PEGylated Gambogic Acid Nanoparticles Enable Efficient Renal-Targeted Treatment of Acute Kidney Injury.

Acute kidney injury (AKI) is a common clinical syndrome lacking effective pharmacotherapy. Gambogic acid (GA), as an active ingredient of herbal medicines, exhibits antioxidant and anti-inflammatory effects that benefit the treatment of AKI, but its poor aqueous solubility limits effective renal delivery. We, for the first time, developed GA-based nanoparticles (GA-NPs) with preferential renal uptake for AKI treatment. By PEGylating with NH2-PEG5000-NOTA, hydrophobic GA was self-assembled into ∼4.5 nm nanoparticles, which showed the enhanced renal accumulation in AKI models from PET images. Importantly, the in vitro cell assays and in vivo tests of the two AKI models have confirmed the obvious nephroprotective effects and biosafety of GA-NPs. Therefore, this work indicates that GA-NPs can be a promising therapeutic candidate for the management of AKI.

Radioiodinated progesterone derivative for progesterone receptor targeting with enhanced nucleus uptake via phenylboronic acid conjugation.

A novel 131 I-radiolabeled probe with aromatic boronate motif (131 I-EIPBA) was designed to target progesterone receptor (PR)-positive breast cancer with enhanced nucleus uptake. Acetylene progesterone was conjugated with pegylated phenylboronic acid via click reaction and radiolabeled with 131 I to afford 131 I-EIPBA. Meanwhile, 131 I-EIPB without boronate was prepared as control agent. After determination of the lipophilicity and stability of these tracers, in vitro cell uptake studies and in vivo biodistribution in rats were performed to verify the enhanced nucleus uptake and PR targeting ability of 131 I-EIPBA. 131 I-EIPBA was obtained with moderate radiochemical yield (40.35 ± 3.52%) and high radiochemical purity (>98%). As expected, the high binding affinity (39.58 nM) of 131 I-EIPBA for PR was determined by cell binding assay. The internalization ratio of 131 I-EIPBA was remarkably higher than that of 131 I-EIPB in PR-positive MCF-7 cells. Furthermore, the enhanced nucleus uptake of 131 I-EIPBA (0.59 ± 0.02%) was found to be significantly higher than that of 131 I-EIPB (0.13 ± 0.01%) in MCF-7 cells. A novel 131 I-EIPBA compound was developed for PR targeting with improved cellular nucleus uptake. Furthermore, the introduction of aromatic boronate motif provides a worthwhile strategy for enhancing the nuclear receptor targeting of tracers.

Liposome-aided metabolic engineering of tumor surface immunogenicity.

Approaches to increase tumor immunogenicity are of therapeutic potentials. We herein reported the use of liposomes for covalent incorporation of neoantigen on tumor surfaces with DNP-conjugated sialic acid (DNPSia). Relative to free DNPSia, sugar-encapsulated biotinylated liposomes (DNPSia@LP@biotin) enables effective cell surface expression of DNPSia on biotin receptor (BR)-expressing cells over BR-free cells in vitro, and on tumor cell surfaces with high tumor-to-normal tissue contrast in a mice model. These findings suggest the potentials of targetable liposomes for modulating tumor surface immunity via metabolic oligosaccharide engineering.

Activatable Dual ROS-Producing Probe for Dual Organelle-Engaged Photodynamic Therapy.

Photodynamic therapy (PDT) necessitates approaches capable of increasing antitumor effects while decreasing nonspecific photodamage. We herein report an activatable probe (Glu-PyEB) comprising two distinct photosensitizers with mutually suppressed photodynamics. Activation by tumor-associated γ-glutamyltranspeptidase gives rise to a generator of superoxide radical (O2-•) accumulated in lysosomes and a producer of singlet oxygen (1O2) enriched in mitochondria. This enables light-irradiation-triggered damage of lysosomes and mitochondria, robust cell death, and tumor retardation in vivo, showing the use of paired photosensitizers subjected to reciprocally suppressed photodynamics for activatable PDT.

Desmin- and vimentin-mediated hepatic stellate cell-targeting radiotracer 99mTc-GlcNAc-PEI for liver fibrosis imaging with SPECT.

Extracellular matrix (ECM) accumulation in liver fibrosis is caused by the activation of hepatic stellate cells (HSCs). The goal of this study was to develop a 99mTc-labeled N-acetylglucosamine (GlcNAc) that specifically interacts with desmin and vimentin expressed on activated HSCs to monitor the progression and prognosis of liver fibrosis using single-photon emission computed tomography (SPECT) imaging. Methods: GlcNAc-conjugated polyethylenimine (PEI) was first prepared and radiolabeled with 99mTc. Noninvasive SPECT imaging with 99mTc-GlcNAc-PEI was used to assess liver fibrosis in a carbon tetrachloride (CCl4) mouse model. The liver uptake value (LUV) of 99mTc-GlcNAc-PEI was measured by drawing the region of interest (ROI) of the whole liver as previously suggested. The LUV of the CCl4 groups was compared with that of the olive oil group. Next, we estimated the correlation between the results of SPECT imaging and physiological indexes. After treatment with clodronate liposome, the LUV of 99mTc-GlcNAc-PEI in fibrotic mice was compared with that in control mice. Results:99mTc-GlcNAc-PEI is a hydrophilic compound with high radiochemical purity (>98%) and good stability. It could specifically target desmin and vimentin on the surface of activated HSCs with high affinity (the Kd values were 53.75 ± 9.50 nM and 20.98 ± 3.56 nM, respectively). The LUV of 99mTc-GlcNAc-PEI was significantly different between the CCl4 and control groups as early as 4 weeks of CCl4 administration (3.30 ± 0.160 vs 2.34 ± 0.114%/cc; P ˂ 0.05). There was a strong correlation between the LUV and Sirius Red quantification (R = 0.92, P ˂ 0.001). Compared with control, clodronate liposome treatment reduced the LUV of 99mTc-GlcNAc-PEI (4.62 ± 0.352 vs 2.133 ± 0.414%/cc; P ˂ 0.05). Conclusion:99mTc-GlcNAc-PEI SPECT/CT was useful in assessing liver fibrosis and monitoring the treatment response.

Simplified quantification method for in vivo SPECT/CT imaging of asialoglycoprotein receptor with (99m)Tc-p(VLA-co-VNI) to assess and stage hepatic fibrosis in mice.

The goal of this study is to develop a noninvasive method of SPECT imaging to quantify and stage liver fibrosis with an Asialoglycoprotein receptor (ASGP-R) targeting tracer-(99m)Tc-p(VLA-co-VNI). ASGP-Rs are well known to specifically express in the mammalian liver. Here, we demonstrated ASGP-R expression decreased in carbon tetrachloride (CCl4)-induced mouse model. ASGP-R expression correlated with liver fibrosis progression. ASGP-R could be a useful marker in the stage of liver fibrosis. Liver uptake value (LUV) derived by SPECT imaging was used to assess liver fibrosis in the CCl4-induced mouse model. LUV = [radioactivity (liver uptake)/radioactivity (injected)] × 100/liver volume. The LUV decreased along with the disease progression. The relationships between LUV and liver hydroxyproline (i.e. collagen), as well as Sirius Red were established and verified. A strong negative linear correlation was found between LUV and hydroxyproline levels (r = -0.83) as well as LUV and Sirius Red quantification (r = -0.83). In conclusion, SPECT imaging with (99m)Tc-p(VLA-co-VNI) is useful in evaluating and staging liver fibrosis in vivo.