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, mannanconjugated 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.

19F magnetic resonance imaging (MRI) is a powerful noninvasive, sensitive, and accurate molecular imaging technique for early diagnosis of diseases. The major challenge of 19F MRI is signal attenuation caused by the reduced solubility of probes with increased number of fluorine atoms and the restriction of molecular mobility. Herein, we present a versatile one-pot strategy for the fabrication of a multifunctional nanoprobe with high 19F loading (~2.0 × 108 19F atoms per Cu1.75S nanoparticle). Due to the high 19F loading and good molecular mobility that results from the small particle size (20.8 ± 2.0 nm) and ultrathin polymer coating, this nanoprobe demonstrates ultrahigh 19F MRI signal. In vivo tests show that this multifunctional nanoprobe is suitable for 19F MRI and photothermal therapy. This versatile fabrication strategy has also been readily extended to other single-particle nanoprobes for ablation and sensitive multimodal imaging.

Abstract: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-D 1 -FA 2 ) was radiolabeled with 99m Tc using tricine and trisodium triphenylphosphine-3,3 1 ,3 11 -trisulfonate (TPPTS) as coligands ( 99m Tc-HYNIC-D 1 -FA 2 ) 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 (IC 50 = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that 99m Tc-HYNIC-D 1 -FA 2 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 99m Tc-HYNIC-D 1 -FA 2 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.

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Fluorinated polyethylenimine derivative labeled with radionuclide (99m) Tc is developed as a (19) F MRI/SPECT/PA multifunctional imaging agent with good asialoglycoprotein receptors (ASGPR)-targeting ability. This multifunctional agent is safe and suitable for (19) F MRI/SPECT/PA imaging and has the potential to detect hepatic diseases and to assess liver function, which provide powerful support for the development of personalized and precision medicine.