Ting Liu

Without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment, cancer immunotherapy generally offers limited clinical benefit for established tumors. Tumor-associated macrophages (TAMs) are the critical driver of this immunosuppressive tumor microenvironment, which also promotes tumor metastasis. Here we successfully reprogrammed TAMs to an antitumor M1 phenotype using precision nanoparticle-based reactive oxygen species photogeneration, which demonstrated superior efficiency and efficacy over lipopolysaccharide stimulation. Meanwhile, antigen presentation and T-cell-priming by TAMs were enhanced by inhibiting lysosomal proton pump and proteolytic activity or by promoting tumor associated antigen release in the cytoplasm. The reprogrammed TAMs orchestrate cytotoxic lymphocyte (CTL) recruitment in the tumor and direct memory T-cells toward tumoricidal responses. This strategy could effectively eradicate tumors, inhibit metastasis, and further prevent their recurrence, which holds tremendous promise to realize potent cancer immunotherapy.

The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D₁-FA₂) was radiolabeled with ^99mTc using tricine and trisodium triphenylphosphine-3,3′,3″-trisulfonate (TPPTS) as coligands (^99mTc-HYNIC-D₁-FA₂) and its in vitro physicochemical properties, ex vivo biodistribution and in vivo micro-SPECT/CT imaging as a potential FR targeted agent were evaluated. It is a hydrophilic compound (log P = −2.52 ± 0.13) with high binding affinity (IC₅₀ = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that ^99mTc-HYNIC-D₁-FA₂ had high uptake in FR overexpressed tumor and kidney at all time-points, and both of them could obviously be inhibited when blocking with free FA in the blocking studies. From the in vivo micro-SPECT/CT imaging results, good tumor uptake of ^99mTc-HYNIC-D₁-FA₂ was observed in KB tumor-bearing mice and it could be blocked obviously. Based on the results, this new radiolabeled dimeric FA tracer might be a promising candidate for FR-targeting imaging with high affinity and selectivity.

Magnetic resonance imaging (MRI) is one of the most important imaging technologies used in clinical diagnosis. Reporter genes for MRI can be applied to accurately track the delivery of cell in cell therapy, evaluate the therapy effect of gene delivery, and monitor tissue/cell-specific microenvironments. Commonly used reporter genes for MRI usually include genes encoding the enzyme (e.g., tyrosinase and β-galactosidase), the receptor on the cells (e.g., transferrin receptor), and endogenous reporter genes (e.g., ferritin reporter gene). However, low sensitivity limits the application of MRI and reporter gene-based multimodal imaging strategies are common including optical imaging and radionuclide imaging. These can significantly improve diagnostic efficiency and accelerate the development of new therapies.

Hypoxia promotes not only the invasiveness of tumor cells, but also chemoresistance in cancer. Tumor associated macrophages (TAMs) residing at the site of hypoxic region of tumors have been known to cooperate with tumor cells, and promote proliferation and chemoresistance. Therefore, there is an urgent need for new strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we have taken advantage of high accumulation of TAMs in hypoxic regions of tumor and high reactivity of manganese dioxide nanoparticles (MnO₂ NPs) toward hydrogen peroxide (H₂O₂) for the simultaneous production of O₂ and regulation of pH to effectively alleviate tumor hypoxia by targeted delivery of MnO₂ NPs to the hypoxic area. Furthermore, we also utilized the ability of hyaluronic acid (HA) modification in reprogramming anti-inflammatory, pro-tumoral M2 TAMs to pro-inflammatory, antitumor M1 macrophages to further enhance the ability of MnO₂ NPs to lessen tumor hypoxia and modulate chemoresistance. The HA-coated, mannan-conjugated MnO₂ particle (Man-HA-MnO₂) treatment significantly increased tumor oxygenation and down-regulated hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor (VEGF) in the tumor. Combination treatment of the tumors with Man-HA-MnO₂ NPs and doxorubicin significantly increased apparent diffusion coefficient (ADC) values of breast tumor, inhibited tumor growth and tumor cell proliferation as compared with chemotherapy alone. In addition, the reaction of Man-HA-MnO₂ NPs toward endogenous H₂O₂ highly enhanced T₁- and T₂-MRI performance for tumor imaging and detection.

¹H MRS, ³¹P MRS and diffusion‐weighted MRI (DW‐MRI) were applied to study the metabolic changes associated with estrogen dependence in estrogen receptor (ER)‐positive BT‐474 and triple‐negative HCC1806 breast cancer xenografts supplemented with or without 17β‐estradiol (E₂) at a dose of 0.18 or 0.72 mg/pellet. Furthermore, the effect of estrogen withdrawal on the metabolism of BT‐474 and HCC1806 breast cancer xenografts was studied on day 0, day 2 and day 10. Increasing the dose of E₂ resulted in a rapid growth and increases in the lactate level and phosphomonoester/β‐nucleoside triphosphate (PME/βNTP), phosphocreatine/inorganic phosphate (PCr/Pi) and βNTP/Pi ratios in BT‐474 breast cancer xenografts; however, no significant changes were found in HCC1806 breast cancer xenografts. Estrogen withdrawal resulted in a marked decrease in lactate level and PME/βNTP ratio and an observed increase in βNTP/Pi, PCr/Pi and apparent diffusion coefficient (ADC) values of BT‐474 breast cancer xenografts on day 10. These data suggest that the lactate level and PME/βNTP, PCr/Pi and βNTP/Pi ratios of ER‐positive tumors are closely related to ER dependence. Copyright © 2015 John Wiley & Sons, Ltd.

To evaluate the reticuloendothelial system (RES) function by real-time imaging blood clearance as well as hepatic uptake of superparamagnetic iron oxide nanoparticle (SPIO) using dynamic magnetic resonance imaging (MRI) with two-compartment pharmacokinetic modeling. Kinetics of blood clearance and hepatic accumulation were recorded in young adult male 01b74 athymic nude mice by dynamic T2* weighted MRI after the injection of different doses of SPIO nanoparticles (0.5, 3 or 10 mg Fe/kg). Association parameter, K_in, dissociation parameter, K_out, and elimination constant, K_e, derived from dynamic data with two-compartment model, were used to describe active binding to Kupffer cells and extrahepatic clearance. The clodrosome and liposome were utilized to deplete macrophages and block the RES function to evaluate the capability of the kinetic parameters for investigation of macrophage function and density. The two-compartment model provided a good description for all data and showed a low sum squared residual for all mice (0.27±0.03). A lower K_in, a lower K_out and a lower K_e were found after clodrosome treatment, whereas a lower K_in, a higher K_out and a lower K_e were observed after liposome treatment in comparison to saline treatment (P<0.005). Dynamic SPIO-enhanced MR imaging with two-compartment modeling can provide information on RES function on both a cell number and receptor function level.