A drug co-delivery platform made of magnesium-based micromotors enhances combination therapy for hepatoma carcinoma cells.

Combination therapy is an emerging strategy to overcome multidrug resistance (MDR) in hepatocellular carcinoma (HCC) chemotherapy treatment. However, the passive diffusion in traditional delivery systems greatly retards the approach and penetration of drugs into hepatocellular carcinoma cells and thus hinders the efficacy of combination therapy. Micro/nanomotors with autonomous locomotion in a tiny scale provide the possibility of tackling this issue. Herein, an active drug delivery micromotor platform delicately designed to load drugs with different physicochemical properties and enhance the drug permeability of cells is demonstrated for HCC chemotherapy treatment. The biocompatible micromotor platform Mg/PLGA/CHI comprised magnesium (Mg) coated with two polymer layers made of poly(lactic-co-glycolic acid) (PLGA) and chitosan (CHI), where the hydrophobic and hydrophilic drugs doxorubicin (Dox) and Curcumin (Cur) were loaded, respectively. The autonomous motion of the micromotors with velocity up to 45 µm s-1 greatly enhanced the diffusion of chemotherapeutic drugs and led to higher extracellular and intracellular drug distribution. Moreover, hydrogen produced during the motion eliminated the excess reactive oxygen species (ROS) in the human hepatocellular carcinoma (HepG2) cells. Compared with inert groups, the absorption of Dox and Cur from the active micromotors was about 2.9 and 1.5 times higher in human hepatocellular carcinoma (HepG2) cells. In addition, the anti-tumor activity also obviously improved at the micromotor concentration of 1 mg mL-1 (cell proliferation was reduced by almost 30%). Overall, this work proposes an approach based on loading different chemotherapy agents on an active delivery system to enhance drug permeability and overcome MDR and provides a potentially effective therapeutic strategy for the treatment of HCC.

Leveraging disulfiram to treat cancer: Mechanisms of action, delivery strategies, and treatment regimens.

Disulfiram (DSF) has been used as an alcoholism drug for 70 years. Recently, it has attracted increasing attention owing to the distinguished anticancer activity, which can be further potentiated by the supplementation of Cu2+. Although encouraging anticancer results are obtained in lab, the clinical outcomes of oral DSF are not satisfactory, which urges an in-depth understanding of the underlying mechanisms, bottlenecks, and proposal of potential methods to address the dilemma. In this review, a critical summarization of various molecular biological anticancer mechanisms of DSF/Cu2+ is provided and the predicament of orally delivering DSF in clinical oncotherapy is explained by the metabolic barriers. We highlight the recent advances in the DSF/Cu2+ delivery strategies and the emerging treatment regimens for cancer treatment. Last but not the least, we summarize the clinical trials regarding DSF and make a prospect of DSF/Cu-based cancer therapy.

A Bacteria-Inspired Morphology Genetic Biomedical Material: Self-Propelled Artificial Microbots for Metastatic Triple Negative Breast Cancer Treatment.

Morphology genetic biomedical materials (MGBMs), referring to fabricating materials by learning from the genetic morphologies and strategies of natural species, hold great potential for biomedical applications. Inspired by the cargo-carrying-bacterial therapy (microbots) for cancer treatment, a MGBM (artificial microbots, AMBs) was constructed. Rather than the inherent bacterial properties (cancerous chemotaxis, tumor invasion, cytotoxicity), AMBs also possessed ingenious nitric oxide (NO) generation strategy. Mimicking the bacterial construction, the hyaluronic acid (HA) polysaccharide was induced as a coating capsule of AMBs to achieve long circulation in blood and specific tissue preference (tumor tropism). Covered under the capsule-like polysaccharide was the combinatorial agent, the self-assembly constructed by the amphiphilic dendrons with abundant l-arginine residues peripherally (as endogenous NO donor) and hydrophobic chemotherapeutic drugs at the core stacking on the surface of SWNTs (the photothermal agent) for a robust chemo-photothermal therapy (chemo-PTT) and the elicited immune therapy. Subsequently, the classic inducible nitric oxide synthase (iNOS) pathway aroused by immune response was revolutionarily utilized to oxidize the l-arginine substrates for NO production, the process for which could also be promoted by the high reactive oxygen species level generated by chemo-PTT. The NO generated by AMBs was intended to regulate vasodilation and cause a dramatic invasion (as the microbots) to disperse the therapeutic agents throughout the solid tumor for a much more enhanced curative effect, which we defined as "self-propulsion". The self-propelled AMBs exhibiting impressive primary tumor ablation, as well as the distant metastasis regression to conquer the metastatic triple negative breast cancer, provided pioneering potential therapeutic opportunities, and enlightened broad prospects in biomedical application.

Bioinspired Artificial Tobacco Mosaic Virus with Combined Oncolytic Properties to Completely Destroy Multidrug-Resistant Cancer.

Although biomimetic virus-like strategies have been widely used in antitumor applications, construction of uniquely shaped virus-like agents and optimization of their specific morphological features to achieve diverse antitumor functions are worthwhile pursuits. Here, a novel strategy to construct an artificial tobacco mosaic virus (ATMV) that closely mimics the structure of the rod-like tobacco mosaic virus (TMV) is developed. The supramolecular array is self-assembled from small, repeated subunits of tailor-made capsid-mimicking dendrons onto RGD-modified single-walled carbon nanotube to construct the ATMVs with high structural stability. The ATMVs are tactfully designed with shielding, targeting, and arming approaches, including shielding the viruses against premature elimination, selectively targeting tumor tissue, and arming the viruses with oncolytic abilities. The elongated particles are concealed in blood until they arrived at a tumor site, then they induce robust composite oncolytic processes including cytomembrane penetration, endoplasmic reticulum disruption to cause Ca2+ release, chemotherapeutic delivery, and photothermal therapy. Excitingly, the ATMVs not only lyse primary infected cells, but permeate adjacent cells for secondary infection, spreading cell-to-cell and continuing to induce lysis even deep in solid tumors. This work inspires a uniquely shaped virus-like agent with tactically optimized oncolytic functions that completely defeated large drug-resistant colon tumor (LoVo/Adr, ≈500 mm3 ).

Abnormal dynamic functional connectivity of amygdalar subregions in untreated patients with first-episode major depressive disorder.

BACKGROUND: Accumulating evidence supports the concept of the amygdala as a complex of structurally and functionally heterogeneous nuclei rather than as a single homogeneous structure. However, changes in resting-state functional connectivity in amygdalar subregions have not been investigated in major depressive disorder (MDD). Here, we explored whether amygdalar subregions - including the laterobasal, centromedial (CM) and superficial (SF) areas - exhibited distinct disruption patterns for different dynamic functional connectivity (dFC) properties, and whether these different properties were correlated with clinical information in patients with MDD. METHODS: Thirty untreated patients with first-episode MDD and 62 matched controls were included. We assessed between-group differences in the mean strength of dFC in each amygdalar subregion in the whole brain using general linear model analysis. RESULTS: The patients with MDD showed decreased strength in positive dFC between the left CM/SF and brainstem and between the left SF and left thalamus; they showed decreased strength in negative dFC between the left CM and right superior frontal gyrus (p < 0.05, family-wise error-corrected). We found significant positive correlations between age at onset and the mean positive strength of dFC in the left CM/brainstem in patients with MDD. LIMITATIONS: The definitions of amygdalar subregions were based on a cytoarchitectonic delineation, and the temporal resolution of the fMRI was slow (repetition time = 2 s). CONCLUSION: These findings confirm the distinct dynamic functional pathway of amygdalar subregions in MDD and suggest that the limbic-cortical-striato-pallido-thalamic circuitry plays a crucial role in the early stages of MDD.

Localized drug release and effective chemotherapy by hyperthermia-governed bubble-generating hybrid nanocapsule system.

AIM: To build up a remote triggering drug delivery system with hyperthermia-responsive ammonium bicarbonate salt and investigate its effects on tumor therapy. MATERIALS & METHODS: This hybrid nanocapsule system was prepared by a different strategy, doxorubicin (DOX) was encapsulated in the heparin shell first and then ammonium bicarbonate was diffused into the nanocapsules to generate DOX-bicarbonate salt, its characterizations and effects on tumor therapy were investigated. RESULTS: Upon exposure to mild external thermal treatment (42°C), DOX-bicarbonate salt began to decompose with the recovery of DOX fluorescence, carbon dioxide generation and rapid DOX release out of the nanocapsules, exhibiting great abilities to accumulate at tumor site rapidly and inhibit tumor cell growth. CONCLUSION: These hybrid nanocapsules demonstrate great potential in clinical applications triggering by external thermal treatment.

Viral mimicking ternary polyplexes: a reduction-controlled hierarchical unpacking vector for gene delivery.

Reduction-controlled hierarchical unpacking is proposed for the development of virus-mimicking gene carriers. Disulfide-bond-modified hyaluronic acid (HA) is deposited onto the surface of diselenide-conjugated oligoethylenimine/DNA polyplexes to form DNA/OEI-SeSex/HA-SS-COOH (DOS) polyplexes. The cleavage of the disulfide and diselenide bonds is triggered by the gradient GSH level at the tumor site and inside the cells. The transfection efficiency of DOS show significant enhancement over DNA/poly(ethylene imine) (DP) in vitro and in vivo.

"Green" functionalization of magnetic nanoparticles via tea polyphenol for magnetic resonance/fluorescent dual-imaging.

Tea polyphenol serves as an environmentally friendly ligand-exchange molecule to synthesize multifunctional metal-doped superparamagnetic iron oxide nanoparticles via a catechol-metal coordination interaction. The resultant particles not only exhibit excellent hydrophilicity and protein adsorption resistance, but also are applicable as magnetic resonance/fluorescent dual-imaging probes due to their high T2 relaxivity, autofluorescence and large cellular uptake.

Novel nanoparticles generated by polymeric amphiphiles with pi-pi conjugated small molecules for anti-tumor drug delivery.

In recent years, the self-assembly polymeric nanoparticles are widely used for anti-tumor drug delivery. Multiple interactions such as hydrogen bonding, host-guest interaction, hydrophobic interaction and electrostatic interaction have been utilized to generate the nanoparticles. Herein, a new polymeric amphiphile with methoxy poly(ethylene glycol) (mPEG) as hydrophilic block and pi-pi conjugated small molecule N-(9-Fluorenylmethoxycarbonyl)-L-phenylalanines (Fmoc-Phe-OH) instead of hydrophobic polymer chain as lipophilic segment was synthesized. Anti-tumor drug doxorubicin (DOX) was trapped in the self-assembly nanoparticles via the dual hydrophobic and pi-pi stacking interactions. The synthesis and morphology of the self-assembly nanoparticles were studied. The interactions between drug and carrier, release profile, cellular uptake and in vitro anti-tumor efficiency of the drug loaded nanoparticles were investigated in details. The results showed that the amphiphiles self-assembled into spindle nanoparticles with the size around 200 nanometers. The pi-pi stacking interaction between DOX and Fmoc-Phe-OH achieved great performance for the efficient drug encapsulation. The DOX could be sustaingly released for 50 hours. The drug loaded nanoparticles were internalized in HepG2 cancer cells efficiently and exhibited good anti-tumor activity in vitro. The nanoparticles generated by mPEG-Phe-Fmoc amphiphiles provided a new strategy to fabricate polymeric nanoparticles for anti-tumor drug delivery.

Development of a reduction-sensitive diselenide-conjugated oligoethylenimine nanoparticulate system as a gene carrier.

BACKGROUND: The reduction-sensitive cationic polymer is a promising nonviral carrier for gene delivery. Until now, disulfide bonds have been the only golden standard for its design. The aim of this research was to develop a novel reduction-responsive cationic polymer as a gene carrier. METHODS: Polycationic carriers were synthesized by addition of branched oligoethylenimine 800 Da (OEI(800)) via an active ester containing diselenide bonds. Disulfide bonds cross-linked with OEI(800)-SS(x) and monoselenide bonds linked with OEI(800)-Se(x) were synthesized and compared. Their molecular weights and degradation properties were determined using gel permeation chromatography. Changes in particle size, morphology, and DNA binding were investigated by dynamic light scattering, transmission electron microscopy, and electrophoresis assay in a reduction environment. Cytotoxicity and transfection in vitro were evaluated in a murine melanoma cell line (B16F10) and a human cervical epithelial carcinoma cell line (HeLa), while intracellular degradation and dissociation with DNA were studied by confocal laser scanning microscopy with FITC-labeled OEI(800) derivatives and Cy5-labeled DNA. RESULTS: Diselenide-conjugated OEI(800) (OEI(800)-SeSe(x)) polymer carriers of high molecular weight were successfully synthesized. After compacting with DNA, the OEI(800)-SeSe(x) polymers formed nanoparticles with an average size of 140 nm at an adequate C/P ratio. OEI(800)-SeSe(x) showed reduction-responsive degradation properties similar to those of the OEI(800)-SS(x) via gel permeation chromatography, dynamic light scattering, and transmission electron microscopy. OEI(800)-SeSe(x) showed much lower cytotoxicity than PEI(25k), and significantly higher transfection efficiency than OEI(800) in both B16F10 and HeLa cells. Transfection of luciferase in the OEI(800)-SeSe(x) group was comparable with that of standard PEI(25k) and traditional reduction-sensitive polymer OEI(800)-SS(x) groups. Furthermore, intracellular degradation of OEI(800)-SeSe(x) and dissociation with DNA were also confirmed by confocal laser scanning microscopy. CONCLUSION: The OEI(800)-SeSe(x) obtained was able to bind plasmid DNA efficiently to yield nanosized particles and had reduction sensitivity which is as efficient as that for OEI(800)-SS(x). In vitro experiments confirmed its low cytotoxicity and high transfection ability. Diselenide bonds can be used as effective and novel reduction-sensitive linkages for gene delivery.

A novel method to prepare water-dispersible magnetic nanoparticles and their biomedical applications: magnetic capture probe and specific cellular uptake.

A novel and simple method to form water-dispersed magnetic nanoparticles was successfully developed through glucosaminic acid-surface modification of iron oxide nanoparticles. The resultant glucosaminic acid-modified magnetic nanoparticles (GA-MNPs) had not only good uniformity in spherical shape with diameter of about 10-13 nm, but also possessed excellent water-dispersity and stability. In cell culture experiments, the internalization of GA-MNPs into different kinds of cells was observed over a 5-day period. The results indicated that the internalization of GA-MNPs into mouse macrophage cells and mouse embryonic fibroblast cells was not observed after 40 h of culturing. However, the GA-MNPs were internalized quickly into cancer cells after just 24 h of culturing. TEM images of the GA-MNPs uptake in ECA-109 cells were used to study the internalization mechanisms of GA-MNPs and their distribution in ECA-109 cells. Additionally, a water-dispersed magnetic capture probe was prepared by immobilization of oligonucleotides onto GA-MNPs, and the probe was used for detection and separation of their complementary oligonucleotides sequence.

Preparation and evaluation of proliposomes containing clotrimazole.

Clotrimazole (CT)-containing proliposomes were prepared by penetrating an ethanol solution of CT and Egg phosphatidylcholine (PC) into microporous sorbitol particles, followed by vacuum evaporation of the solvent. As a result, CT proliposomes with free-flowing flowability were obtained. On contact with water, the proliposomes were rapidly converted into a liposomal dispersion, in which a certain amount of CT was entrapped by the liposomes. The result in scanning electronic micrograph confirmed the formation of liposomes structures from proliposomes, and the particles revealed round or ellipse. The ratio of drug to total lipid, ratio of PC to cholesterol and ratio of lipid to sorbitol affected the entrapment efficiency (EE%). The EE% of optimized formulation (CT 10 mg, 0.1 g total lipid, PC/CH ratio is 60 : 40 and 1 g sorbitol) in this investigation was 96.2+/-1.5%. The proliposomes system can provide sustaining release in simulated vaginal fluid at 37+/-1 degrees C for 24 h. In-vivo performance of blank proliposomes, a physical mixture of sorbitol and drug, clotrimazole proliposomes and commercial ointment formulation were evaluated using antifungal activity test. At 7 d post-dose, the c.f.u. of C. albicans decreased in proliposomes-treated groups than ointment and the physical mixture (t-Student, p<0.05). The results indicated that CT-containing vaginal proliposomes prolonged drug release and may increase amount of drug retention into the mucosa to result in more antifungal efficacy. In addition, CT-proliposomes did not affect the morphology of vaginal tissues. Therefore, the dosage form might be further developed for safe, convenient, and effective treatment of vaginal candidasis with reduced dosing interval.