scholarly journals Nanoparticle-enhanced chemo-immunotherapy to trigger robust antitumor immunity

2020 ◽  
Vol 6 (35) ◽  
pp. eabc3646 ◽  
Author(s):  
Jingjing Liang ◽  
Huifang Wang ◽  
Wenxiu Ding ◽  
Jianxiang Huang ◽  
Xuefei Zhou ◽  
...  
Keyword(s):  
Triblock Copolymer ◽  
Rational Design ◽  
Antitumor Immunity ◽  
Chemotherapeutic Agent ◽  
Therapeutic Benefit ◽  
Combination Regimen ◽  
Cross Presentation ◽  
New Class ◽  
Immunosuppressive Tumor Microenvironment ◽  
Novel Strategy

Mounting evidence suggests that immunotherapies are a promising new class of anticancer therapies. However, the immunosuppressive tumor microenvironment (TME), poor immunogenicity, and off-target toxicity hinder the broader implementation of immunotherapies. Here, we describe a novel strategy combining chemotherapy and immunotherapy to modulate the TME by systemically and concurrently delivering the chemotherapeutic agent SN38 (7-ethyl-10-hydroxycamptothecin) and the STING agonist DMXAA (5,6-dimethylxanthenone-4-acetic acid) into tumors using triblock copolymer nanoparticles, named PS3D1@DMXAA, which enhances antigen cross-presentation and induces the conversion of the immunosuppressive TME to immunogenic TME through the newly found synergistic function between SN38 and STING activation. PS3D1@DMXAA thus shows potent therapeutic efficacy in three mice tumor models and elicits remarkable therapeutic benefit when combined with anti–PD-1 therapy. Our engineered nanosystem offers a rational design of an effective immunotherapy combination regimen to convert uninflamed “cold” tumors into “hot” tumors, addressing the major challenges immunotherapies faced.

Size Control of Block Polymer Templated Mesoporous Silicate Materials

2000 ◽  
Vol 628 ◽  
Author(s):  
Takeo Yamada ◽  
Keisuke Asai ◽  
Kenkichi Ishigure ◽  
Akira Endo ◽  
Hao S. Zhou ◽  
...  
Keyword(s):  
Mesoporous Materials ◽  
Molecular Sieve ◽  
Mesoporous Material ◽  
Triblock Copolymer ◽  
Size Control ◽  
Block Polymer ◽  
New Class ◽  
Mesoporous Silicate ◽  
Cubic Structure ◽  
Silicate Materials

ABSTRACTMesoporous materials have attracted considerable interest because of applications in molecular sieve, catalyst, and adsorbent. It will be useful for new functional device if functional molecules can be incorporated into the pore of mesoporous material. However, it is necessary to synthesize new mesoporous materials with controlled large pore size. Recently, new class of mesoporous materials has been prepared using triblock copolymer as a template. In this paper, we reported that hexagonal and cubic structure silicate mesoporous materials can be synthesized through triblock copolymer templating, and their size was controlled by synthesis condition at condensation.

scholarly journals DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells

2021 ◽  
Vol 9 (5) ◽  
pp. e002054
Author(s):  
Francisco J Cueto ◽  
Carlos del Fresno ◽  
Paola Brandi ◽  
Alexis J. Combes ◽  
Elena Hernández-García ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Elevated Serum ◽  
Dead Cell ◽  
Type I ◽  
Cross Presentation ◽  
Patients With Cancer ◽  
Deficient Mice

BackgroundConventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet.MethodsB16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s.ResultsHere, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth.ConclusionDNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.

scholarly journals Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging

2021 ◽  
Vol 22 (5) ◽  
pp. 2238
Author(s):  
Nao Nagai ◽  
Yotaro Kudo ◽  
Daisuke Aki ◽  
Hayato Nakagawa ◽  
Koji Taniguchi
Keyword(s):  
Colorectal Cancer ◽  
Chronic Inflammation ◽  
Antitumor Immunity ◽  
Suppressor Cells ◽  
Treg Cells ◽  
Cytotoxic T Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Age Related ◽  
Immunosuppressive Tumor Microenvironment ◽  
Pro Inflammatory Cytokines

Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.

The Synthesis and Catalytic Application of a New Class of Imprinted Silica

2003 ◽  
Vol 787 ◽  
Author(s):  
John D. Bass ◽  
Sandra L. Anderson ◽  
Alexander Katz
Keyword(s):  
Rational Design ◽  
Chemical Reactivity ◽  
Phenylboronic Acid ◽  
Coupling Reaction ◽  
Suzuki Coupling ◽  
Outer Sphere ◽  
Suzuki Coupling Reaction ◽  
New Class ◽  
Catalytic Application ◽  
Rate Acceleration

AbstractThe effect of chemical environment surrounding a synthetic heterogeneous catalyst active site is investigated using the hydrophilic imprinting of silica. Two model reaction systems have been used for this study: (i) Knoevenagel condensation of 3-nitrobenzaldehyde and malononitrile and (ii) Suzuki coupling of bromobenzene and phenylboronic acid. Using a catalyst in which isolated imprinted amines are surrounded by an acidic silanol-rich environment led to rate accelerations of over 120-fold relative to catalysts in which the amines are surrounded by a hydrophobic environment consisting of trimethylsilyl functional groups for system (i). This result parallels our previous study on the effect of the outer sphere composition on rate acceleration of Knoevenagel reactions using isophthalaldehyde as the aldehyde reactant. We also extended our method for the hydrophilic imprinting of bulk silica to organometallic systems, by successfully synthesizing a tethered palladium complex within the imprinted pocket. This material was used as an active catalyst for (ii). Our results show that a hydrophobic framework environment results in higher initial turnover frequencies than an acidic silanol-rich framework for the Suzuki coupling reaction of bromobenzene and phenylboronic acid, albeit with a lower overall effect than observed in the Knoevenagel system (i). Altogether, these results demonstrate the control of chemical reactivity via the rational design of the outer sphere using an imprinting approach.

Nucleoside Transporter-guided Cytarabine Conjugated Liposomes for Intracellular Methotrexate Delivery and Cooperative Choriocarcinoma Therapy

2021 ◽  
Author(s):  
Weidong Fei ◽  
Yunchun Zhao ◽  
Xiaodong Wu ◽  
Dongli Sun ◽  
Yao Yao ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Rational Design ◽  
High Efficiency ◽  
Nucleoside Transporter ◽  
Childbearing Age ◽  
Equilibrative Nucleoside Transporter ◽  
Choriocarcinoma Cells ◽  
Tumor Accumulation ◽  
Novel Strategy ◽  
Distribution Studies

Abstract The gestational trophoblastic tumor seriously endangers child productive needs and the health of women in childbearing age. Nanodrug-based therapy mediated by transporters provides novel strategy for the treatment of trophoblastic tumors. Focus on the overexpressed human equilibrative nucleoside transporter 1 (ENT1) on the membrane of choriocarcinoma cells (JEG-3), the cytarabine (Cy, a substrate of ENT1) grafted liposome (Cy-Lipo) was introduced for targeted delivery of methotrexate (Cy-Lipo@MTX) for choriocarcinoma therapy in this study. The ENT1 has high affinity for Cy-Lipo and can mediate the endocytosis of the designed nanovehicles into JEG-3 cells. The ENT1 protein maintains its transporting function through circulation and regeneration during endocytosis. Therefore, Cy-Lipo-based formulations achieved high tumor accumulation and retention in pharmacokinetic and distribution studies. More importantly, the designed Cy-lipid conjugation exhibited a synergistic therapeutic effect on choriocarcinoma. Finally, Cy-Lipo@MTX exerts an extremely powerful anti-choriocarcinoma effect with fewer side effects. This study suggests that the overexpressed ENT1 on choriocarcinoma cells holds a great potential to be a high-efficiency target for the rational design of active targeting nanotherapeutics.

Simple and rational design of a polymer nano-platform for high performance of HCV related miR-122 reduction in the liver

2018 ◽  
Vol 6 (10) ◽  
pp. 2667-2680 ◽  
Author(s):  
Hao Fu ◽  
XiangYu Zhang ◽  
Qi Wang ◽  
Yin Sun ◽  
Lei Liu ◽  
...  
Keyword(s):  
Triblock Copolymer ◽  
High Performance ◽  
Rational Design ◽  
Loading Capacity

Efficient long-term liver specific miR-122 reduction is achieved by utilizing high antagomir loading capacity NPs consisting of an mPEG-b-PLGA-b-PLL triblock copolymer.

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