Pharmaceutical development of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum anticancer agent AP 5280

AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water. However, as aqueous solutions of AP 5280 proved to be labile upon sterilization by moist heat, it was decided to develop a lyophilized dosage form. Initially, glass vials were used as primary packaging, but this led to a high breakage rate, which could be completely prevented by the use of CZ® resin vials. Stability studies to date show that the lyophilized product in glass vials is stable for at least 12 months when stored at 2-8°C in the dark and the lyophilized product in CZ resin vials is stable for at least 6 months under these conditions. Photostability testing revealed photolability of AP 5280 drug substance and lyophilized product in both types of primary container, necessitating storage in the dark. The first clinical experiences indicate that the proposed formulation is fully applicable for use in the clinical setting.     

Corrections for inhomogeneities in biological tissue caused by blood vessels

In tissue optics, the assumption that blood is homogeneously distributed in tissue can give rise to miscalculations because blood is found only in blood vessels. In our paper randomly oriented blood vessels are treated as particles for which we obtained apparent absorption and scattering coefficients by means of the Monte Carlo method. Apart from this correction for the contribution of blood properties in tissue, a correction for the contribution of the surrounding tissue proved to be needed as well. The results found with our model were compared with available results from the literature.     

2-(Dimethylamino)ethyl methacrylate based (co)polymers as gene transfer agents

Poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) is a water-soluble cationic polymer, which is able to bind to DNA by electrostatic interactions. At a polymer/plasmid ratio above 2 (w/w) positively charged complexes were formed with a size around 0.2 microm. The transfection efficiency of polymer/plasmid complexes was evaluated in cell culture (COS-7 and OVCAR-3 cells) using a pCMV-lacZ plasmid, encoding for beta-galactosidase, as a reporter gene. The optimal transfection efficiency was found at a PDMAEMA/plasmid ratio of 3-5 (w/w). Under these conditions 3-6% of the cells were actually transfected. Like other cationic polymers, PDMAEMA is slightly cytotoxic. This activity was partially masked by complexing the polymer with DNA. A pronounced effect of the molecular weight of the polymer on the transfection efficiency was observed. An increasing molecular weight resulted in an increasing number of transfected cells. Dynamic light scattering experiments showed that high molecular weight polymers (Mw>300 kDa) were able to condense DNA effectively (particle size 0.15-0.20 microm). In contrast, when plasmid was incubated with low molecular weight PDMAEMA, large complexes were formed (size 0.5-1.0 microm). Copolymers of DMAEMA with methyl methacrylate (MMA), ethoxytriethylene glycol methacrylate (triEGMA) or N-vinyl-pyrrolidone (NVP) also acted as transfection agents. A copolymer with 20 mol % of MMA showed a reduced transfection efficiency and a substantial increased cytotoxicity compared with a homopolymer of the same molecular weight. A copolymer with triEGMA (48 mol %) showed both a reduced transfection efficiency and a reduced cytotoxicity, whereas a copolymer with NVP (54 mol %) showed an increased transfection efficiency and a decreased cytotoxicity as compared to a DMAEMA homopolymer.     

Enhancing Molecular n‐Type Doping of Donor–Acceptor Copolymers by Tailoring Side Chains

In this contribution, for the first time, the molecular n‐doping of a donor–acceptor (D–A) copolymer achieving 200‐fold enhancement of electrical conductivity by rationally tailoring the side chains without changing its D–A backbone is successfully improved. Instead of the traditional alkyl side chains for poly{[N,N′‐bis(2‐octyldodecyl)‐naphthalene‐1,4,5,8‐bis(dicarboximide)‐2,6‐diyl](NDI)‐alt‐5,5′‐(2,2′‐bithiophene)} (N2200), polar triethylene glycol type side chains is utilized and a high electrical conductivity of 0.17 S cm^?1 after doping with (4‐(1,3‐dimethyl‐2,3‐dihydro‐1H‐benzoimidazol‐2‐yl)phenyl)dimethylamine is achieved, which is the highest reported value for n‐type D–A copolymers. Coarse‐grained molecular dynamics simulations indicate that the polar side chains can significantly reduce the clustering of dopant molecules and favor the dispersion of the dopant in the host matrix as compared to the traditional alkyl side chains. Accordingly, intimate contact between the host and dopant molecules in the NDI‐based copolymer with polar side chains facilitates molecular doping with increased doping efficiency and electrical conductivity. For the first time, a heterogeneous thermoelectric transport model for such a material is proposed, that is the percolation of charge carriers from conducting ordered regions through poorly conductive disordered regions, which provides pointers for further increase in the themoelectric properties of n‐type D–A copolymers.     

Nursing and health care for an aging society: the case of The Netherlands

1. Demographic developments in European and western countries are not unique. Nurses should embrace the opportunity to learn from each others' care and research initiatives for the elderly population. 2. Current transitions in health care systems should be seized as an opportunity to further establish and develop the nursing profession, for example, through joining and initiating multidisciplinary initiatives. 3. The aging population is the fastest growing population in a number of countries. The training, recruitment, and retainment of nursing staff are key to continuously provide high quality care for the elderly.     

On‐Chip Chemical Self‐Assembly of Semiconducting Single‐Walled Carbon Nanotubes (SWNTs): Toward Robust and Scale Invariant SWNTs Transistors

In this paper, the fabrication of carbon nanotubes field effect transistors by chemical self‐assembly of semiconducting single walled carbon nanotubes (s‐SWNTs) on prepatterned substrates is demonstrated. Polyfluorenes derivatives have been demonstrated to be effective in selecting s‐SWNTs from raw mixtures. In this work the authors functionalized the polymer with side chains containing thiols, to obtain chemical self‐assembly of the selected s‐SWNTs on substrates with prepatterned gold electrodes. The authors show that the full side functionalization of the conjugated polymer with thiol groups partially disrupts the s‐SWNTs selection, with the presence of metallic tubes in the dispersion. However, the authors determine that the selectivity can be recovered either by tuning the number of thiol groups in the polymer, or by modulating the polymer/SWNTs proportions. As demonstrated by optical and electrical measurements, the polymer containing 2.5% of thiol groups gives the best s‐SWNT purity. Field‐effect transistors with various channel lengths, using networks of SWNTs and individual tubes, are fabricated by direct chemical self‐assembly of the SWNTs/thiolated‐polyfluorenes on substrates with lithographically defined electrodes. The network devices show superior performance (mobility up to 24 cm² V^?1 s^?1), while SWNTs devices based on individual tubes show an unprecedented (100%) yield for working devices. Importantly, the SWNTs assembled by mean of the thiol groups are stably anchored to the substrate and are resistant to external perturbation as sonication in organic solvents.     

Oviposition Cues for a Specialist Butterfly–Plant Chemistry and Size

The oviposition choice of an insect herbivore is based on a complex set of stimuli and responses. In this study, we examined the effect of plant secondary chemistry (the iridoid glycosides aucubin and catalpol) and aspects of size of the plant Plantago lanceolata, on the oviposition behavior of the specialist butterfly Melitaea cinxia. Iridoid glycosides are known to deter feeding or decrease the growth rate of generalist insect herbivores, but can act as oviposition cues and feeding stimulants for specialized herbivores. In a previous observational study of M. cinxia in the field, oviposition was associated with high levels of aucubin. However, this association could have been the cause (butterfly choice) or consequence (plant induction) of oviposition. We conducted a set of dual- and multiple-choice experiments in cages and in the field. In the cages, we found a positive association between the pre-oviposition level of aucubin and the number of ovipositions. The association reflects the butterfly oviposition selection rather than plant induction that follows oviposition. Our results also suggest a threshold concentration below which females do not distinguish between levels of iridoid glycosides. In the field, the size of the plant appeared to be a more important stimulus than iridoid glycoside content, with bigger plants receiving more oviposition than smaller plants, regardless of their secondary chemistry. Our results illustrate that the rank of a cue used for oviposition may be dependent on environmental context.     

Liposomes as Carriers for Drugs and Antigens: Approaches to Preserve Their Long Term Stability

Liposomes can be used for several different reasons in therapy. In this brief review the sources of chemical and physical instability of liposomes and the approaches for long term stabilization will be discussed.