Exosome-based hybrid nanostructures for enhanced tumor targeting and hyperthermia therapy.

Recently, natural exosomes have attracted attention as an ideal drug carrier to overcome the limitations of existing drug delivery systems which are toxicity induction and low cancer-targeting performance. In this study, we propose an exosome-based hybrid nanostructure (EHN) with improved targeting ability and therapeutic efficacy against colorectal cancer by using exosomes isolated from the tumor cell line as a drug carrier. The proposed EHN can have high biocompatibility by using exosomes, a biologically derived material, and show improved targeting performance by adding a tumor-targeting ligand (folic acid). In addition, the proposed EHN is capable of chemotherapy because doxorubicin, an anticancer drug, is encapsulated by the exosome with high efficiency, and it can induce hyperthermia therapy because of the magnetic nanoparticles (MNPs) attached to the surface of exosomes. Through in vitro and in vivo experiments using a xenograft tumor mouse model, it was confirmed that the proposed EHN could exhibit increased apoptosis and excellent tumor growth inhibition ability. Therefore, the proposed EHN is expected to overcome the limitations of existing drug delivery systems and be utilized as an effective drug delivery system in cancer treatment.

Magnetically Actuated Drug Delivery Helical Microrobot with Magnetic Nanoparticle Retrieval Ability.

Therapeutic drug delivery microrobots capable of accurate targeting using an electromagnetic actuation (EMA) system are being developed. However, these drug delivery microrobots include a large number of magnetic nanoparticles (MNPs) for accurate EMA targeting, which causes side effects, such as problems with membrane integrity and normal cell apoptosis. Here, a biocompatible and hydrolyzable PEGDA-based drug delivery helical microrobot capable of MNP retrieval is proposed in which doxorubicin (DOX), an anticancer drug, is encapsulated and MNPs are conjugated by a disulfide bond. After being accurately delivered to the lesion of cancer cells through magnetic field manipulation, the fabricated microrobot provides rapid MNP separation and retrieval from the microrobot because of the use of dithiothreitol (DTT), a reducing agent, as an environment similar to the surrounding cancer cells and near-infrared (NIR) as an external stimulus. The characteristics of the fabricated microrobot are analyzed, and fundamental tests for active electromagnetic field manipulation, separation/retrieval of MNPs from the microrobot, and its hydrolysis are discussed. The therapeutic performance of the fabricated microrobot is verified through an in vitro test using tumor cells. Consequently, by use of an integrated system of microscope, eight-coil EMA, and NIR it is shown that the proposed microrobot can be moved to the target site by electromagnetic manipulation. The MNPs conjugated to the microrobot can be separated and retrieved, and the therapeutic effect on tumor cells by the encapsulated drug can be seen.

Active delivery of multi-layer drug-loaded microneedle patches using magnetically driven capsule.

In this paper, we propose the active delivery of multi-layer drug-loaded microneedle (MN) patches using a capsule that can be driven by an external magnetic field. Firstly, the multi-layer drug-loaded MN patches consist of three delivered MN patches which are composed of a drug-loaded MN patch and polydimethylsiloxane layer. The drug-loaded MN patch is made of a 10% gelatin solution and a drug. The multi-layer MN patches are attached to a permanent magnet in a magnetically driven capsule. Under an external magnetic field generated by an electromagnetic actuation system, the capsule with the multi-layer MN patches can reach the target lesions, and each MN patch can be delivered to the target lesions for medical treatment. The active delivery of the multi-layer MN patches using the proposed magnetically driven capsule was confirmed via phantom experiments. Accordingly, the adhesion of the three separated faces of the multi-layer MN patches and the adhesion between the porcine small intestine and the MN patch were measured using a load cell. We demonstrate the feasibility of the active delivery of the multi-layer MN patches to the target lesions on a porcine small intestine. Consequently, we expect that the active delivery of the multi-layer drug-loaded MN patches using the magnetically driven capsule presented in this study can be a useful method for drug delivery to lesions at various locations in the gastrointestinal tract.

Bilayer Hydrogel Sheet-Type Intraocular Microrobot for Drug Delivery and Magnetic Nanoparticles Retrieval.

By virtue of minimum invasiveness and driving ability using a magnetic field, drug delivery with the aid of a microrobot has an inherent potential for targeted treatment for the eye. The use of microrobots, however, has the limitation of leaving magnetic nanoparticles (MNPs) in the eye that can cause side effects. In this study, a bilayer hydrogel microrobot capable of retrieving MNPs after drug delivery is proposed that overcomes the limitations of existing microrobots. The bilayer hydrogel microrobot is composed of an MNPs layer and a therapeutic layer. Upon applying an alternating magnetic field (AMF) at the target point, the therapeutic layer is dissolved to deliver drug particles, and then the MNPs layer can be retrieved using a magnetic field. The targeting and MNPs retrieval tests validate the drug delivery and MNPs retrieval ability of the microrobot. The ex vivo bovine vitreous and in vitro cell tests demonstrate the potential for the vitreous migration of the microrobot and the therapeutic effect against retinoblastoma Y79 cancer cells. This bilayer hydrogel sheet-type intraocular microrobot provides a new drug delivery paradigm that overcomes the limitations of microrobot by maintaining the advantages of conventional microrobots in delivering drugs to the eye and retrieving MNPs after drug delivery.

Organocatalytic asymmetric synthesis of chiral pyrrolizines by cascade conjugate addition-aldol reactions.

As the first N-centered heteroaromatic nucleophile for organocatalytic cascade reactions, pyrroles underwent the enantio- and diastereoselective organocatalytic cascade conjugate addition-aldol reactions of α,ß-unsaturated aldehydes that afford the highly functionalized chiral pyrrolizines bearing three consecutive stereocenters in good yields, high enantioselectivities (90-98% ee), and excellent diastereoselectivities (>20:1 dr in all cases).

New method of predicting dry weight using bioelectrical impedance analysis in haemodialysis patients.

AIM: There were significant differences in the slopes of the ultrafiltration (UF) amount removed during haemodialysis (HD) sessions versus the percentage change in the extracellular fluid/total body water ratio for the right lower extremity (ECF/TBW(right leg)) plot in normohydrated (NH) and overhydrated states. The purpose of this study was to develop and validate a method for predicting dry weight (DW) using these results. METHODS: It was hypothesized that for patients to become NH, the slope of the UF amount versus the percentage changes in ECF/TBW(right leg) plot should be same as that of NH patients and a method for predicting DW was developed. To validate the accuracy of this method, the ECF/TBW(right leg) was measured by eight-point tactile-electrode bioelectrical impedance analysis before and after HD in 17 newly enrolled NH patients. Using the current DW (cDW) of subjects as a reference, we compared the accuracies of pDW1 (our devised method) and pDW2 (the normovolaemia/hypervolaemia slope method). RESULTS: The mean cDW, pDW1 and pDW2 values were 56.8 +/- 7.9, 56.4 +/- 7.7 and 56.3 +/- 8.0 kg, respectively. No significant differences existed between cDW, pDW1 and pDW2. pDW1 had a lower root mean square error than pDW2 (1.12 vs 1.69). On the Bland-Altman plot, differences between pDW1 and cDW were closer to zero than between pDW2 and cDW. CONCLUSION: A new method was developed of predicting the DW using the relationship between the UF amount and the percentage change in the ECF/TBW ratio of the lower extremities after HD. The devised method appears to be as accurate as the normovolaemia/hypervolaemia slope method.

Different pattern of fluid loss from the lower extremities in normohydrated and overhydrated stage 5 chronic-kidney-disease patients after haemodialysis.

AIM: It is unclear whether fluid is lost from each body segment in a similar manner during haemodialysis (HD) in normohydrated (NH) and overhydrated (OH) patients. METHODS: The authors measured changes in regional-body fluid compartments using segmental multifrequency bioelectrical impedance analysis before and after HD in 26 stage 5 chronic-kidney-disease patients. Patients were divided into NH and OH groups. Correlation between ultrafiltration (UF) amount and per cent changes in extracellular fluid (ECF)/total body water (TBW) ratios measured in five body segments were analysed in NH and OH groups. RESULTS: No differences were found between the two groups with respect to per cent decreases in body weight, TBW, or intracellular fluid levels. Correlation coefficients between UF amounts and per cent decreases in TBW, intracellular fluid and ECF were higher in the NH group than in the OH group. UF amounts were found to be correlated with per cent ECF/TBW decreases in all body segments in the NH group but, to be only correlated with per cent decreases in ECF/TBW(Left arm) and ECF/TBW(Trunk) in the OH group. Positive correlations were found between UF amounts and per cent ECF/TBW(Right leg) decreases (r = 0.66, P = 0.01), regardless of age in the NH group only. CONCLUSION: NH and OH patients show different patterns of fluid loss from regional-body fluid compartments. This may be useful for determining patient hydration status.