Anticancer effects of a single intramuscular dose of a minicircle DNA vector expressing anti-CD3/CD20 in a xenograft mouse model.

Bispecific antibodies (BsAbs) are a class of promising anticancer immunotherapies. Among them, the US Food and Drug Administration (FDA)-approved blinatumomab (BLI) is very effective in eliminating the minimum residual disease (MRD) of acute lymphoblastic leukemia (ALL), resulting in long-term remission in many individuals. However, the need for months-long intravenous delivery and high cost limit its clinical acceptance. Here we demonstrate that these problems can be solved by a BsAb expressed by one intramuscular (i.m.) dose of a minicircle DNA vector (MC). In a human B lymphoma xenograft mouse model, when microcancers became detectable in bone marrow, the mice received an i.m. dose of the MC encoding the BsAb anti-CD3/CD20 (BsAb.CD20), followed by 8 subsequent intravenous (i.v.) doses, one every other day (q2d), of human T cells to serve as effectors. The treatment resulted in persistent expression of a therapeutic level of serum BsAb.CD20 and complete regression or growth retardation of the cancers in the mice. These results suggest that the i.m. MC technology can eliminate the physical and financial burdens of i.v. delivered BLI without compromising anticancer efficacy and that cancer can be treated as easily as injecting a vaccine. This, together with other superior MC features, such as safety and affordability, suggests that the i.m. MC BsAb technology has great clinical application potential.

Calcium phosphate nanoneedle based gene delivery system for cancer genetic immunotherapy.

Ovarian cancer has become one of the most common gynecological cancers with a high mortality. However, conventional surgery together with combination chemotherapy is difficult to achieve ideal therapeutic effect. Although genetic immunotherapy is applied to active immune responses against cancer, the absence of efficient in vivo gene delivery technique is still an obstacle in clinical application. To overcome these problems, a minicircle DNA vector encoding humanized anti-EpCAM/CD3 bispecific antibody (BsAbEPH) has been constructed. Moreover, different shapes of calcium phosphate (CaPO) biomaterials were prepared. Specifically, the CaPO-nanoneedle-mediated "cell perforation" transfection technology achieves high levels of gene expression in peritoneal cavity. In an intraperitoneal xenograft model with human ovarian cancer cell line SKOV3, the CaPO-nanoneedle/minicircle DNA system expressed BsAbEPH resulted in significant retardation of cancer growth and extension of mouse life-span with limited toxicity. And this system can be made as off-the-shelf and easy-to-use products. Therefore, CaPO-nanoneedle based non-viral gene delivery technology will have great potential in clinical application.

Photoinduced electron-driven proton transfer from water to an N-heterocyclic chromophore: nonadiabatic dynamics studies for pyridine-water clusters.

It has been found in recent molecular beam experiments that pyridine molecules photoexcited at 255 nm can abstract hydrogen atoms from hydrogen-bonded water molecules in pyridine-water clusters, resulting in pyridinyl-hydroxyl radical pairs. The reaction could only be detected for clusters containing at least four water molecules. To provide insight into the mechanisms of this reaction, we performed ab initio excited-state trajectory surface-hopping dynamics simulations for two pyridine-water complexes, containing one and four water molecules, respectively, using the second-order algebraic-diagrammatic-construction (ADC(2)) electronic-structure method. A computationally efficient surface-hopping algorithm based on the Landau-Zener formula has been used to evaluate the transition probability between electronic states. The formation of the pyridinyl radical via an electron-driven proton transfer (EDPT) process from water to pyridine is confirmed by the simulations. The analysis of the competing excited-state reaction mechanisms up to 500 fs reveals that adiabatic relaxation to local minima of the S1(nπ*) potential-energy surface is the dominant channel in both clusters, followed by internal conversion to the electronic ground state via so-called ring-puckering conical intersections. The efficiency of the latter contribution is weakly dependent of the size of the clusters. The EDPT reaction occurs on the fastest time scales (faster than 200 fs) with a branching ratio of several percent. It is found to be four times more efficient in the pyridine-(H2O)4 cluster than in the pyridine-H2O cluster, which is qualitatively consistent with the experimental observations. A detailed understanding of the photoinduced reaction mechanisms in complexes of N-heterocyclic chromophores with water molecules is of relevance for future systematic knowledge-based developments of optimized materials for photocatalytic water splitting with sunlight.

Ultrafast unidirectional chiral rotation in the Z-E photoisomerization of two azoheteroarene photoswitches.

Unidirectional rotation represents a very important functional feature in photochemistry, such as in the design of light-driven molecular rotary motors. Great attention has recently been devoted to the unidirectional preference of the torsional motion of azobenzene and other molecules. Azoheteroarenes offer functional advantages over their more conventional azobenzene counterparts due to the introduction of heteroaromatic rings. In this paper, the Z-E photoisomerization dynamics of two azoheteroarenes, 1,2-bis(1-methyl-1H-imidazol-2-yl)diazene and 1,2-bis(1H-imidazol-2-yl)diazene, are investigated with trajectory surface-hopping molecular dynamics at the semi-empirical OM2/MRCI level. Starting from the S1 excited state of the M-helical Z-isomer of both azoheteroarenes, more than 99% of the trajectories decay to their ground states through the M-helical conical intersections by twisting about the central N[double bond, length as m-dash]N double bond. This chiral path preference can be well understood by the energy profiles generated by the linear interpolation between the Franck-Condon geometry of the M-helical Z-isomer and the relevant S1/S0 conical intersections. The Z-E photoisomerization mechanisms of these two azoheteroarenes display a higher preference for unidirectional rotary dynamics under a chiral path than their counterpart azobenzene.

The synthesis of amphiphilic polyethyleneimine/calcium phosphate composites for bispecific T-cell engager based immunogene therapy.

Bispecific T-cell engagers (BiTEs) are single chain variable fragments with specific structures, which could connect the surface antigen on cancer cells and CD3 ligands on T cells, and then engage the T cells for cancer immunotherapy. In this report, a novel organic-inorganic hybrid gene delivery system composed of stearic acid modified polyethyleneimine (stPEI) and calcium phosphate (CaP) was used to deliver MC.DNA into cells to express BiTE antibodies. This gene delivery system exhibits high transfection efficiency, long-term effects and low cytotoxicity in vitro. Furthermore, the gene production, anti-IGF1R/CD3 bispecific T-cell engager, exhibited a rapid redirection activity in T cells to induce cancer cell apoptosis. In summary, the results confirmed that stPEI-CaP could be an efficient gene delivery system for BiTE encoding MC.DNA based gene immunotherapy.

Magnetically-targeted and near infrared fluorescence/magnetic resonance/photoacoustic imaging-guided combinational anti-tumor phototherapy based on polydopamine-capped magnetic Prussian blue nanoparticles.

In recent years, Prussian blue (PB)-based nanoagents have become a new platform in photothermal cancer treatment. However, there is little research for PB-based nanoagents to achieve synergistic phototherapy guided by multimodal imaging diagnosis and monitoring. Herein, a novel single wavelength near infrared (NIR) laser-induced magnetically targeted theranostic nanoplatform has been successfully designed and synthesized for the first time based on polydopamine (PDA)/aluminum phthalocyanine (AlPc)/bovine serum albumin (BSA) coated magnetic Prussian blue nanoparticles (Fe3O4@PB NPs) for multiple imaging-guided combinatorial cancer therapy. The resultant multifunctional Fe3O4@PB@PDA/AlPc/BSA nanocomposites show excellent stability and superparamagnetism, facilitating them to achieve superior photothermal therapy in physiological environments under magnetic guidance. In addition, the delivery vehicles can remarkably increase tumor accumulation of AlPc, thus leading to an enhanced photodynamic therapy efficacy. Furthermore, Fe3O4@PB@PDA/AlPc/BSA can be utilized as a multimodality nanoprobe for simultaneous diversified imaging, including near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), and photoacoustic imaging (PAI). Most importantly, without noticeable dark toxicity, the obtained Fe3O4@PB@PDA/AlPc/BSA nanocomposites are able to significantly suppress tumor growth via combined photothermal and photodynamic therapies upon a single 660 nm laser irradiation, achieving a superior synergetic manner compared to monotherapy both in vitro and in vivo. Therefore, our strategy provides Fe3O4@PB@PDA/AlPc/BSA nanocomposites for trimodality cancer imaging-guided synergistic therapy, with a great potential for new generation theranostics nanoagents.

Hollow Au-Cu Nanocomposite for Real-Time Tracing Photothermal/Antiangiogenic Therapy.

High absorption in the near-infrared (NIR) region is essential for a photoabsorbing agents to realize efficient photothermal therapy (PTT) for cancer. Here, a novel hollow Au-Cu nanocomposite (HGCNs) is developed, which displays a significantly enhanced NIR surface plasmon resonance absorption and photothermal transduction efficiency. Besides, fluorescent polymer dots poly(9,9-dioctylfluorene-2,7-diyl-co-benzothiadiazole) (PFBT) and chemotherapeutic mammalian target of rapamycin (mTOR) inhibitor agent rapamycin (RAPA) are attached onto the HGCNs (RAPA/PFBT-HGCNs) for real-time NIR fluorescence tracing and combined PTT/antiangiogenesis therapy. In particular, due to the fluorescence resonance energy transfer effect, RAPA/PFBT-HGCNs can act as NIR-activatable on/off probe system for real-time tracing of tumor tissues. A standard in vitro cellular uptake study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, dual-staining study, and flow cytometry assay reveal that the RAPA/PFBT-HGCNs combined with NIR laser exhibit higher drug accumulation and cytotoxicity in both tumor cells and epithelial cells. Moreover, the margins of tumor and normal tissue can be accurately indicated by NIR-stimulated dequenched PFBT after 24 h intravenous administration. Further, tumor growth can be considerably hampered by the optimal formulation plus laser treatment with relatively lower side effects. Consequently, the work highlights the real-time tracing and enhanced PTT/antiangiogenesis therapy prospects of the established HGCNs with tremendous potential for treatment of cancer.

A triple-synergistic strategy for combinational photo/radiotherapy and multi-modality imaging based on hyaluronic acid-hybridized polyaniline-coated WS2 nanodots.

In this study, we report a strategy for integrating hyaluronic acid (HA), polyaniline (PANI), WS2 nanodots (WS2), and chlorin e6 (Ce6) into a single nanoplatform (HA-WS2@PANI/Ce6) for fluorescence, photoacoustic, and computed tomography multi-modality imaging-guided trimodal photothermal/radiation/photodynamic combination therapy of tumors. The WS2 nanodot core is used as the radiosensitizer with the PANI shell as the hyperthermal agent and the photosensitizer reservoir. HA and Ce6 were adsorbed on the outer shell for tumor targeting and photodynamic therapy, respectively. The in vivo trimodal imaging uncovered that HA-WS2@PANI/Ce6 nanoparticles showed enhanced tumor uptake and diagnosis effects after intravenous injection. More importantly, in the in vitro and in vivo experiments, the nanoparticles exhibited an evident near-infrared induced photothermal effect, which remarkably improved the radiation and photodynamic therapy efficiency by accelerating the blood flow and subsequently increasing oxygen supply in the tumor. The nanohybrids were found to be safe to cells in vitro and organs in vivo. Taken together, our current work demonstrates a nanoplatform for multimodal imaging guided targeted triple-therapy, which reveals a potential strategy for tumor treatment.

A photoresponsive and rod-shape nanocarrier: Single wavelength of light triggered photothermal and photodynamic therapy based on AuNRs-capped & Ce6-doped mesoporous silica nanorods.

Rod-shape nanocarriers have attracted great interest because of their better cell internalization capacity and higher drug loading properties. Besides, the combination of photodynamic therapy (PDT) and photothermal therapy (PTT) holds great promise to overcome respective limitations of the anti-cancer treatment. In this work, we first report Au nanorods-capped and Ce6-doped mesoporous silica nanorods (AuNRs-Ce6-MSNRs) for the single wavelength of near infrared (NIR) light triggered combined phototherapy. AuNRs-Ce6-MSNRs are not only able to generate hyperthermia to perform PTT effect based on the AuNRs, but also can produce singlet oxygen (1O2) for PDT effect based on Ce6 after uncapping of AuNRs under the single NIR wavelength irradiation. In addition, the combined therapy can be dual-imaging guided by taking the photoacoustic (PA) and NIR fluorescence (NIRF) imaging of AuNRs and Ce6, respectively. What's more, by utilizing the special structure of MSNRs, this nanocarrier can serve as a drug delivery platform with high drug loading capacity and enhanced cellular uptake efficiency. The multi-functional nanocomposite is designed to integrate photothermal and photodynamic therapy, in vivo dual-imaging into one system, achieving synergistic anti-tumor effects both in vitro and in vivo.

"Watching" the Dark State in Ultrafast Nonadiabatic Photoisomerization Process of a Light-Driven Molecular Rotary Motor.

Photoisomerization dynamics of a light-driven molecular rotary motor, 9-(2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-ylidene)-9H-fluorene, is investigated with trajectory surface-hopping dynamics at the semiempirical OM2/MRCI level. The rapid population decay of the S1 excited state for the M isomer is observed, with two different decay time scales (500 fs and 1.0 ps). By weighting the contributions of fast and slow decay trajectories, the averaged lifetime of the S1 excited state is about 710 fs. The calculated quantum yield of the M-to-P photoisomerization of this molecular rotary motor is about 59.9%. After the S0 → S1 excitation, the dynamical process of electronic decay is followed by twisting about the central C═C double bond and the motion of pyramidalization at the carbon atom of the stator-axle linkage. Although two S0/S1 minimum-energy conical intersections are obtained at the OM2/MRCI level, only one conical intersection is found to be responsible for the nonadiabatic dynamics. The existence of "dark state" in the molecular rotary motor is confirmed through the simulated time-resolved fluorescence emission spectrum. Both quenching and red shift of fluorescence emission spectrum observed by Conyard et al. [ Conyard, J.; Addison, K.; Heisler, I. A.; Cnossen, A.; Browne, W. R.; Feringa, B. L.; Meech, S. R. Nat. Chem. 2012 , 4 , 547 - 551 ; Conyard, J.; Conssen, A.; Browne, W. R.; Feringa, B. L.; Meech, S. R. J. Am. Chem. Soc. 2014 , 136 , 9692 - 9700 ] are well understood. We find that this "dark state" in the molecular rotary motor is not a new electronic state, but the "dark region" with low oscillator strength on the initial S1 state.

A single-light triggered and dual-imaging guided multifunctional platform for combined photothermal and photodynamic therapy based on TD-controlled and ICG-loaded CuS@mSiO2.

Near-infrared (NIR)-responsive drug delivery systems have received enormous attention because of their good biocompatibility and high biological penetration. In this work, we report a novel 1-tetradecanol (TD)-controlled and indocyanine green (ICG)-loaded CuS@mSiO2 phototherapy nanoplatform (CuS@mSiO2-TD/ICG). The CuS@mSiO2 nanoparticles prepared by a facile one-pot approach can serve as drug-delivery vehicles to transport the NIR absorbing phototherapeutic agent (ICG) within the mesoporous cavities. Meanwhile a phase-change molecule (PCM), TD, is introduced as a thermosensitive gatekeeper to avoid the premature release of loaded ICG. Noticeably, the combined therapy is irradiated at an 808 nm single-light wavelength, thus performing the photothermal therapy (PTT) based on CuS@mSiO2 as well as simultaneously triggering the photodynamic (PDT)/PTT effect based on ICG. Furthermore, ICG also has the function of dual in vivo fluorescence imaging and photoacoustic (PA) imaging. This dual imaging-guided and gatekeeper-controlled nanoplatform for the single-light triggered PTT/PDT treatment holds significant promise for future cancer therapy due to their markedly improved therapeutic efficacy and decreased systemic toxicity.

Photosensitizer loaded PEG-MoS2-Au hybrids for CT/NIRF imaging-guided stepwise photothermal and photodynamic therapy.

In this study, we developed X-ray computed tomography (CT)/near-infrared fluorescence (NIRF) imaging for visually guiding the photothermal therapy (PTT)/photodynamic therapy (PDT) of antitumor nanocomposites (PEG-MoS2-Au-Ce6), by adsorbing chlorin e6 (Ce6) to the gold nanoparticle (AuNPs)-decorated molybdenum disulfide (PEG-MoS2) nanosheets. The NIR photosensitizer Ce6 was adsorbed onto the PEG-MoS2-Au hybrids viaπ-π stacking and hydrophobic interactions, where Ce6 remained in its quenched state due to the surface plasmon resonance (SPR) capacity of AuNPs, as well as the coupling interaction with PEG-MoS2 nanosheets. However, Ce6 was dequenched and boosted strong NIR fluorescence signals after being released from the surface of PEG-MoS2-Au hybrids upon heat generation, thus producing the PDT effect for anti-tumor therapy. Moreover, the PEG-MoS2 nanosheets and Ce6 in the PEG-MoS2-Au-Ce6 nanocomposites could be further used for CT and NIRF dual-modal imaging, respectively. In vitro NIR-triggered drug release studies indicated that the PEG-MoS2-Au-Ce6 nanocomposites rapidly release the drug around the tumor site under the photothermal effect. Therefore, this dual-modality nanosystem simultaneously enables precise cancer diagnosis and therapy.

Treatment of Human B-Cell Lymphomas Using Minicircle DNA Vector Expressing Anti-CD3/CD20 in a Mouse Model.

Bispecific antibodies (BsAbs), capable of directing T cells to kill specific cancer cells by transiently binding the two cell types, have emerged as one class of promising cancer immunotherapies. However, their wide clinical application might be hampered by two deficiencies: high cost and inconvenience in drug administration. This study presents concept-proving data that these problems could be bypassed by using an enhanced nonviral DNA vector minicircle (MC) to produce BsAb in vivo. It was found that the anti-CD3/CD20 produced from the minicircle (MC.CD20) could effectively mediate the T-cell killing of multiple CD20-positive human B-cell lymphoma cell lines in vitro. More importantly, it was demonstrated that delivery of 5 µg of MC.CD20 to mouse liver via hydrodynamic injection resulted in both the expression of a therapeutic level of anti-CD3/CD20 throughout the 32-day experiment and effective anticancer activity in a B-cell lymphoma xenograft mouse model. The data suggest that MC encoding the BsAbs may become an attractive cancer immunotherapy modality based on its excellent features of safety, efficacy, and convenience in both preparation and use, and its affordability once the delivery technology matures.

Indocyanine Green-Loaded Silver Nanoparticle@Polyaniline Core/Shell Theranostic Nanocomposites for Photoacoustic/Near-Infrared Fluorescence Imaging-Guided and Single-Light-Triggered Photothermal and Photodynamic Therapy.

Photoacoustic (PA)/near-infrared fluorescence (NIRF) dual-modal imaging-guided phototherapy has been wide explored very recently. However, the development of high-efficiency and simplified-performed theranostic system for amplifying imaging-guided photothermal therapy/photodynamic therapy (PTT/PDT) is still a great challenge. Herein, a single-light-triggered indocyanine green (ICG)-loaded PEGylation silver nanoparticle core/polyaniline shell (Ag@PANI) nanocomposites (ICG-Ag@PANI) for PA/NIRF imaging-guided enhanced PTT/PDT synergistic effect has been successfully constructed. In this study, the synthesized Ag@PANI nanocomposites are utilized not only as the promising photothermal agent but also as potential nanovehicles for loading photosensitizer ICG via π-π stacking and hydrophobic interaction. The as-prepared ICG-Ag@PANI possesses many superior properties such as strong optical absorption in the near-infrared (NIR) region, enhanced photostability of ICG, as well as outstanding NIR laser-induced local hyperthermia and reactive oxygen species (ROS) generation. In the in vivo study, PA/NIRF dual-modal imaging confirms the accumulation and distribution of ICG-Ag@PANI in the tumor region via enhanced permeability and retention (EPR) effect. Moreover, the PTT effect of ICG-Ag@PANI rapidly raised the tumor temperature to 56.8 °C within 5 min. It is also demonstrated that the cytotoxic ROS generation ability of ICG is well maintained after being loaded onto Ag@PANI nanocomposites. Remarkably, in comparison with PTT or PDT alone, the single 808 nm NIR laser-triggered combined PTT/PDT therapy exhibits enhanced HeLa cells lethality in vitro and tumor growth inhibition in vivo.

Phosphorylation of PPARγ at Ser84 promotes glycolysis and cell proliferation in hepatocellular carcinoma by targeting PFKFB4.

Peroxisome proliferator-activating receptor γ (PPARγ), a transcription factor, is involved in many important biological processes, including cell terminal differentiation, survival and apoptosis. However, the role of PPARγ, which regulates tumour promoter and oncogene expression, is not well understood in hepatocellular carcinoma (HCC). In the present study, based on evidence from clinical samples that phosphorylation of PPARγ at Ser84 is up-regulated in human liver tumours, we confirmed that phosphorylation of PPARγ was also significantly increased in an HCC mouse model and was increased by Mitogen-activated protein kinase (MEK)/ Extracellular-signal-regulated kinases (ERK) kinase. Next, we performed an RNA microarray analysis, and our data indicated that dephosphorylation of PPARγ at Ser84 affects the expression of glycolysis-related genes and pro-proliferation genes, which supposedly promote proliferation of HCC cells. Using a chromatin immunoprecipitation (ChIP) assay, we demonstrated that the observed PPARγ-mediated induction of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) expression was directly modulated by the transcriptional activity of its promoter. Furthermore, using knockdown of PFKFB4, we elucidated that the stimulation of PPARγ phosphorylation on glycolysis and proliferation in HCC is dependent on PFKFB4. Together, these findings extend our understanding of how liver tumour cells reprogram their glycolytic pathways by post-translational modification of specific transcription factors and lay a foundation for the screening of new targets for the treatment of HCC.

MoS2 Quantum Dot@Polyaniline Inorganic-Organic Nanohybrids for in Vivo Dual-Modal Imaging Guided Synergistic Photothermal/Radiation Therapy.

In this study, we introduce a versatile nanomaterial based on MoS2 quantum dot@polyaniline (MoS2@PANI) inorganic-organic nanohybrids, which exhibit good potential to not only enhance photoaccoustic (PA) imaging/X-ray computed tomography (CT) signal but also perform efficient radiotherapy (RT)/photothermal therapy (PTT) of cancer. Upon the intravenous injection of MoS2@PANI hybrid nanoparticles, the in vivo tumor could be precisely positioned and thoroughly eliminated under the PA/CT image-guided combination therapy of PTT/RT. This versatile nanohybrid could show good potential to facilitate simultaneously dual-modal imaging and synergetic PTT/RT to realize better anticancer efficiency.

Dual-Modal Imaging-Guided Theranostic Nanocarriers Based on Indocyanine Green and mTOR Inhibitor Rapamycin.

The development of treatment protocols that resulted in a complete response to photothermal therapy (PTT) was usually hampered by uneven heat distribution and low effectiveness. Here, we reported an NIR fluorescence and photoacoustic dual-modal imaging-guided active targeted thermal sensitive liposomes (TSLs) based on the photothermal therapy agent Indocyanine green (ICG) and antiangiogenesis agent Rapamycin (RAPA) to realize enhanced therapeutic and diagnostic functions. As expected, the in vitro drug release studies exhibited the satisfactory result of drug released from the TSLs under hyperthermia conditions induced by NIR stimulation. The in vitro cellular studies confirmed that the FA-ICG/RAPA-TSLs plus NIR laser exhibited efficient drug accumulation and cytotoxicity in tumor cells and epithelial cells. After 24 h intravenous injection of FA-ICG/RAPA-TSLs, the margins of tumor and normal tissue were accurately identified via the in vivo NIR fluorescence and photoacoustic dual-modal imaging. In addition, FA-ICG/RAPA-TSLs combined with NIR irradiation treated tumor-bearing nude mice inhibited tumor growth to a great extent and possessed much lower side effects to normal organs. All detailed evidence suggested that the theranostic TSLs which were capable of enhancing the therapeutic index might be a suitable drug delivery system for dual-modal imaging-guided therapeutic tools for diagnostics as well as the treatment of tumors.

An efficient dual-loaded multifunctional nanocarrier for combined photothermal and photodynamic therapy based on copper sulfide and chlorin e6.

The therapeutic effectiveness of photodynamic therapy (PDT) was hampered by the poor water solubility and instability in physiological conditions of the photosensitizers. Here, we designed folate conjugated thermosensitive liposomes (TSL) as the nanocarrier to improve the solubility, stability and biocompatibility of photosensitizer Chlorin e6 (Ce6). Based on the photothermal effect, we combined copper sulfide (CuS) as the photothermal agent to realize heat-triggered Ce6 release as well as synergistic effect of photothermal and photodynamic therapy. In vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that Ce6-CuS-TSL had low dark toxicity, while performed excellent phototoxicity under the combined 660 and 808 nm laser irradiation compared to any single laser irradiation alone. Moreover, in vivo combination therapy study revealed that Ce6-CuS-TSL inhibited tumor growth to a great extent without evident side effect under the laser irradiation. All detailed evidence demonstrated a considerable potential of Ce6-CuS-TSL for synergistic cancer treatment.

A dual pH/thermal responsive nanocarrier for combined chemo-thermotherapy based on a copper-doxorubicin complex and gold nanorods.

The development of treatment protocols that results in a complete response to chemotherapy has been hampered by low efficacy and systemic toxicity. Here, we created a pH sensitive copper-doxorubicin complex within the core of temperature-sensitive liposomes to maintain the stability during blood circulation and trigger Dox release in the tumor site. Synergistically, we also rationally applied gold nanorods (AuNRs) coupled with near-infrared (NIR) field strength to produce a precise and localized temperature, which not only remotely controlled the drug release but also directly destroyed the tumor, to enhance the therapeutic efficacy. As expected, the in vitro release studies showed that the drug release from CuDox-TSLs (Copper ion mediated Doxorubicin loading-Temperature Sensitive Liposomes) was both pH-dependent and temperature-dependent. Furthermore, MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assays showed that CuDox-TSLs combined with AuNRs exhibited a closer antiproliferative activity to free Dox in MCF-7 cells. The efficient intracellular Dox release from CuDox-TSLs toward the tumor cells further confirmed the anti-tumor effect. Moreover, the in vivo imaging and biodistribution studies revealed that CuDox-TSLs combined with AuNRs could actively target the tumor site. In addition, the therapeutic studies in MCF-7 nude mice exhibited CuDox-TSLs plus AuNRs in combination with NIR irradiation inhibited tumor growth to a great extent and possessed much lower side effects, which were further confirmed by systemic histological analyses. All detailed evidence suggested a considerable potential of CuDox-TSLs combined with AuNRs for treatment of metastatic cancer.

PPARγ1 phosphorylation enhances proliferation and drug resistance in human fibrosarcoma cells.

Post-translational regulation plays a critical role in the control of cell growth and proliferation. The phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) is the most important post-translational modification. The function of PPARγ phosphorylation has been studied extensively in the past. However, the relationship between phosphorylated PPARγ1 and tumors remains unclear. Here we investigated the role of PPARγ1 phosphorylation in human fibrosarcoma HT1080 cell line. Using the nonphosphorylation (Ser84 to alanine, S84A) and phosphorylation (Ser84 to aspartic acid, S84D) mutant of PPARγ1, the results suggested that phosphorylation attenuated PPARγ1 transcriptional activity. Meanwhile, we demonstrated that phosphorylated PPARγ1 promoted HT1080 cell proliferation and this effect was dependent on the regulation of cell cycle arrest. The mRNA levels of cyclin-dependent kinase inhibitor (CKI) p21(Waf1/Cip1) and p27(Kip1) descended in PPARγ1(S84D) stable HT1080 cell, whereas the expression of p18(INK4C) was not changed. Moreover, compared to the PPARγ1(S84A), PPARγ1(S84D) up-regulated the expression levels of cyclin D1 and cyclin A. Finally, PPARγ1 phosphorylation reduced sensitivity to agonist rosiglitazone and increased resistance to anticancer drug 5-fluorouracil (5-FU) in HT1080 cell. Our findings establish PPARγ1 phosphorylation as a critical event in human fibrosarcoma growth. These findings raise the possibility that chemical compounds that prevent the phosphorylation of PPARγ1 could act as anticancer drugs.