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Ho Yub Yoon,1,* In Ho Chang,2,* Yoon Tae Goo,1 Chang Hyun Kim,1 Tae Hoon Kang,1 Soo-Yeon Kim,3 Sang Jin Lee,3 Seh Hyon Song,4 Young Mi Whang,2 Young Wook Choi1 1College of Pharmacy, Chung-ang University, Seoul, Korea; 2College of Medicine, Chung-ang University, Seoul, Korea; 3Research Institute, National Cancer Center, Goyang, Korea; 4College of Pharmacy, Kyungsung University, Busan, Korea*These authors contributed equally to this workPurpose: To develop an intravesical instillation system for the treatment of bladder cancer, rapamycin (Rap) was encapsulated into liposomes and then homogeneously dispersed throughout a poloxamer 407 (P407)-based hydrogel.Methods: Rap-loaded conventional liposomes (R-CL) and folate-modified liposomes (R-FL) were prepared using a film hydration method and pre-loading technique, and characterized by particle size, drug entrapment efficiency, and drug loading. The cellular uptake behavior in folate receptor-expressing bladder cancer cells was observed by flow cytometry and confocal laser scanning microscopy using a fluorescent probe. In vitro cytotoxic effects were evaluated using MTT assay, colony forming assay, and Western blot. For in vivo intravesical instillation, Rap-loaded liposomes were dispersed in P407-gel, generating R-CL/P407 and R-FL/P407. Gel-forming capacities and drug release were evaluated. Using the MBT2/Luc orthotopic bladder cancer mouse model, in vivo antitumor efficacy was evaluated according to regions of interest (ROI) measurement.Results: R-CL and R-FL were successfully prepared, at approximately 12 hrs, both R-CL/P407 and R-FL/P407 preparations transformed into gel immediately after instillation into the mouse bladder. Drug release from the liposomal gel was erosion controlled. In orthotopic bladder cancer mouse model, statistically significant differences in ROI values were found between R-CL/P407 and R-FL/P407 groups at day 11 (P=0.0273) and day 14 (P=0.0088), indicating the highest tumor growth inhibition by R-FL/P407.Conclusion: Intravesical instillation of R-FL/P407 might represent a good candidate for bladder cancer treatment, owing to its enhanced retention and FR-targeting.Keywords: bladder cancer, prolonged retention, enhanced uptake, antitumor efficacy, autophagy, mTOR signaling

Application of fertilizers to supply appropriate nutrients has become an essential agricultural strategy for enhancing the efficiency of phytoremediation in heavy metal contaminated soils. The present study was conducted to investigate the beneficial effects of three types of phosphate fertilizers (i.e., oxalic acid-activated phosphate rock (APR), Ca(HPO), and NaHPO) in the range of 0-600 mg P kg soil, on castor bean growth, antioxidants [antioxidative enzymes and glutathione (GSH)], and Cu uptake. Results showed that with the addition of phosphorus fertilizers, the dry weight of castor bean and the Cu concentration in roots increased significantly, resulting in increased Cu extraction. The phosphorus concentration in both shoots and roots was increased as compared with the control, and the Ca(HPO) treatment had the greatest effect. Application of APR, NaHPO, and Ca(HPO) reduced the malondialdehyde (MDA) content, and the activity of the two antioxidant enzymes superoxide dismustase (SOD, EC 1.15.1.1) and catalase (CAT, EC 1.11.1.6) in the leaves of castor bean. GSH concentration in leaves increased with the increasing levels of phosphorus applied to soil as well as the accumulation of phosphorus in shoots, compared to the control. These results demonstrated that the addition of phosphorus fertilizers can enhance the resistance of castor bean to Cu and increase the Cu extraction efficiency of the plant from contaminated soils. [ABSTRACT FROM AUTHOR]

We previously showed (1) that a peptide, Ac-hE18A-NH2, in which the arginine-rich heparin-binding domain of apolipoprotein E (apoE) [residues 141–150] (LRKLRKRLLR), covalently linked to 18A (DWLKAFYDKVAEKLKEAF; a class A amphipathic helix with high lipid affinity), enhanced LDL uptake and clearance. Because VLDL and remnants contain more cholesterol per particle than LDL, enhanced hepatic clearance of VLDL could lead to an effective lowering of plasma cholesterol. Therefore, in the present article we compared the ability of this peptide to mediate/facilitate the uptake and degradation of LDL and VLDL in HepG2 cells. The peptide Ac-hE18A-NH2, but not Ac-18A-NH2, enhanced the uptake of LDL by HepG2 cells 5-fold and its degradation 2-fold. The association of the peptides with VLDL resulted in the displacement of native apoE; however, only Ac-hE18A-NH2 but not Ac-18A-NH2 caused markedly enhanced uptake (6-fold) and degradation (3-fold) of VLDL. Ac-hE18A-NH2 also enhanced the uptake (15-fold) and degradation (2-fold) of trypsinized VLDL Sf 100–400 (containing no immunodetectable apoE), indicating that the peptide restored the cellular interaction of VLDL in the absence of its essential native ligand (apoE). Pretreatment of HepG2s with heparinase and heparitinase abrogated all peptide-mediated enhanced cellular activity, implicating a role for cell-surface heparan sulfate proteoglycans (HSPG). Intravenous administration of Ac-hE18A-NH2 into apoE gene knockout mice reduced plasma cholesterol by 88% at 6 h and 30% at 24 h after injection. We conclude that this dual-domain peptide associates with LDL and VLDL and results in rapid hepatic uptake via a HSPG-facilitated pathway.—Datta, G., D. W. Garber, B. H. Chung, M. Chaddha, N. Dashti, W. A. Bradley, S. H. Gianturco, and G. M. Anantharamaiah. Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo.

The technique of diffusive gradients in thin films (DGT) has been shown to be a promising tool to assess metal uptake by plants in a wide range of soils. With the DGT technique, diffusion fluxes of trace metals through a diffusion layer towards a resin layer are measured. The DGT technique therefore mimics the metal uptake by plants if uptake is limited by diffusion of the free ion to the plant roots, which may not be the case at high metal supply. This study addresses the capability of DGT to predict cadmium (Cd) uptake by plants at varying Cd supply. To test the performance of DGT in such conditions, we used the chloride (Cl−) enhancement effect, i.e. the increase in Cd solution concentrations—due to chloride complexation of Cd—and Cd uptake with increasing Cl− concentrations, as previously characterized in pot, field and solution culture experiments. The uptake of Cd by spinach was assessed in soil amended with Cd (0.4–10.5 mg Cd kg−1) and NaCl (up to 120 mM) in a factorial design. Treatments with NaNO3 were included as a reference to correct for ionic strengths effects. The effect of Cl− on the shoot Cd concentrations was significant at background Cd but diminished with increasing soil Cd. Increasing Cl− concentrations increased the root area based Cd uptake fluxes by more than a factor of 5 at low soil Cd, but had no significant effect at high soil Cd. Short-term uptake of Cd in spinach from nutrient solutions confirmed these trends. In contrast, increasing Cl− concentrations increased the DGT measured fluxes by a factor of 5 at all Cd levels. As a result, DGT fluxes were able to explain soil Cl− effects on plant Cd concentrations at low but not at high Cd supply. This example illustrates under which conditions DGT mimics trace metal bioavailability. If biouptake is controlled by diffusive limitations, DGT should be a successful tool for predicting ion uptake across different conditions. [ABSTRACT FROM AUTHOR]

Abstract: A hydroponic experiment was conducted to investigate the effect of rhamnolipids, a biosurfactant, on the uptake of polycyclic aromatic hydrocarbons (PAHs) by ryegrass. Results showed that rhamnolipids could enhance the uptake of PAHs by ryegrass roots. With increasing concentration of rhamnolipids, the PAH content in ryegrass roots initially increased and then decreased, while the PAH content in ryegrass shoots did not change. Batch studies also showed that the sorption of phenanthrene by fresh ryegrass roots was dependent on rhamnolipid concentration and showed the same trends as the uptake experiment. The increase of permeability of ryegrass root cells with the increase of rhamnolipid concentration may lead to the initial enhancement of PAH content in ryegrass roots, and the decrease of PAH adsorption onto the root surface with further increase of rhamnolipids led to the decrease of PAH content in ryegrass roots. [Copyright &y& Elsevier]

An orthogonally designed experiment was conducted to study the single and combined effects of N, P and K on phytoremediation of Cu-polluted soil by Indian mustard. Addition of fertilizer N and P significantly increased Indian mustard shoot yield. Two high treatments combined with N resulted in the highest yields, followed by low-P combined with N. In contrast, high P with no N gave no yield increase and K had no effect on yield of Indian mustard. Nitrogen and P increased the amount of chlorophyll in the leaves, indicating that the yield increases were due to enhanced photosynthesis. Nitrogen application had no effect on plant Cu concentrations but addition of P slightly decreased plant Cu concentrations, likely a dilution effect resulting from the increase in yield. Among the treatments, N and P applied at 100 and 200 mg kg-1 respectively with no K application resulted in the highest Cu uptake. Thus, a combination of low N and high P produced a yield increase in Indian mustard that was more than adequate to compensate for a slight decrease in Cu concentration, resulting in the highest Cu removal from the contaminated soil. [ABSTRACT FROM AUTHOR]

• Multifunctional trimethyl chitosan/human serum albumin nanosystems were generated. • IR780 and bufalin were loaded into polysaccharide nanoplatforms via ionic gelation. • IR780-loaded nanoplatform generated a highly photothermal effect upon irradiation. • Tumor distribution was enhanced by human serum albumin interaction. • Nanoplatforms displayed superior synergistic tumor therapy. Current metastatic breast cancer therapies are not only affected by limited drug delivery options, but also restricted to the monotherapies. Here, we synthesized trimethyl chitosan (TMC), loaded it with photosensitizer IR780 or bufalin by ionic gelation, and coated it with human serum albumin (HSA) by electrostatic absorption (designated TIH or TBH, respectively). The near-spherical nanoparticles had a size of approximately 30 nm, exerted strong photothermal effects, and enhanced cellular mitochondrion colocation and phototoxicity. Tumor microenvironments were disrupted by TIH-mediated photothermal effects, which enhanced the accumulation of a second TBH dose in the tumor that promoted deep penetration in the whole tumor mass. After laser irradiation our nanoplatform enhanced cancer tissue accessibility and substantially suppressed tumor growth, and causing a 98.46 % inhibition of lung metastasis. Thus HSA-masked TMC represents a promising tumor-targeted drug delivery strategy with synergistic modality that may improve the therapeutic outcome of metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Folic acid is often used for active targeting of tumor cells to enhance therapeutic outcomes. Here, folic acid was conjugated with chitosan and folate-conjugated chitosan-lipid hybrid nanoparticles were prepared by ionic gelation method using anionic lipid. These nanoparticles were in size range of 200 to 400 nm with spherical shape. In vitro drug release data suggested a sustained release of cisplatin. The therapeutic efficacy of the folate-conjugated hybrid nanoparticles was evaluated in SK-OV-3, A2780 and MCF-7 cancer cell lines. A significant increase in cytotoxicity was observed with folate targeted LPHNPs compared to non-targeted LPHNPs. Significantly enhanced cellular uptake and cell cycle arrest resulting from folate-targeted nanoparticles were confirmed using fluorescence microscopy and flow cytometry. The therapeutic efficacy and tumor penetration were further evaluated in 3D spheroid tumor models. These studies suggest that folate-conjugated lipid-chitosan nanoparticles could enhance therapeutic activity and may represent a promising platform for active targeting of tumor cells. Folate conjugated lipid-chitosan hybrid nanoparticles were successfully developed by ionic gelation method using negatively charged lipids for enhanced biocompatibility and cytotoxicity. Folate targeted lipid-chitosan hybrid nanoparticles showed enhanced penetration via folate receptor mediated endocytosis. Unlabelled Image [ABSTRACT FROM AUTHOR]

Folic acid is often used for active targeting of tumor cells to enhance therapeutic outcomes. Here, folic acid was conjugated with chitosan and folate-conjugated chitosan-lipid hybrid nanoparticles were prepared by ionic gelation method using anionic lipid. These nanoparticles were in size range of 200 to 400 nm with spherical shape. In vitro drug release data suggested a sustained release of cisplatin. The therapeutic efficacy of the folate-conjugated hybrid nanoparticles was evaluated in SK-OV-3, A2780 and MCF-7 cancer cell lines. A significant increase in cytotoxicity was observed with folate targeted LPHNPs compared to non-targeted LPHNPs. Significantly enhanced cellular uptake and cell cycle arrest resulting from folate-targeted nanoparticles were confirmed using fluorescence microscopy and flow cytometry. The therapeutic efficacy and tumor penetration were further evaluated in 3D spheroid tumor models. These studies suggest that folate-conjugated lipid-chitosan nanoparticles could enhance therapeutic activity and may represent a promising platform for active targeting of tumor cells., Competing Interests: Declaration of competing interest There is no conflict of interest among authors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Owing to the complex and still not fully understood physiological environment, the development of traditional nanosized drug delivery systems is very challenging for precision cancer therapy. It is very difficult to control the in vivo distribution of nanoparticles after intravenous injection. The ideal drug nanocarriers should not only have stealth surface for prolonged circulation time but also possess enhanced cellular internalization in tumor sites. Unfortunately, the stealth surface and enhanced cellular uptake seem contradictory to each other. How to integrate the two opposite aspects into one system is a very herculean but meaningful task. As an alternative drug delivery strategy, chameleon-like drug delivery systems were developed to achieve long circulation time while maintaining enhanced cancer cell uptake. Such drug nanocarriers can "turn off" their internalization ability during circulation. However, the enhanced cellular uptake can be readily activated upon arriving at tumor tissues. In this way, stealth surface and enhanced uptake are of dialectical unity in drug delivery. In this review, we focus on the surface engineering of drug nanocarriers to obtain simultaneous stealth surfaces in circulation and enhanced uptake in tumors. The current strategies and ongoing developments, including programmed tumor-targeting strategies and some specific zwitterionic surfaces, will be discussed in detail.