Gradient Redox-Responsive and Two-Stage Rocket-Mimetic Drug Delivery System for Improved Tumor Accumulation and Safe Chemotherapy.

Recent drug delivery nanosystems for cancer treatment still suffer from the poor tumor accumulation and low therapeutic efficacy due to the complex in vivo biological barriers. To resolve these problems, in this work, a novel gradient redox-responsive and two-stage rocket-mimetic drug nanocarrier is designed and constructed for improved tumor accumulation and safe chemotherapy. The nanocarrier is constructed on the basis of the disulfide-doped organosilica-micellar hybrid nanoparticles and the following dual-functional modification with disulfide-bonded polyethylene glycol (PEG) and amido-bonded polyethylenimine (PEI). First, prolonged circulation duration in the bloodstream is guaranteed due to the shielding of the outer PEG chains. Once the nanocarrier accumulates at the tumoral extracellular microenvironment with low glutathione (GSH) concentrations, the first-stage redox-responsive behavior with the separation of PEG and the exposure of PEI is triggered, leading to the improved tumor accumulation and cellular internalization. Furthermore, with their endocytosis by tumor cells, a high concentration of GSH induces the second-stage redox-responsiveness with the degradation of silsesquioxane framework and the release of the encapsulated drugs. As a result, the rocket-mimetic drug carrier displays longer circulation duration in the bloodstream, higher tumor accumulation capability, and improved antitumor efficacy (which is 2.5 times higher than that with inseparable PEG). It is envisioned that the rocket-mimetic strategy can provide new solutions for improving tumor accumulation and safety of nanocarriers in further cancer chemotherapy.

Synthesis of a Pillar[5]arene-Based Polyrotaxane for Enhancing the Drug Loading Capacity of PCL-Based Supramolecular Amphiphile as an Excellent Drug Delivery Platform.

A pillar[5]arene-based nonionic polyrotaxane (PR) with star-poly(ε-caprolactone) ( S-PCL) as the axle, pillar[5]arene (DEP5) as the wheel and adamantane as the end-capped group is designed and synthesized. The resulting PR is subsequently assembled with ß-cyclodextrin end-capped pH-stimulated poly(acrylic acid) (CD-PAA) via a host-guest interaction to form the supramolecular pseudoblock polymer PR-PAA. This supramolecular pseudoblock polymer could self-assemble in aqueous solution to produce PR-PAA-based supramolecular vesicular nanoparticles (PR-SVNPs), which present significantly enhanced drug loading capacity (DLC, 45.6%) of DOX, much higher than those of superamphiphiles (PCL-PAA, 17.1%). Such a high DLC of PR-SVNPs can be most probably attributed to the greatly decreased crystallinity of PCL in PR. Moreover, the loaded drugs could be selectively released in an acidic microenvironment-responsive manner. Compared to free DOX, the DOX-loaded PR-SVNPs (DOX@PR-SVNPs) shows much enhanced cellular uptake and cytotoxicity against the SMMC-7721. More importantly, thanks to the enhanced permeability and retention (EPR) effect, DOX@PR-SVNPs exhibits appealing features such as extremely low toxicity, highly efficient intratumoral accumulation and substantial antitumor efficacy in vivo.

Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy.

Levetiracetam (LEV) has antiepileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients was unknown. We report pharmacokinetics of TBI subjects≥6years with high PTE risk treated with LEV 55mg/kg/day orally, nasogastrically or intravenously for 30days starting ≤8h after injury in a phase II safety and pharmacokinetic study. Forty-one subjects (26 adults and 15 children) were randomized to PK studies on treatment days 3 and 30. Thirty-six out of forty-one randomized subjects underwent PK study on treatment day 3, and 24/41 subjects underwent PK study on day 30. On day 3, mean T(max) was 2.2h, C(max) was 60.2µg/ml and AUC was 403.7µg/h/ml. T(max) was longer in the elderly than in children and non-elderly adults (5.96h vs. 1.5h and 1.8h; p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4µg/h/ml vs. 461.4µg/h/ml and 450.2µg/h/ml; p=0.08). C(max) trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4µg/ml vs. 59µg/ml and 48.2µg/ml; p=0.07). AUC of n.g. and i.v. administrations was 79% and 88% of AUC of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies.

A confined crosslinking strategy towards an intelligent organosilica-micellar hybrid drug delivery system.

An ideal drug delivery system must have a high level of stability to ensure effective circulation and passive aggregation, good retention performance, and dynamic delivery and treatment monitoring. Thus, the development of a smart drug delivery carrier with both precise drug release and real-time detection remains a challenge. Herein, we propose a confined crosslink protocol to prepare an intelligent hybrid delivery system for auto-fluorescent monitoring, protonation-induced retention and precise drug release. The construction of this system involves the hydrolysis and condensation of (3-aminopropyl)triethoxysilane (APTES) silanes inside the Pluronic polymer micelles and thereafter a confined Schiff base crosslinking between glutaraldehyde (GA) and residual silane amino groups. The size of the intelligent docetaxel (DTX)-loaded nanosystem changes from ∼25 nm in blood circulation or normal tissues (pH ∼ 7.4) to ∼250 nm in slightly acidic environments (pH ∼ 6.5-7.0) owing to intra-molecular hydrogen bond-induced aggregation and imine cleavage-induced disintegration in the endosome (pH ∼ 5.0-6.2) along with auto-fluorescent monitoring contributing to the high-efficiency chemotherapy. This work provides a new method to construct smart, acid-responsive and fluorescent-guided drug-delivery carrier systems for efficient and safe tumor chemotherapy.

Wafer-Scale Uniform Carbon Nanotube Transistors for Ultrasensitive and Label-Free Detection of Disease Biomarkers.

Carbon nanotube (CNT) field-effect transistor (FET)-based biosensors have shown great potential for ultrasensitive biomarker detection, but challenges remain, which include unsatisfactory sensitivity, difficulty in stable functionalization, incompatibility with scalable fabrication, and nonuniform performance. Here, we describe ultrasensitive, label-free, and stable FET biosensors built on polymer-sorted high-purity semiconducting CNT films with wafer-scale fabrication and high uniformity. With a floating gate (FG) structure using an ultrathin Y2O3 high-κ dielectric layer, the CNT FET biosensors show amplified response and improved sensitivity compared with those sensors without Y2O3, which is attributed to the chemical gate-coupling effect dominating the sensor response. The CNT FG-FETs are modified to selectively detect specific disease biomarkers, namely, DNA sequences and microvesicles, with theoretical record detection limits as low as 60 aM and 6 particles/mL, respectively. Furthermore, the biosensors exhibit highly uniform performance over the 4 in. wafer as well as superior bias stress stability. The FG CNT FET biosensors could be extended as a universal biosensor platform for the ultrasensitive detection of multiple biological molecules and applied in highly integrated and multiplexed all CNT-FET-based sensor architectures.

Biodegradable organosilica magnetic micelles for magnetically targeted MRI and GSH-triggered tumor chemotherapy.

Recently, block copolymer micelles have attracted widespread attention due to their controlled biodegradability and excellent loading capability. Unfortunately, the poor in vivo stability and low delivery efficiency of drug-loaded micelles greatly hampered their biomedical applications. Herein, we develop a new kind of biodegradable magnetite/doxorubicin (Fe3O4/DOX) co-loaded PEGylated organosilica micelles (designated as FDPOMs) with both high circulating stability and smart GSH-triggered biodegradability for magnetically targeted magnetic resonance imaging (MRI) and tumor chemotherapy. The FDPOMs are prepared by the self-assembly of biodegradable polycaprolactone-block-poly(glutamic acid) (PCL-b-PGA), a chemotherapeutic DOX drug and Fe3O4 nanoparticles in an oil/water system, subsequent organosilica cross-linking with 3-mercaptopropyltrimethoxysilane (MPTMS) molecules and surface PEGylation. The resultant FDPOMs exhibit excellent dispersity and stability in biological media, remarkable T2-weighted MR imaging capability, unique GSH-responsive release behavior and selective toxicity to tumor cells. The in vivo experiments show that the FDPOMs not only have improved MR tumor imaging capability, but also exhibit high anti-tumor efficacy due to the strong magnetic targeting ability under an external magnetic field. Consequently, the FDPOMs are promising candidates for magnetically targeted MR imaging and imaging-guided tumor chemotherapy.

An insight into the influence of hydrogen bond acceptors on cellulose/1-allyl-3-methyl imidazolium chloride solution.

Although ionic liquids have been well established as effective solvents for the dissolution and processing of natural cellulose fibers, the detailed dissolution mechanism at the molecular level still remains unclear. Herein, the turbidimetric measurement showed that the solubility of cellulose in 1-allyl-3-methyl imidazolium chloride (AmimCl) decreased with increasing temperature. The temperature dependence of the OH stretching vibration band of cellulose in AmimCl was investigated by infrared spectroscopy. The interaction between AmimCl and different hydrogen bond acceptors were investigated by turbidimetry and NMR spectroscopy, which indicated that the excellent compatibility of the hydrogen bond acceptors with AmimCl provides more interaction sites for the hydroxyl groups of the cellulose. In addition, ionic liquids with a similar anionic structure of hydrogen bond acceptors have been synthesized. This study provides a green and safe guide for the preparation of ionic liquids with excellent solubility of cellulose.