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Covalent conjugation of poly(ethylene glycol) (PEG) is frequently employed to enhance the pharmacokinetics and biodistribution of various protein and nanoparticle therapeutics. Unfortunately, some PEGylated drugs can induce elevated levels of antibodies that can bind PEG, i.e., anti-PEG antibodies (APA), in some patients. APA in turn can reduce the efficacy and increase the risks of allergic reactions, including anaphylaxis. There is currently no intervention available in the clinic that specifically mitigates allergic reactions to PEGylated drugs without the use of broad immunosuppression. We previously showed that infusion of high molecular weight free PEG could safely and effectively suppress the induction of APA in mice and restore prolonged circulation of various PEGylated therapeutics. Here, we explored the effectiveness of free PEG as a prophylaxis against anaphylaxis induced by PEG-specific allergic reactions in swine. Injection of PEG-liposomes (PL) resulted in anaphylactoid shock (pseudoanaphylaxis) within 1–3 min in both naïve and PL-sensitized swine. In contrast, repeated injection of free PEG alone did not result in allergic reactions, and injection of free PEG effectively suppressed allergic reactions to PL, including in previously PL-sensitized swine. These results strongly support the further investigation of free PEG for reducing APA and allergic responses to PEGylated therapeutics.

Thermoelectric interface materials (TEiMs) are key to optimizing the electrical contact and stability of the interface between thermoelectric material and metal electrode in high-performance thin-film thermoelectric coolers (TECs). Herein, we explored TEiMs applicable to representative Bi–Te films and found that Cr and Ag are effective TEiMs for p-type Bi0.5Sb1.5Te3and n-type Bi2Te3, respectively. By introducing 200 nm Cr and 200 nm Ag as TEiMs for p-type Bi0.5Sb1.5Te3/Cu and n-type Bi2Te3/Cu interfaces, Cu diffusion is suppressed, and excellent electrical contact is achieved (1.81 × 10–12Ω m2for p-type and 3.32 × 10–12Ω m2for n-type) and remains stable after heat treatment (2.37 × 10–12Ω m2for p-type and 1.63 × 10–12Ω m2for n-type). Furthermore, the cooling flux of TECs with optimized TEiMs increases from 122.74 to 296.56 W/cm2, while the performance degradation caused by contact resistance decreases from 50.81 to 4.15%. In addition, our results show that diffusion occurs between not only Cu but also Ag and the thermoelectric material, as TEiMs diffuse slightly. The diffusion of Cu and Ag at the interface can optimize the electrical contact of Bi2Te3/Cu but strongly degrade the electrical contacts of Bi0.5Sb1.5Te3/Cu. Our work provides an optimal selection of TEiMs for high-performance Bi–Te thin film coolers and provides guidance for further miniaturization of devices.

Pressure reduction station (PRS) is an essential facility in natural gas transmission, which owns the function of pressure reduction, demand-supply management and flow metering. However, a large number of PRSs are located in off-grid areas and powered by battery equipment resulting in high maintenance costs. So, how to realize the energy independence of these PRSs is an urgent issue to be solved. Therefore, the natural gas fired thermoelectric generation (FTEG) module, including gas flue, cover, TEGs and heat radiators, is designed for PRS in off-grid areas. Phase change material is introduced into the FTEG module to change the operation mode from continuous mode into a periodic mode, and the prototype of the FTEG module is built to discuss the generation performance in different modes. The results show that the generation efficiency of the FTEG module is improved by 63% in periodic mode compared with the continuous mode. Then, the numerical model is established to investigate the impacts of air coefficient, cold-side heat radiator and number of TEGs on the module performance. It found that the impacts of cold-side heat radiator and the number of TEGs are more significant than those of the air coefficient. After adjusting these key parameters, an optimized FTEG module with 32 TEGs is proposed, which has an average power generation of 16.4 W and a heat collection efficiency of 84.6%. Eventually, 3 to 6 modules can be connected in series to meet the power requirement of 50 W to 100 W for PRS. This high-performance FTEG module can accelerate the process of achieving the energy independence of PRS and promote its application in mesoscale equipment.

In this paper, a one-dimensional thermodynamic model was developed to evaluate the device-level performance of thermoelectric cooler (TEC) with the Thomson effect, contact resistance, gap heat leakage, heat sink, and heat load taken into account. The model was generalized and simplified by introducing dimensionless parameters. Experimental measurements showed good agreement with analytical results. The parametric analysis indicated that the influence of the Thomson effect on cooling capacity continued to expand with increasing current, while the effect on COP hardly changed with current. Low thermal contact resistance was beneficial to obtain lower hot-junction temperature, which can even reduce 2 K compared with the electrical contact resistance in the case study. The gap heat leakage was a negative factor affecting the cooling performance. When the thermal resistance of the heat sink was small, the negative effect of heat leakage on performance would be further enlarged. The enhancement of heat load temperature would increase the cooling power of the TEC. For example, an increase of 5 K in heat load can increase the cooling capacity by about 4%. However, once the current exceeded the optimum value, the raising effect on the cooling power would be weakened. The research can provide an analytical approach for the designer to perform trade studies to optimize the TEC system.

Microsatellite-stable colorectal cancer (CRC) is known to be resistant to immunotherapy. The combination of quercetin (Q) and alantolactone (A) was found to induce synergistic immunogenic cell death (ICD) at a molar ratio of 1:4 (Q:A). To achieve ratiometric loading and delivery, the micellar delivery of Q and A (QA-M) was developed with high entrapment efficiency and drug loading at an optimal ratio. QA-M achieved prolonged blood circulation and increased tumor accumulation for both drugs. More importantly, QA-M retained the desired drug ratio (molar ratio of Q to A = 1:4) in tumors at 2 and 4 h after intravenous injection for synergistic immunotherapy. Tumor growth was significantly inhibited in murine orthotopic CRC by the treatment of QA-M compared to PBS and the combination of free drugs (p< 0.005). The combination of nanotherapy stimulated the host immune response to induce long-term tumor destruction and induced memory tumor surveillance with a 1.3-fold increase in survival median time compared to PBS (p< 0.0001) and a combination of free drugs (p< 0.0005). The synergistic therapeutic effect induced by codelivery of Q and A is capable of reactivating antitumor immunity by inducing ICD, causing cell toxicity and modulating the immune-suppressive tumor microenvironment. Such a combination of Q and A with synergistic effects entrapped in a simple and safe nanodelivery system may provide the potential for scale-up manufacturing and clinical applications as immunotherapeutic agents for CRC.

Local immunomodulation can be a promising strategy to augment the efficacy and decrease off-target toxicities associated with cancer treatment. Pancreatic cancer is resistant to immunotherapies due to the immunosuppressive tumor microenvironment. Herein, we investigated a therapeutic approach involving delivery of a short interfering double-stranded RNA (dsRNA), specific to Bcl2, with 5′ triphosphate ends, by lipid calcium phosphate nanoparticles, in an orthotopic allograft KPC model of pancreatic cancer. Retinoic acid-inducible gene I (RIG-I)-like receptors can bind to 5′ triphosphate dsRNA (ppp dsRNA), a pathogen-associated molecular pattern, producing type I interferon, while Bcl2silencing can drive apoptosis of cancer cells. Our approach demonstrated a robust enrichment of tumor tissue with therapeutic nanoparticles and enabled a significant tumor growth inhibition, prolonging median overall survival. Nanoparticles encapsulating dual-therapeutic ppp dsRNA allowed strong induction in levels of pro-inflammatory Th1 cytokines, further increasing proportions of CD8+T cells over regulatory T cells, M1 over M2 macrophages, and decreased levels of immunosuppressive B regulatory and plasma cells in the tumor microenvironment. Thus, these results provide a new immunotherapy approach for pancreatic cancer.

Desmoplastic tumors are normally resistant to nanoparticle-based chemotherapy due to dense stroma and limited particle permeability inside the tumor. Herein, we reported that hydralazine (HDZ)—an antihypertension vasodilator—would dramatically promote nanoparticle penetration in advanced desmoplastic tumors. First, a HDZ–liposome system was developed for tumor-selective delivery of HDZ. After three injections of HDZ–liposomes at a dose of 15 mg/kg, the tumor stroma was remarkably reduced, along with ameliorated tumor hypoxia in murine models of desmoplastic melanoma (BPD6). Furthermore, HDZ–liposome treatment altered the immunosuppressive tumor microenvironment, which provided opportunities for applying this therapeutic system to aid immunotherapy in desmoplastic tumors. Using DiD-loaded liposome as a model nanoparticle, we showed that HDZ–liposome treatment significantly increased nanoparticle accumulation and penetration inside desmoplastic tumors. As a result, one single injection of doxorubicin–liposomes at a dose of 5 mg/kg resulted in strong tumor inhibition effect after HDZ–liposome pretreatment in the advanced desmoplastic melanoma with sizes over 400 mm3. Because HDZ is a widely used antihypertension drug, the findings here should be readily translatable for clinical benefits.

In many cancers, the tumor microenvironment (TME) is largely immune suppressive, blocking the antitumor immunity and resulting in immunotherapy resistance. Interleukin 10 (IL-10) is a major player controlling the immunosuppressive TME in different murine tumor models. Increased IL-10 production suppresses intratumoral dendritic cell production of interleukin 12, thereby limiting antitumor cytotoxic T-cell responses and activation of NK cells during therapy. We engineered, formulated, and delivered genes encoding an IL-10 protein trap to change immunosuppressive TME, which could enhance antitumor immunity. Additionally, to achieve stronger and long-term therapeutic efficacy in a pancreatic cancer model, we targeted C-X-C motif chemokine ligand 12 (CXCL12), a key factor for inhibiting T-cell tumor infiltration, and simultaneously delivered an IL-10 trap. Following three injections of the lipid-protamine-DNA (LPD) nanoparticles loaded with trap genes (IL-10 trap and CXCL12 trap), we found tumor growth reduction and significantly prolonged survival of the host compared to control groups. Furthermore, the combination trap gene treatment significantly reduced immunosuppressive cells, such as M2 macrophages, MDSCs, and PD-L1+cells, and activated immunosuppressive tolerogenic dendritic cells, NK cells, and macrophages intratumorally. We have also shown that, when effectively delivered to the tumor, the IL-10 trap gene alone can inhibit triple-negative breast cancer growth. This strategy may allow clinicians and researchers to change the immunosuppressive microenvironment in the tumor with either a single therapeutic agent or in combination with other immunotherapies to prime the immune system, preventing cancer invasion and prolonging patient survival.

In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing desmoplastic melanoma.

Development of an effective treatment against advanced tumors remains a major challenge for cancer immunotherapy. Approximately 50% of human melanoma is driven by B-Raf proto-oncogene mutation (BRAF mutant). Tumors with such mutation are desmoplastic, highly immunosuppressive, and often resistant to immune checkpoint therapies. We have shown that immunotherapy mediated by low-dose doxorubicin-induced immunogenic cell death was only partially effective for this type of tumor and not effective in long-term inhibition of tumor progression. Wnt family member 5A (Wnt5a), a signaling protein highly produced by BRAF mutant melanoma cells, has been implicated in inducing dendritic cell tolerance and tumor fibrosis, thus hindering effective antigen presentation and T-cell infiltration. We hypothesized that Wnt5a is a key molecule controlling the immunosuppressive tumor microenvironment in metastatic melanoma. Accordingly, we have designed and generated a trimeric trap protein, containing the extracellular domain of Fizzled 7 receptor that binds Wnt5a with a Kd∼ 278 nM. Plasmid DNA encoding for the Wnt5a trap was delivered to the tumor by using cationic lipid-protamine-DNA nanoparticles. Expression of Wnt5a trap in the tumor, although transient, was greater than that of any other major organs including liver, resulting in a significant reduction of the Wnt5a level in the tumor microenvironment without systematic toxicity. Significantly, combination of Wnt5a trapping and low-dose doxorubicin showed great tumor growth inhibition and host survival prolongation. Our findings indicated that efficient local Wnt5a trapping significantly remodeled the immunosuppressive tumor microenvironment to facilitate immunogenic cell-death-mediated immunotherapy.

Synergistic activation of dendritic cells by combinations of TLR ligands requires both MyD88‐ and TRIF‐dependent signaling. Recently, it has been shown that certain combinations of TLR ligands act in synergy to induce the release of IL‐12 by DCs. In this study, we sought to define the critical parameters underlying TLR synergy. Our data show that TLR ligands act synergistically if MyD88‐ and TRIF‐dependent ligands are combined. TLR4 uses both of these adaptor molecules, thus activation via TLR4 proved to be a synergistic event on its own. TLR synergy did not affect all aspects of DC activation but enhanced primarily the release of certain cytokines, particularly IL‐12, whereas the expression of costimulatory molecules remained unchanged. Consequently, synergistic activation of DC did not affect their ability to induce T cell proliferation but resulted in TH1‐biased responses in vitro and in vivo. Furthermore, we examined the impact of TLR ligand combinations on primary DC in vitro but observed only modest effects with a combination of CpG + Poly (I:C). However, noticeable synergy in terms of IL‐12 production by DCs was detectable in vivo after systemic administration of CpG + Poly (I:C). Finally, we show that synergy is partially dependent on IFNAR signaling but does not require the release of IFNs to the enviroment, suggesting an autocrine action of type I IFNs.