled RGD-K peptide can pass through the brain blood barrier, selectively target at GBM brain tumor sites, and deliver high therapeutic dosage (50.5 µg 10 B g-1 cells) of boron atoms to tumor cells with a good tumor-to-blood boron ratio of 2.8. The 10 BSGRF NPs not only can enhance the contrast of magnetic resonance (MR) imaging to help diagnose the location/size/progress of brain tumor, but also effectively suppress murine brain tumors via MR imaging-guided BNCT, prolonging the half-life of mice from 22 d (untreated group) to 39 d.

Theranostic nanohybrids are promising for effective delivery of therapeutic drug or energy and for imaging-guided therapy of tumors, which is demanded in personalized medicine. Here, a size-changeable graphene quantum dot (GQD) nanoaircraft (SCNA) that serves as a hierarchical tumor-targeting agent with high cargo payload is developed to penetrate and deliver anticancer drug into deep tumors. The nanoaircraft is composed of ultrasmall GQDs (less than 5 nm) functionalized with a pH-sensitive polymer that demonstrates an aggregation transition at weak acidity of tumor environment but is stable at physiological pH with stealth function. A size conversion of the SCNA at the tumor site is further actuated by near-infrared irradiation, which disassembles 150 nm of SCNA into 5 nm of doxorubicin (DOX)/GQD like a bomb-loaded jet, facilitating the penetration into the deep tumor tissue. At the tumor, the penetrated DOX/GQD can infect neighboring cancer cells for repeated cell killing. Such a SCNA integrated with combinational therapy successfully suppresses xenograft tumors in 18 d without distal harm. The sophisticated strategy displays the hierarchically targeted and penetrated delivery of drugs and energy to deep tumor and shows potential for use in other tumor therapy.