Engineering nanoparticles-enabled tumor-associated macrophages repolarization and phagocytosis restoration for enhanced cancer immunotherapy.

Tumor-associated macrophages (TAMs) are pivotal within the immunosuppressive tumor microenvironment (TME), and recently, have attracted intensive attention for cancer treatment. However, concurrently to promote TAMs repolarization and phagocytosis of cancer cells remains challenging. Here, a TAMs-targeted albumin nanoparticles-based delivery system (M@SINPs) was constructed for the co-delivery of photosensitizer IR820 and SHP2 inhibitor SHP099 to potentiate macrophage-mediated cancer immunotherapy. M@SINPs under laser irradiation can generate the intracellular reactive oxygen species (ROS) and facilitate M2-TAMs to an M1 phenotype. Meanwhile, inhibition of SHP2 could block the CD47-SIRPa pathway to restore M1 macrophage phagocytic activity. M@SINPs-mediated TAMs remodeling resulted in the immunostimulatory TME by repolarizing TAMs to an M1 phenotype, restoring its phagocytic function and facilitating intratumoral CTLs infiltration, which significantly inhibited tumor growth. Furthermore, M@SINPs in combination with anti-PD-1 antibody could also improve the treatment outcomes of PD-1 blockade and exert the synergistic anticancer effects. Thus, the macrophage repolarization/phagocytosis restoration combination through M@SINPs holds promise as a strategy to concurrently remodel TAMs in TME for improving the antitumor efficiency of immune checkpoint block and conventional therapy.

Electromagnetic Interference Effects of Continuous Waves on Memristors: A Simulation Study.

As two-terminal passive fundamental circuit elements with memory characteristics, memristors are promising devices for applications such as neuromorphic systems, in-memory computing, and tunable RF/microwave circuits. The increasingly complex electromagnetic interference (EMI) environment threatens the reliability of memristor systems. However, various EMI signals' effects on memristors are still unclear. This paper selects continuous waves (CWs) as EMI signals. It provides a deeper insight into the interference effect of CWs on the memristor driven by a sinusoidal excitation voltage, as well as a method for investigating the EMI effect of memristors. The optimal memristor model is obtained by the exhaustive traversing of the possible model parameters, and the interference effect of CWs on memristors is quantified based on this model and the proposed evaluation metrics. Simulation results indicate that CW interference may affect the switching time, dynamic range, nonlinearity, symmetry, time to the boundary, and variation of memristance. The specific interference effect depends on the operating mode of the memristor, the amplitude, and the frequency of the CW. This research provides a foundation for evaluating EMI effects and designing electromagnetic protection for memristive neuromorphic systems.

Indoor Localization Method of Personnel Movement Based on Non-Contact Electrostatic Potential Measurements.

The indoor localization of people is the key to realizing "smart city" applications, such as smart homes, elderly care, and an energy-saving grid. The localization method based on electrostatic information is a passive label-free localization technique with a better balance of localization accuracy, system power consumption, privacy protection, and environmental friendliness. However, the physical information of each actual application scenario is different, resulting in the transfer function from the human electrostatic potential to the sensor signal not being unique, thus limiting the generality of this method. Therefore, this study proposed an indoor localization method based on on-site measured electrostatic signals and symbolic regression machine learning algorithms. A remote, non-contact human electrostatic potential sensor was designed and implemented, and a prototype test system was built. Indoor localization of moving people was achieved in a 5 m × 5 m space with an 80% positioning accuracy and a median error absolute value range of 0.4-0.6 m. This method achieved on-site calibration without requiring physical information about the actual scene. It has the advantages of low computational complexity and only a small amount of training data is required.

Dynamic Gesture Recognition Model Based on Millimeter-Wave Radar With ResNet-18 and LSTM.

In this article, a multi-layer convolutional neural network (ResNet-18) and Long Short-Term Memory Networks (LSTM) model is proposed for dynamic gesture recognition. The Soli dataset is based on the dynamic gesture signals collected by millimeter-wave radar. As a gesture sensor radar, Soli radar has high positional accuracy and can recognize small movements, to achieve the ultimate goal of Human-Computer Interaction (HCI). A set of velocity-range Doppler images transformed from the original signal is used as the input of the model. Especially, ResNet-18 is used to extract deeper spatial features and solve the problem of gradient extinction or gradient explosion. LSTM is used to extract temporal features and solve the problem of long-time dependence. The model was implemented on the Soli dataset for the dynamic gesture recognition experiment, where the accuracy of gesture recognition obtained 92.55%. Finally, compare the model with the traditional methods. The result shows that the model proposed in this paper achieves higher accuracy in dynamic gesture recognition. The validity of the model is verified by experiments.

Design of Light-Activated Nanoplatform through Boosting "Eat Me" Signals for Improved CD47-Blocking Immunotherapy.

Here, the authors propose a light-activated reactive oxygen species (ROS)-responsive nanoplatform that can boost immunogenic cell death (ICD) to release "eat me" signals, and improve CD47-blocking immunotherapy by tumor-targeted codelivery of photosensitizer IR820 and anti-CD47 antibody (αCD47). Human serum albumin and αCD47 are first constructed into a single nanoparticle using ROS-responsive linkers, which are further conjugated with photosensitizer IR820 via a matrix metalloproteinase-sensitive peptide as linker and then modified with poly(ethylene glycol) on the surface of the obtained nanoparticles. When exposed to the first wave of near-infrared (NIR) laser irradiation, the obtained nanoplatform (M-IR820/αCD47@NP) can generate ROS, which triggers nanoparticles dissociation and thus, facilitates the release of αCD47 and IR820. The second wave of NIR laser irradiation is subsequently used to perform phototherapy and induce ICD of tumor cells. An in vitro cellular study shows that M-IR820/αCD47@NP can stimulate dendritic cells activation while simultaneously enhancing the phagocytic activity of macrophage against tumor cells. In 4T1 tumor-bearing mice, M-IR820/αCD47@NP-mediated combination of phototherapy and CD47 blockade can effectively induce the synergistic antitumor immune responses to inhibit the growth of tumors and prevent local tumor recurrence. This work offers a promising strategy to improve the CD47-blocking immunotherapy efficacy using αCD47 nanomedicine.

Tumor microenvironment-activated therapeutic peptide-conjugated prodrug nanoparticles for enhanced tumor penetration and local T cell activation in the tumor microenvironment.

Nanomedicine-based chemoimmunotherapy has shown a great potential for cancer therapies application in recent years. However, most nanoparticles still face a problem of low accumulation and limited penetration of chemotherapeutic drugs and immunotherapeutic drugs into solid tumors. Here, we developed a tumor microenvironment (TME)-activable therapeutic peptide-conjugated prodrug nanoparticle for enhanced tumor penetration and synergistic antitumor effects of chemotherapy and immune checkpoint blockade therapy. The prodrug nanoparticle is composed of a short D-peptide antagonist of PD-L1 (DPPA) conjugated doxorubicin (DOX) prodrug and a PEGylated DOX prodrug, which can dissociate into small DOX nanoparticles (<30 nm) and release DPPA antagonist in TME. The prodrug nanoparticles could co-deliver DOX and DPPA antagonist by one nanocarrier and improve tumor accumulation and penetration of the prodrug nanoparticels via a transcytosis process. It is demonstrated that co-delivery of DOX and DPPA antagonist directly killed tumor cells, promoted the tumor-infiltrating cytotoxic T lymphocytes, reduced the tumor-infiltrating regulatory T cells, and elicited a long-term immune memory effect to prevent tumor recurrence and metastasis. This TME-activable prodrug nanoparticle holds promise as a co-delivery nanoplatform for the improved chemoimmunotherapy of solid tumors.

Tumor microenvironment-responsive prodrug nanoplatform via co-self-assembly of photothermal agent and IDO inhibitor for enhanced tumor penetration and cancer immunotherapy.

Nanomedicine-based phototherapy in combination with immune checkpoint blockade therapy has been reported as a promising strategy for improved cancer immunotherapy. However, tumor penetration of nanomedicine into solid tumor is still an unresolved obstacle to an effective drug delivery, leading to limitations in their applications. Here, we developed a tumor microenvironment-responsive prodrug nanoplatform for efficient penetration and photo-immunotherapy of cancer. The prodrug nanoplatform is performed by integrating PEGylated indoleamine-2,3-dioxygenase (IDO) inhibitor (Epacadostat) and photosensitizer (Indocyanine green, ICG) into a core-shell nanostructure via intermolecular interactions, which can transform into small dual-drug complexes (<40 nm) at tumor microenvironment. The resulting small dual-drug complexes could undergo caveolae-mediated endocytosis, enhance cellular uptake, directly kill tumor cells, in situ trigger antitumor immune response and modulate IDO-mediated immunosuppression. More significantly, the prodrug nanoplatform in combination with PD-L1 checkpoint blockade synergistically promoted the antitumor immunity and efficiently inhibited the growth of both primary and abscopal tumors. The present study provides a novel delivery strategy for nanoenabled phototherapy and IDO inhibition to combine PD-L1 checkpoint blockade for achieving more effective therapy of solid tumors.

Research on action behavior of neuron system in case of single pulse stimulus.

Facing on the complex electromagnetic environment of electrical equipment, based on the bio-anti-interference characteristics of neuron system, the bio-inspired electromagnetic protection is proposed in order to improve and assist the traditional electromagnetic protection method. In order to analyze the dynamical characteristics of electrical signal transfer process of neuron system, Hodgkin-Huxley (HH) model is adopted to calculate the action potential of single neuron. The initial value problem used in the parameters of Hodgkin-Huxley model is studied in order to satisfy the physiological phenomenon. The stability of HH model is analyzed to assess the dynamic stable performance of neuron. Based on the investigation of single neuron, a simple neuron system consisted of two neurons and one synapse is studied. The compassion between the action potential of posterior neuron and different synapse is performed, which explores how the mathematic models of different synapses influence the action potential. The relationship between action potential of posterior neuron and coupling strength of simplified synapse is calculated to explain the diversity of electrical signal output of neuron system. These numerical results enable to provide some datum for deeply developing the bio-inspired electromagnetic protection and well designing the bio-inspired circuit.

Antigen-Inorganic Hybrid Flowers-Based Vaccines with Enhanced Room Temperature Stability and Effective Anticancer Immunity.

Particle-based antigen carriers as adjuvants play an important role in vaccine development. Herein, an antigen-inorganic hybrid flower-like particle is developed as a novel vaccine carrier. Model antigen ovalbumin (OVA)-copper (II) sulfate hybrid vaccines (OVA-Cu-HVs) are mildly and facilely constructed through a biomimetic mineralization process. OVA-Cu-HVs facilitate cellular uptake in antigen-presenting cells and the internalization of OVA-Cu-HVs involves macropinocytosis-mediated endocytosis. OVA-Cu-HVs can release OVA in a pH-responsive behavior and promote cytosolic release of antigen to enhance antigen cross-presentation. Immunization with OVA-Cu-HVs promotes the maturation of dendritic cells in draining lymph nodes, induces robust antigen-specific T lymphocyte response, and inhibits tumor growth in vivo. In addition, OVA-Cu-HVs are efficacious after being stored for 4 weeks at room temperature and are expected to simplify vaccine storage and lower the cost of cold storage for transportation. Looking forward, OVA-Cu-HVs may hold strong potential to be as an effective vaccine delivery platform, which will facilitate the application of organic-inorganic hybrid flowers in biomedical areas.

Chitosan/calcium phosphates nanosheet as a vaccine carrier for effective cross-presentation of exogenous antigens.

Chitosan/calcium phosphate nanosheet as a promising antigen carrier was prepared via the direct mixture of modified chitosan, PBS and CaCl2. Specifically, chitosan was modified with catechol groups, and its water solubility under neutral conditions was improved. Then, nanosheet was formed by mixing modified chitosan and PBS followed by addition of CaCl2. Antigen was entrapped into the nanosheet via coprecipitation during its preparation. The nanosheet composed of CaHPO4·2H2O crystals, was internalized by dendritic cells (DCs) via macropinocytosis with enhanced efficiency. The antigen endosomal escape induce by nanosheet was successful observed with intracellular Lysotracker and Lamp-1 staining. Moreover, DCs activation was triggered by the nanosheet along with the up-regulated expression of co-stimulation marker and production of Th1-type cytokines. More importantly, cross-presentation of antigens achieved by the nanosheet was markedly increased when compared to free antigen. Therefore, chitosan/calcium phosphate nanosheet could be used as a vaccine carrier for effective cross-presentation of exogenous antigens.

A Generic Coordination Assembly-Enabled Nanocoating of Individual Tumor Cells for Personalized Immunotherapy.

A generic and effective tumor cells encapsulation strategy enabled by metal-organic coordination is developed to prepare a vaccine for personalized immunotherapy. Specifically, an epigallocatechin-3-gallate (EGCG)-Al(III) coordination layer is in situ formed onto individual living cells in aqueous phase and the process can be completed within an hour. 98% of proteins in the cells are entrapped within the microparticles, which are endowed with high antigens loading capacity. The microparticles enhance the uptake efficiency of antigens, protect antigens from degradation in vivo, and delay the retention time of antigens in the lymph nodes. Moreover, dendritic cells (DCs) activation is triggered by the microparticles, and simultaneously, the expression of costimulation marker on DCs and the production of Th1-related cytokines are significantly upregulated. Moreover, six kinds of tumor cells are utilized and successfully coated with the EGCG/Al(III) layer, suggesting the generalization of this strategy. More importantly, the microparticles exhibit a comparative antitumor effect with polyinosinic-polycytidylic acid (PolyI:C) in B16 pulmonary metastasis model. Overall, the encapsulation strategy enabled by metal-organic coordination can be potentially useful for personalized immunotherapy customized to individual patient's tumor cells.

Coordination microparticle vaccines engineered from tumor cell templates.

A method for encapsulation of individual tumor cells with an epigallocatechin-3-gallate (EGCG)-Al(iii) coordination layer, which can be used as potential tumor vaccines, was developed. The interaction between microparticle vaccines and dendritic cells was investigated in vitro. The microparticles (∼10 µm) were efficiently internalized by DCs with enhanced uptake efficiency via actin polymerization and clathrin-mediated endocytosis.

Alum-functionalized graphene oxide nanocomplexes for effective anticancer vaccination.

Aluminum-based adjuvant (e.g., aluminum oxyhydroxide (AlO(OH), known as the commercial Alhydrogel® (Alum)) is the first adjuvant to be used in human vaccines. Although Alum shows a robust induction of antibody-mediated immunity, its weak stimulation of cell-mediated immunity makes it a questionable adjuvant for cancer immunotherapy. Herein, we described a novel formulation of Alum-based adjuvant by preparing AlO(OH)-modified graphene oxide (GO) nanosheets (GO-AlO(OH)), which, in addition to maintaining the induction of humoral immune response by AlO(OH), could further elicit the cellular immune response by GO. Similar to Alum, GO-AlO(OH) vaccine formulation could be constructed by the incorporation of antigen using a facile mixing/adsorption approach. Antigen-loaded GO-AlO(OH) nanocomplexes facilitated cellular uptake and cytosolic release of antigens and promoted DC maturation, thereby eliciting higher antigen-specific IgG titers, inducing robust CD4+ and CD8+ T lymphocyte response, and inhibiting tumor growth in vivo. Furthermore, by employing tumor cell lysate-based cancer vaccines, GO-AlO(OH) nanocomplexes led to significant inhibition of tumor growth and can be implemented as a personalized treatment strategy for cancer vaccine development. Overall, GO-AlO(OH) nanocomplexes described herein may serve as a facile and efficient approach for effective anticancer vaccination. STATEMENT OF SIGNIFICANCE: Herein, we described a novel formulation of aluminum-based adjuvant by preparing aluminum oxyhydroxide (AlO(OH)) (known as "Alum")-modified graphene oxide (GO) nanocomplexes (GO-AlO(OH)), which, in addition to maintaining the induction of humoral immune response by AlO(OH), could further elicit the cellular immune response by GO. GO-AlO(OH) nanocomplexes can be prepared easily and in large scale by a chemical precipitation method. Similar to "Alum," antigen-loaded GO-AlO(OH) vaccine formulation could be constructed by the incorporation of antigen using a facile mixing/adsorption approach. The very simple and reproductive preparation process of vaccines and the powerful ability to raise both humoral and cellular immune responses provide a novel approach for improving cancer immunotherapy efficacy.

Nanoscale Reduced Graphene Oxide-Mediated Photothermal Therapy Together with IDO Inhibition and PD-L1 Blockade Synergistically Promote Antitumor Immunity.

Despite the potential efficacy of immune checkpoint blockade for effective treatment of cancer, this therapeutic modality is not generally curative, and only a fraction of patients respond. Combination approaches provide strategies to target multiple antitumor immune pathways to induce synergistic antitumor immunity. Here, a multi-combination immunotherapy, including photothermal therapy (PTT), indoleamine-2,3-dioxygenase (IDO) inhibition, and programmed cell death-ligand 1 (PD-L1) blockade, is introduced for inducing synergistic antitumor immunity. We designed a multifunctional IDO inhibitor (IDOi)-loaded reduced graphene oxide (rGO)-based nanosheets (IDOi/rGO nanosheets) with the properties to directly kill tumor cells under laser irradiation and in situ trigger antitumor immune response. In vivo experiments further revealed that the triggered immune response can be synergistically promoted by IDO inhibition and PD-L1 blockade; the responses included the enhancement of tumor-infiltrating lymphocytes, including CD45+ leukocytes, CD4+ T cells, CD8+ T cells, and NK cells; the inhibition of the immune suppression activity of regulator T cells (Tregs); and the production of INF-γ. We also demonstrate that the three combinations of PTT, IDO inhibition, and PD-L1 blockade can effectively inhibit the growth of both irradiated tumors and tumors in distant sites without PTT treatment. This work can be thought of as an important proof of concept to target multiple antitumor immune pathways to induce synergistic antitumor immunity.

Encapsulation of Poly I:C and the natural phosphodiester CpG ODN enhanced the efficacy of a hyaluronic acid-modified cationic lipid-PLGA hybrid nanoparticle vaccine in TC-1-grafted tumors.

FDA approval of CpG oligodeoxynucleotide (CpG ODN) adjuvants for a human hepatitis B virus vaccine has been delayed until late 2017 because of concerns regarding the severe side effects, which may be attributed to the high dosage and systemic diffusion of this proinflammatory material. Considering that PLGA could provide shelter to resist nucleases in tissue and that cationic lipids could confine anionic oligonucleotides in the nanoparticles via electrostatic attraction to avoid systemic diffusion, we encapsulated a natural phosphodiester or the expensive phosphorothioate CpG ODNs in our previously reported hyaluronic acid-modified cationic lipid-PLGA hybrid nanoparticles and evaluated vaccine efficacy in a TC-1-grafted mouse model. Our results showed that together with Poly I:C, CpG ODN could promote the maturation of bone marrow-derived dendritic cells and the cross-presentation of exogenous antigens in vitro. For the coencapsulation with Poly I:C, in vivo studies showed that adjuvant effects on the vaccine efficacy of tumor depression, immune cell activation, and memory T-cell elevation of phosphodiester CpG ODNs were comparable to those of the phosphorothioate CpG ODNs at a low concentration (5 µg/dose). In conclusion, the combination of oligonucleotide adjuvants and synthetic particulate systems not only potentiated the immunogenicity of these nanoparticles but also made these adjuvants safer and more economical, which may be helpful for their wide application.

Nanovaccine Incorporated with Hydroxychloroquine Enhances Antigen Cross-Presentation and Promotes Antitumor Immune Responses.

Induction of effective antigen-specific CD8+ T-cell responses is critical for cancer immunotherapy success. Hydroxychloroquine (HCQ) is a widely used classical antimalarial and antirheumatic drug. HCQ is also an endosomal membrane disrupting agent that can lead to vesicular swelling and membrane permeabilization, which likely facilitates the release of therapeutic agents from lysosomes into the cytoplasm. Here, we develop a minimalistic nanovaccine, which is composed of poly(lactide- co-glycolide)acid (PLGA) nanoparticles (NPs) encapsulating a physical mixture of ovalbumin (OVA, a model antigen) and HCQ (HCQ-OVA-PLGA NPs). We tested whether HCQ could spatiotemporally control the cytosolic delivery of antigens, enhance antigen processing and presentation via the major histocompatibility complex (MHC)-I pathway, and thus generate a sufficient antitumor cytotoxic T-cell response. The results of in vitro experiments showed that HCQ-OVA-PLGA NPs significantly enhanced OVA escape from lysosomes into the cytoplasm within bone-marrow-derived dendritic cells. We also observed that HCQ-OVA-PLGA NPs enhanced the expression level of MHC-I on dendritic cells and improved cross-presentation of antigen, compared to free OVA or OVA-PLGA NPs. Results of in vivo experiments confirmed that HCQ initiated Th1-type responses and strong CD8+ T-cell responses that induced tumor cell apoptosis. Moreover, vaccination of mice with HCQ-OVA-PLGA NPs effectively generated memory immune responses in vivo and prevented tumor progression. We conclude that co-encapsulation of HCQ with antigens in nanovaccines can boost antigen-specific antitumor immune responses, particularly through CD8+ T-cells, serving as a simple and effective platform for the treatment of tumors and infectious diseases.

Photothermally Controlled MHC Class I Restricted CD8+ T-Cell Responses Elicited by Hyaluronic Acid Decorated Gold Nanoparticles as a Vaccine for Cancer Immunotherapy.

Cancer vaccines aim to induce a strong major histocompatibility complex class I (MHC-I)-restricted CD8+ cytotoxic T-cell response, which is an important prerequisite for successful cancer immunotherapy. Herein, a hyaluronic acid (HA) and antigen (ovalbumin, OVA)-decorated gold nanoparticle (AuNPs)-based (HA-OVA-AuNPs) vaccine is developed for photothermally controlled cytosolic antigen delivery using near-infrared (NIR) irradiation and is found to induce antigen-specific CD8+ T-cell responses. Chemical binding of thiolated HA and OVA to AuNPs facilitates antigen uptake of dendritic cells via receptor-mediated endocytosis. HA-OVA-AuNPs exhibit enhanced NIR absorption and thermal energy translation. Cytosolic antigen delivery is then permitted through the photothermally controlled process of local heat-mediated endo/lysosome disruption by laser irradiation along with reactive oxygen species generation, which helps to augment proteasome activity and downstream MHC I antigen presentation. Consequently, the HA-OVA-AuNPs nanovaccine can effectively evoke a potent anticancer immune response in mice under laser irradiation. This NIR-responsive nanovaccine is promising as a potent vaccination method for improving cancer vaccine efficacy.

A visible and controllable porphyrin-poly(ethylene glycol)/α-cyclodextrin hydrogel nanocomposites system for photo response.

The real-time controlling and tracking of the evolution and status of the hydrogel are important challenges for accurate and precise assessments. In this article, a visible and controllable hydrogel nanocomposites system for photo response was designed and developed based on a thermosensitive porphyrin-poly(ethylene glycol)/α-cyclodextrin hydrogel loaded with multi-walled carbon nanotubes (PPEG-MWNTs/α-CD). The PPEG-MWNTs/α-CD hydrogel was simply self-assembled with a carbon nanotubes dispersed porphyrin-poly(ethylene glycol) solution and an aqueous solution of α-cyclodextrin by homogeneous stirring. The structure and the optical and photothermal abilities of the hydrogel nanocomposites system were characterized in vitro. Moreover, the controlled disassembly of the hydrogel was monitored in real time by in vivo fluorescence imaging after subcutaneous injection using mice as models. The results demonstrated that the hydrogel disassembly can be efficiently accelerated under laser irradiation with the loading of carbon nanotubes by fluorescence imaging visualization. With the advantages of the photo response, fluorescence imaging tracking and photothermal remote controlling were combined into the hydrogel nanocomposites system.

Evaluation of PLGA containing anti-CTLA4 inhibited endometriosis progression by regulating CD4+CD25+Treg cells in peritoneal fluid of mouse endometriosis model.

Our study investigated poly(lactic-co-glycolic acid) (PLGA) as protein delivery vehicles encapsulate CTLA-4-antibody (anti-CTLA-4) which is essential for CD4+CD25+Treg cells suppressive function exposing superior potential for inhibiting endometriosis progress in mouse model than single anti-CTLA-4. Anti-CTLA-4 loaded PLGA combined to ligands CTLA-4 in surface of CD4+CD25+Treg cells which distributed in peritoneal fluid of mouse endometriosis model. The particle size, zeta potential of the anti-CTLA-4 loaded nanoparticles was detected by dynamic light scattering. Morphology of nanoparticles was evaluated by transmission electron microscopy (TEM). Confocal laser scanning microscopy (CLSM) indicated distribution of anti-CTLA-4 with PLGA or without in peritoneal fluid. Cumulative anti-CTLA-4 release from nanoparticles was evaluated by Micro BCA assay. The percentage of CD4+CD25+Treg cells in peritoneal fluid was demonstrated by flow cytometer. In vitro experiment we co-culture ectopic endometrial cells (EEC) with isolated CD4+CD25+Treg cells in peritoneal fluid (PF), proliferation and invasion of ectopic endometrial cells (EEC) was measured by BrdU ELISA assay and Matrigel invasion assay. In comparison with anti-CTLA-4 without nanoparticles, the bioconjugates PLGA/anti-CTLA-4 were tolerated in peritoneal fluid with a controlled release of anti-CTLA-4 in 3, 7, 14days. Moreover, PLGA/anti-CTLA-4 had superior protective regulation ability to reduce level of CD4+CD25+Treg cells in peritoneal fluid. Most strikingly, in vitro experiment, PLGA/anti-CTLA-4 exhibited better ability in inhibiting proliferation and invasion of ectopic endometrial cells in co-culture system compared with anti-CTLA-4. Progressively, PLGA/anti-CTLA-4 had better suppressive activity to inhibited IL-10 and TGF-beta secreted by CD4+CD25+Treg cells which indicating that PLGA/anti-CTLA-4 suppressed cells proliferation and invasion through reduced IL-10 and TGF-beta production. Thus, PLGA/anti-CTLA-4 may be a potential strategy for endometriosis therapy.

An Activatable Theranostic Nanomedicine Platform Based on Self-Quenchable Indocyanine Green-Encapsulated Polymeric Micelles.

Self-quenchable indocyanine green (ICG)-encapsulated micelles with folic acid (FA)-targeting specificity (FA-ICG-micelles) were developed for biologically activatable photodynamic theranostics. FA-ICG-micelles were successfully prepared using the thin-film hydration method, which allows ICG to be encapsulated with a high drug loading that induces an efficient ICG-based quenched state. FA-ICG-micelles are initially in the "OFF" state with no fluorescence signal or phototoxicity, but they become highly fluorescent and phototoxic in cellular degradative environments. Importantly, via folate receptor-mediated endocytosis, the FA targeting of FA-ICG-micelles enhanced intracellular uptake and photodynamic therapy (PDT) efficacy. Systematic administration of FA-ICG-micelles to folate receptor-positive tumor-bearing mice elicited prolonged blood circulation, enhanced tumor accumulation and improved therapeutic efficiency compared to free ICG. Therefore, based on the FA-targeted specificity and switchable photoactivity, FA-ICG-micelles have potential for photodynamic theranostics in cancer.