The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a ...proof-of-concept study testing aptamer-drug conjugate (ApDC) targeted delivery systems for chemotherapeutic drugs.
Aptamer library targeting human epidermal growth factor receptor 3 (HER3) was screened and affinity was determined by enzyme-linked immunosorbent assay. Specificity was tested in MCF-7
, BT474
, and 293T
cells using flow cytometry and confocal microscopy. We further developed a HER3 aptamer-functionalized liposome encapsulating DOX and the efficiency of this ApDC was detected by cellular uptake analysis and cell viability assay. In MCF-7 tumor-bearing mice, tumor targeting evaluation, efficacy, toxicity and preliminary pharmocokinetic study was performed.
The candidate #13 aptamer had highest affinity (Kd =98±9.7 nM) and specificity. ApDC effectively reduces the half maximal inhibitory concentration of DOX compared with lipsome-DOX and free DOX. In vivo imaging and preliminary distribution studies showed that actively targeted nanoparticles, such as Apt-Lip-DOX molecules, could facilitate the delivery of DOX into tumors in MCF-7-bearing mice. This targeted chemotherapy caused greater tumor suppression than other groups and alleviated side effects such as weight loss, low survival rate, and organ (heart and liver) injury demonstrated by H&E staining.
The results indicate that targeted chemotherapy using the aptamer-drug conjugate format could provide better tolerability and efficacy compared with non-targeted delivery in relatively low-dose toxic drugs.
Abstract We developed a system of nanoparticles of poly(lactide)- d -α-tocopheryl polyethylene glycol succinate (PLA-TPGS) and carboxyl group-terminated TPGS (TPGS–COOH) copolymer blend for ...multimodality treatment of cancer, which formulated docetaxel for chemotherapy, herceptin for biotherapy and targeting, and iron oxides (IOs) for hyperthermia therapy, which are denoted as MMNPs. It is demonstrated that the MMNPs achieved a significantly higher therapeutic effects than the various combination of the corresponding individual modality treatment NPs and the dual modality treatment NPs due to the synergistic effects among the chemo, bio, and thermo therapies. We further developed a method by employing the concept of NPs IC50, the concentration of the agent-, or agents-loaded nanoparticles that is needed to kill 50% of the cancer cells, to quantitatively access the synergistic effects of the multimodality treatment. It is shown by employing the SK-BR-3 cell line as an in vitro model of the HER2-positive breast cancer that the NPs IC50 is 0.42 mg/mL DCL-NPs plus 1.33 mg/mL Her-NPs plus 0.59 mg/mL IOs-NPs, a total NPs concentration of 2.34 mg/mL for the treatment of a physical mixture of the DCL-NPs, Her-NPs and IOs-NPs at the 1:2:7 weight ratio, while it is only 0.0011 mg/mL for the MMNPs for 24 h, which is 2130 fold more efficient than the physical mixture of the corresponding single modality treatments.
Paclitaxel is one of the most effective antineoplastic drugs. Its current clinical administration is formulated in Cremophor EL, which causes serious side effects. Nanoparticle (NP) technology may ...provide a solution for such poisonous adjuvant problems and promote a sustained chemotherapy, in which biodegradable polymers play a key role. Our group has successfully synthesized novel poly(lactide)–tocopheryl polyethylene glycol succinate (TPGS) (PLA–TPGS) copolymers of desired hydrophobic–hydrophilic balance for NP formulation of anticancer drugs. The present work is focused on effects of the PLA:TPGS composition ratio on drug encapsulation efficiency, in vitro drug release, in vitro cellular uptake and viability of the PLA–TPGS NP formulation of paclitaxel. The PLA–TPGS copolymers of various PLA:TPGS ratios were synthesized by the ring-opening polymerization method and characterized by GPC and
1H NMR for their molecular structure. Paclitaxel-loaded PLA–TPGS NPs were prepared by a modified solvent extraction/evaporation method and characterized by laser light scattering for size and size distribution, scanning electron microscopy for surface morphology and zeta potential for surface charge. High performance liquid chromatography was used to measure the drug encapsulation efficiency and in vitro drug release profile. Cancer cell lines HT-29 and Caco-2 were used to image and measure the cellular uptake of fluorescent PLA–TPGS NPs. Cancer cell viability of the drug-loaded PLA–TPGS was measured by MTT assay. It was found that the PLA:TPGS composition ratio has little effects on the particle size and size distribution. However, the PLA–TPGS NPs of 89:11 PLA:TPGS ratio achieved the best effects on the drug encapsulation efficiency, the cellular uptake and the cancer cell mortality of the drug-loaded PLA–TPGS NPs. This research was also carried out in close comparison with the drug-loaded PLGA NPs.
Abstract Nanoparticles of biodegradable polymers (NPs) have been widely used for drug delivery. However, there has been little research on their fate after internalized into the cells. We show in ...this research by using docetaxel as a model anticancer drug, which is formulated in the cholic acid conjugated nanoparticles of poly(lactic-co-glycolic acid (PLGA NPs) that the NPs induce autophagy of the cancer cells and thus may hinder the advantages of the nanomedicine. Moreover, we show both in vitro and in vivo that co-administration of autophagy inhibitors such as 3-methyladenine (3-MA) and Chloroquine (CQ) could greatly enhance the therapeutic effects of the nanoparticle formulation. The IC50 values of the drug formulated in the PLGA NPs after 24 h treatment with no autophagy inhibitor or in combination with 10 m m 3-MA or 30 μ m CQ are 38.27 ± 1.23, 6.7 ± 1.05, 4.78 ± 1.75 μg/mL, which implie 5.7 or 8,0 fold efficient by the autophagy inhibition respectively. Moreover, both the volume and the weight of the shrunk tumor of the mice after 20 day treatment with the PLGA NPs formulation combined with 3-MA or CQ are found to be only about a half in comparison with the treatment with the PLGA NPs formulation alone. In this research, we reported such a new mechanism of cancer cells to have PLGA NPs captured and degraded by auto-lysosomes. The findings provide advanced knowledge for development of nanomedicine for clinical application.
Abstract Research on quantitative control of targeting effect for the drug delivery system of ligand-conjugated nanoparticles of biodegradable polymers is at the cutting edge in the design of drug ...delivery device. In this work, we developed a post-conjugation strategy, which makes the ligand conjugation after the preparation of the drug-loaded nanoparticles of two copolymers blend. We synthesized the PLGA-PEG copolymer with PEG functioning as the linker molecule needed for herceptin conjugation. Docetaxel-loaded nanoparticles of the PLGA-PEG/PLGA copolymer blend were prepared by the nanoprecipitation method. Anti-HER2 antibody (heceptin), which targets the breast cancer cells of HER2 receptor overexpression, was conjugated on the drug-loaded PLGA-PEG/PLGA nanoparticles for sustained, controlled and targeted delivery of docetaxel. We demonstrated that the targeting effect can be quantitatively controlled by two ways, i.e. (1) adjusting the copolymer blend ratio of the nanoparticle matrix, which showed within the range of 20% PLGA/PEG in the copolymer blend a linear relation with the ligand density on the nanoparticle surface, and (2) adjusting the herceptin feed molar ratio to NH2 in the linker molecules appearing on the nanoparticle surface, which also showed a linear relation. Compared with the pre-conjugation strategy developed recently in the literature, in which the ligand was firstly conjugated onto the PLGA-PEG copolymer before preparation of the nanoparticles of the PLGA-PEG/PLGA copolymer blend, the post-conjugation strategy provides more efficient use of the ligand and protects its bioactivity in the nanoparticle preparation process, thus resulting in much better performance in drug targeting, which was assessed in vitro with SK-BR-3 breast cancer cells of HER2 receptor overexpression and MCF7 breast cancer cells of HER2 receptors moderate expression.
Influenza A virus infection and its complications effect a large population worldwide. Endothelial cells are an important component in lung inflammation caused by influenza A virus infection. The ...roles of endothelial sphingosine 1-phophate receptor 1 (S1PR1) in the regulation of molecules involved in leukocyte recruitment during influenza A virus infection still remain unknown. In this report, we tested our hypothesis that S1PR1 agonist CYM5442 inhibits expression of intracellular adhesion molecules 1 (ICAM1) in endothelial cells infected with influenza A virus.
Human pulmonary microvascular endothelial cells (HPMEC) were infected with influenza A virus H1N1. Expression of cytokines, chemokines, interferons, and cellular adhesion molecules was measured by q-PCR. Expression of ICAM1 was further tested by Western Blotting. A S1PR1 agonist CYM5442 was added to the culture media to assess CYM5442's inhibitory effects during virus infection.
HPMEC could be infected with H1N1 and responded to produce pro-inflammatory cytokines, chemokines, type I interferons, and cellular adhesion molecules. Addition of CYM5442 in culture media reduced the production of ICAM1 via a dosage- and time-dependent manner. CYM5442 inhibited the activation of nuclear factor (NF)-κB. The regulatory effects of CYM5442 were β-arrestin2-dependent.
Activated S1PR1 signaling regulates the production of cellular adhesion molecules by inhibiting NF- κB activation via a β-arrestin2-dependent manner.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
In this paper, we report a unique type of core-shell crystalline material that combines an inorganic zeolitic cage structure with a macrocyclic host arrangement and that can remove trace ...levels of iodine from water effectively. These unique assemblies are made up of an inorganic Archimedean truncatedhexahedron (
tcu
) polyhedron in the kernel which possesses six calixarene-like shell cavities. The cages have good adaptability to guests and can be assembled into a series of supramolecular structures in the crystalline state with different lattice pore shapes. Due to the unique core-shell porous structures, the compounds are not only stable in organic solvents but also in water. The characteristics of the cages enable rapid iodine capture from low concentration aqueous I
2
/KI solutions (down to 4 ppm concentration). We have studied the detailed process and mechanism of iodine capture and aggregation at the molecular level. The facile synthesis, considerable adsorption capacity, recyclability, and β- and γ-radiation resistance of the cages should make these materials suitable for the extraction of iodine from aqueous effluent streams (most obviously, radioactive iodide produced by atomic power generation).
The effects of blue (BL) and green light (GL) treatment during the dark period were examined in Camellia sinensis as a first step to understanding the spectral effects of artificial BL and GL on ...plant secondary metabolism and light signaling interactions. BL could induce the expression of CRY2/3, SPAs, HY5, and R2R3-MYBs to promote the accumulation of anthocyanins and catechins in tea plants. GL, on the other hand, could stimulate the accumulation of several functional substances (e.g., procyanidin B2/B3 and l-ascorbate) and temper these BL responses via down-regulation of CRY2/3 and PHOT2. Furthermore, the molecular events that triggered by BL and GL signals were partly overlapped with abiotic/biotic stress responses. We indicate the possibility of a targeted use of BL and GL to regulate the amount of functional metabolites to enhance tea quality and taste, and to potentially trigger defense mechanisms of tea plants.
Hepatic osteodystrophy (HOD) is a metabolic bone disease that is often associated with chronic liver disease and is marked by bone loss. Here, we demonstrate that hepatic expression of the ...phosphatase PP2Acα is upregulated during HOD, leading to the downregulation of expression of the hepatokine lecithin-cholesterol acyltransferase (LCAT). Loss of LCAT function markedly exacerbates the bone loss phenotype of HOD in mice. In addition, we found that alterations in cholesterol levels are involved in the regulation of osteoblast and osteoclast activities. We also found that LCAT improves liver function and relieves liver fibrosis in the mouse HOD model by promoting reversal of cholesterol transport from the bone to the liver. In summary, defects in a liver-bone axis occur during HOD that can be targeted to ameliorate disease progression.
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•High levels of PP2Acα in the liver correlate with bone loss in individuals with HOD•Upregulation of LCAT expression in the liver ameliorates bone loss in HOD mice•PP2Acα downregulates LCAT expression through dephosphorylation of USF1•LCAT improves liver function by reversing cholesterol transport from bone to liver
Hepatic osteodystrophy (HOD) is a metabolic bone disease caused by chronic liver injuries. Lu et al. discovered a novel liver-bone axis in the pathogenesis of HOD involving the upregulation of hepatic PP2Acα that leads to reduced expression of the hepatokine lecithin-cholesterol acyltransferase (LCAT) and defects in reverse cholesterol transport from the bone to the liver.
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