Transcatheter aortic valve replacement: clinical safety and performance data.

Introduction: Patients with severe aortic stenosis and regurgitation who are inoperable or at high-risk for surgery can be treated with transcatheter aortic valve replacement (TAVR). The aim of this study was to provide a comprehensive overview of the literature of TAVR and reported clinical and performance outcomes. Areas covered: A total of 16 devices, described in 204 articles describing clinical and performance outcomes, were included. The most frequently observed outcome was 30-day mortality, ranging between 0-23%. Other commonly reported clinical outcomes were 30-day stroke, ranging between 0-14.3% and pacemaker implantation, ranging from 0-44.9%. The most common valve performance outcome was aortic valve regurgitation, however, mostly reported at 7 days follow-up. Next to a follow-up period of 30 days, numerous articles reported outcomes at 6 months and 1 year. The numbers of articles describing outcomes with a longer follow-up as well as including intermediate and low-risk patients were limited. Expert commentary: This literature review provided a clear overview of the reported clinical and performance outcomes of TAVR devices. Despite the frequently used VARC-2 definitions, we identified a huge variation across studies. Future studies using standardized definitions of study set-ups and outcomes are essential and might lead to better insights of TAVR.

Preclinical evaluation of thermosensitive poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate)-grafted liposomes for cancer thermochemotherapy.

Thermosensitive liposomes grafted with cholesterol-conjugated poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate) (chol-pHPMAlac) have been developed for heat-induced release of doxorubicin (DOX). These liposomes release DOX completely during mild hyperthermia, but their interaction with blood cells and cancer cells has not been studied. Following intravenous administration, liposomes may interact with plasma proteins and various types of cells (e.g., endothelial cells, platelets, and macrophages), which would reduce their disposition in the tumor stroma. Interaction between liposomes and platelets may further cause platelet activation and thrombosis, which could lead to vascular occlusion and thromboembolic complications. The aim was to investigate DOX release kinetics in the presence of serum, stability, in vitro uptake by and toxicity to cancer cells and somatic cells, and platelet activating potential of the chol-pHPMAlac liposomes. DOX release was determined spectrofluorometrically. Liposome stability was determined in buffer and serum by dynamic light scattering and nanoparticle tracking analysis. Association with/uptake by and toxicity of empty liposomes to AML-12, HepG2 (both hepatocyte-derived cancer cells), RAW 264.7 (macrophages), and HUVEC (endothelial) cells was assayed in vitro. Platelet activation was determined by analysis of P-selectin expression and fibrinogen binding. DOPE:EPC liposomes (diameter = 135 nm) grafted with 5% chol-pHPMAlac (cloud point (CP) = 16 °C; Mn = 8.5 kDa) released less than 10% DOX at 37 °C in 30 min, whereas complete release took place at 47 °C or higher within 10 min. The size of these liposomes remained stable in buffer and serum during 24 h at 37 °C. Fluorescently labeled but DOX-lacking chol-pHPMAlac-liposomes exhibited poor association with/uptake by all cells under investigation, were not cytotoxic, and did not activate platelets in both buffered solution and whole blood. In conclusion, thermosensitive chol-pHPMAlac-grafted liposomes rapidly release DOX during mild hyperthermia. The liposomes are stable in a physiological milieu, are not taken up by cells that are encountered in an in vivo setting, and are non-antagonistic towards platelets. Chol-pHPMAlac-grafted liposomes are therefore good candidates for DOX delivery to tumors and temperature-triggered release in tumor stroma.

Considerations for Safe Innovation: The Case of Graphene.

The terms "Safe innovation" and "Safe(r)-by-design" are currently popular in the field of nanotechnology. These terms are used to describe approaches that advocate the consideration of safety aspects already at an early stage of the innovation process of (nano)materials and nanoenabled products. Here, we investigate the possibilities of considering safety aspects during various stages of the innovation process of graphene, outlining what information is already available for assessing potential hazard, exposure, and risks. In addition, we recommend further steps to be taken by various stakeholders to promote the safe production and safe use of graphene.

Nanomedicines for advanced cancer treatments: Transitioning towards responsive systems.

The development of nanomedicines for the treatment of cancer focuses on the local targeted delivery of chemotherapeutic drugs to enhance drug efficacy and reduce adverse effects. The nanomedicines which are currently approved for clinical use are mainly successful in terms of improved bioavailability and tolerability but do not necessarily increase drug performance. Therefore, there is a need for improved drug carrier systems which are able to deliver high doses of anti-cancer drugs to the tumor. Stimuli responsive carriers are promising candidates since drug release can be triggered locally in the tumor via internal (i.e. pH, redox potential, metabolite or enzyme concentration) or external (i.e. heat, ultrasound, light, magnetic field) stimuli. This review summarizes the recent progress in the transition towards stimuli responsive nanomedicines (i.e. liposomes, polymeric micelles, nanogels and mesoporous silica nanoparticles) and other therapy modalities that are currently developed in the fight against cancer like the application of ultrasound, tumor normalization and phototherapy. Furthermore, the potential role of image guided drug delivery in the development of new nanomedicines and its clinical application is discussed.

MRI monitoring of nanocarrier accumulation and release using Gadolinium-SPIO co-labelled thermosensitive liposomes.

Encapsulation of anticancer drugs in triggerable nanocarriers can beneficially modify pharmacokinetics and biodistribution of chemotherapeutic drugs, and consequently increase tumor drug concentration and efficacy, while reducing side effects. Thermosensitive liposomes release their contents triggered by hyperthermia, which can be, for example, precisely delivered using an MR Imaging-guided focused ultrasound procedure. In such a scenario, it is attractive to demonstrate the accumulation of liposomes before applying hyperthermia, as well as to document the release of liposome content using MRI. To address this need, thermosensitive liposomes were developed and characterized, which were doubly loaded by iron oxide nanoparticles and Gd-chelate, as opposed to loading with a single contrast agent. When intact, the transverse relaxivity of the liposomes is high allowing detection of carriers in tissue. After heating the longitudinal relaxivity steeply increases indicating release of the small molecular contents. By choosing the appropriate MR sequences, availability and release can be evaluated without interference of one contrast agent with the other. Copyright © 2016 John Wiley & Sons, Ltd.

Alginate Microspheres Containing Temperature Sensitive Liposomes (TSL) for MR-Guided Embolization and Triggered Release of Doxorubicin.

OBJECTIVE: The objective of this study was to develop and characterize alginate microspheres suitable for embolization with on-demand triggered doxorubicin (DOX) release and whereby the microspheres as well as the drug releasing process can be visualized in vivo using MRI. METHODS AND FINDINGS: For this purpose, barium crosslinked alginate microspheres were loaded with temperature sensitive liposomes (TSL/TSL-Ba-ms), which release their payload upon mild hyperthermia. These TSL contained DOX and [Gd(HPDO3A)(H2O)], a T1 MRI contrast agent, for real time visualization of the release. Empty alginate microspheres crosslinked with holmium ions (T2* MRI contrast agent, Ho-ms) were mixed with TSL-Ba-ms to allow microsphere visualization. TSL-Ba-ms and Ho-ms were prepared with a homemade spray device and sized by sieving. Encapsulation of TSL in barium crosslinked microspheres changed the triggered release properties only slightly: 95% of the loaded DOX was released from free TSL vs. 86% release for TSL-Ba-ms within 30 seconds in 50% FBS at 42°C. TSL-Ba-ms (76 ± 41 µm) and Ho-ms (64 ± 29 µm) had a comparable size, which most likely will result in a similar in vivo tissue distribution after an i.v. co-injection and therefore Ho-ms can be used as tracer for the TSL-Ba-ms. MR imaging of a TSL-Ba-ms and Ho-ms mixture (ratio 95:5) before and after hyperthermia allowed in vitro and in vivo visualization of microsphere deposition (T2*-weighted images) as well as temperature-triggered release (T1-weighted images). The [Gd(HPDO3A)(H2O)] release and clusters of microspheres containing holmium ions were visualized in a VX2 tumor model in a rabbit using MRI. CONCLUSIONS: In conclusion, these TSL-Ba-ms and Ho-ms are promising systems for real-time, MR-guided embolization and triggered release of drugs in vivo.

Triggered release of doxorubicin from temperature-sensitive poly(N-(2-hydroxypropyl)-methacrylamide mono/dilactate) grafted liposomes.

The objective of this study was to design temperature-sensitive liposomes with tunable release characteristics that release their content at an elevated temperature generated by high intensity focused ultrasound (HIFU) exposure. To this end, thermosensitive polymers of N-(2-hydroxypropyl)methacrylamide mono/dilactate of different molecular weights and composition with a cholesterol anchor (chol-pHPMAlac) were synthesized and grafted onto liposomes loaded with doxorubicin (DOX). The liposomes were incubated at different temperatures and their release kinetics were studied. A good correlation between the release-onset temperature of the liposomes and the cloud point (CP) of chol-pHPMAlac was found. However, release took place at significantly higher temperatures than the CP of chol-pHPMAlac, likely at the CP, the dehydration and thus hydrophobicity is insufficient to penetrate and permeabilize the liposomal membrane. Liposomes grafted with chol-pHPMAlac with a CP of 11.5 °C released 89% DOX within 5 min at 42 °C while for the liposomes grafted with a polymer with CP of 25.0 °C, a temperature of 52 °C was needed to obtain the same extent of DOX release. At a fixed copolymer composition, an increase in molecular weight from 6.5 to 14.5 kDa decreased the temperature at which DOX was released with a release-onset temperature from 52 to 42 °C. Liposomes grafted with 5% chol-pHPMAlac exhibited a rapid release to a temperature increase, while at a grafting density of 2 and 10%, the liposomes were less sensitive to an increase in temperature. Sequential release of DOX was obtained by mixing liposomes grafted with chol-pHPMAlac having different CPs. Chol-pHPMAlac grafted liposomes released DOX nearly quantitatively after pulsed wave HIFU. In conclusion, the release of DOX from liposomes grafted with thermosensitive polymers of N-(2-hydroxypropyl)methacrylamide mono/dilactate can be tuned to the characteristics and the grafting density of chol-pHPMAlac, making these liposomes attractive for local drug delivery using hyperthermia.

Gut derived lactic acid bacteria induce strain specific CD4(+) T cell responses in human PBMC.

BACKGROUND & AIMS: Probiotic bacteria are used as food supplement in many different disease settings. The immune modulating capacity of different strains is not always properly tested which might result in a suboptimal choice of strains for clinical use. METHODS: The CD4 T cell responses to 19 different gut derived lactic acid bacteria were tested with different methods to show their diversity in immune modulation and to make a well-founded choice on which strains to use in future clinical trials. After co-culture of PBMC with bacteria, the induction of CD4(+) T cell subsets (regulatory T cells, T helper type (TH)1, TH2 and TH17) was analysed by rtPCR of transcription factor mRNA, intracellular FACS staining of transcription factors and cytokine production. RESULTS: Bacterial strains all have diverse, unique immune modulatory properties. Strains can induce Treg, TH1, TH2 and TH17 cells which can be shown at different levels of T cell activation, and is consistent for most strains tested. For TH1, TH17 and Treg, a positive correlation between the different methods was found. For TH2 cells the correlation was less consistent. CONCLUSIONS: Probiotic bacteria have very different immune modulating capacities. Analysis of transcription factor mRNA is a suitable method for in vitro characterization of strains prior to clinical application.