Polyester-based excipients to formulate lipophilic drugs into nanoparticles directly at the bed of the patient

In recent decades there has been an increased interest in polymeric nanoparticles as drug delivery systems thanks to their several advantages, such as continuous maintenance of drug levels in a therapeutically desirable range, and reduction of harmful side effects. These nano-colloids are generally made up of polyesters as long as they are able to easily degrade into the body. However, NP production is often a process that requires complex microfluidic devices. In addition, expensive purification steps are necessary to eliminate the unloaded drug and the high amount of organic solvent used in the NP production step. In the end, a lyophilization step is general adopted to assure a good shelf-life of the final product. All the above-mentioned steps hamper the cost-effective use of a re-formulation of the same therapeutic agent and, in turn, reduce the availability of these treatments among the patient population. For this reason, in this work, a novel NP production protocol that consists only in the use of a syringe and a needle without the need of subsequent purification and freeze-drying steps has been developed. This has been possible by the optimization of the hydrophilic/lipophilic balance of block-copolymers that are able to directly self-assemble in water. The additional degree of freedom necessary for this optimization was introduced via the synthesis of these materials thorough the combination of the reversible addition-fragmentation chain transfer (RAFT) polymerization and the ring opening polymerization (ROP). The NPs has been used to formulate Trabectedin (ET-743), a widely adopted anticancer therapeutic known for its local adverse effect. The pharmacokinetic behavior, antitumor activity and toxicity of this novel NP-based formulation has been compared to the commercially available formulation Yondelis®. NPs have shown the ability to retain the drug into circulation for a longer time in the blood stream compared to the free ET-743 allowing to considerably reduce the local toxic effects. In addition, the shift of the NP preparation step from a specialist to the final user allows to avoid all the purifications and post-processing steps necessary to assure a good shelf-life of the product. In this way, a ET-743 formulation less toxic than the commercially available Yondelis® can be produced at a competitive price taking also into account that this expensive drug is not lost in any of the NP production steps here adopted. In order to prove the versatility of this novel technology, Paclitaxel (PTX), an anticancer therapeutic that it usually formulated with a toxic surfactant (Chremophor EL), have been also formulated into this NPs. In this way, a novel PTX formulation can be produced at a lower cost compared to the ones already approved and present into the market. In particular, it has shown the same advantage in reduction of the toxicity given by the elimination of the Chremophor EL (e.g in Abraxane® and Genexol®)

Mission Planning for the Estimation of the Field Coverage of Unmanned Aerial Systems in Monitoring Mission in Precision Farming

In the recent years, Unmanned Aerial Systems (UAS) have been largely employed in civil applications, such as aerial photography and topographic mapping, environmental monitoring, search and rescue, prevent of fires and disasters, environmental research and general photography and videos. Nevertheless, according to (AUVSI, 2013), agriculture is the main application where UAS will be employed in the near future. Small Unmanned Aerial Vehicles (UAVs) are flexible, easy to use and relative low-cost; thus, they can be employed in monitoring activities in precision farming, ensuring a prompt reaction to plant disease, lack of plants nutrients and environmental changes that are the main focus for farm efficiency and productivity. Recent development in high-resolution remote sensing and image processing technology has yield to small- size sensors compatible with small UAV payload weight. Each kind of sensor needs a certain flight pattern over the fields. However, a Remotely Piloted Aircraft Systems (RPAS) used for specialized operations or experimental activities has to be compliant with National Civil Aviation Authority regulations. On 2015, the Italian Aviation Authority (ENAC) published the second edition of the regulatory issue for this kind of aircrafts. The aim of this paper is the management analysis of RPAS for their use in survey missions for precision faming, taking into account the Italian regulatory prescription and two different kind of commercial sensors. UAVs are considered similarly to any other farm machine, describing the operative workflow and analysing the elementary time procedures associated to the different ways of planning a flight mission of the UAS on the field to be monitored. Actual rates of works, Effective Field Capacity (EFC) and Field Efficiency (FE), field coverage and survey cost are finally provided. The analysis includes also in-field pre-flight calibration procedures

A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia

This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which MAFB was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs.The Pharmacogenomics Journal advance online publication, 13 December 2016; doi:10.1038/tpj.2016.76

Cell cycle perturbations and apoptosis induced by isohomohalichondrin B (IHB), a natural marine compound

Isohomohalichondrin B (IHB), a novel marine compound with anti-tumoral activity, extracted from the Lissodendorix sponge, inhibits GTP binding to tubulin, preventing microtubule assembly. Cell cycle perturbations and apoptosis induced by IHB were investigated on selected human cancer cell lines by using flow cytometric and biochemical techniques. Monoparameter flow cytometric analysis showed that 1 h IHB exposure caused a delayed progression through S-phase, a dramatic block in G2M phase of the cell cycle and the appearance of tetraploid cell population in LoVo, LoVo/DX, MOLT-4 and K562 cells. At 24 h after IHB exposure, the majority of cells blocked in G2M were in prophase as assessed by morphological analysis and by the fact that they expressed high levels of cyclin A/cdc2 and cyclin B1/cdc2. At 48 h, all cells were tetraploid as assessed by biparameter cyclin A/DNA and cyclin B1/DNA content analysis. Apoptotic death was detected in both leukaemic MOLT-4 and K562 cells, which express wild-type and mutated p53 respectively, when the cells were blocked in mitotic prophase. In conclusion, IHB is a novel potent anti-tumour drug that causes delayed S-phase progression, mitotic block, tetraploidy and apoptosis in cancer cell lines. © 1999 Cancer Research Campaig

Marine Compounds Selectively Induce Apoptosis in Female Reproductive Cancer Cells but Not in Primary-Derived Human Reproductive Granulosa Cells

Anticancer properties of tyrindoleninone and 6-bromoisatin from Dicathais orbita were tested against physiologically normal primary human granulosa cells (HGC) and reproductive cancer cell lines. Tyrindoleninone reduced cancer cell viability with IC50 values of 39 µM (KGN; a tumour-derived granulosa cell line), 39 μM (JAr), and 156 μM (OVCAR-3), compared to 3516 μM in HGC. Apoptosis in HGC’s occurred after 4 h at 391 µM tyrindoleninone compared to 20 µM in KGN cells. Differences in apoptosis between HGC and KGN cells were confirmed by TUNEL, with 66 and 31% apoptotic nuclei at 4 h in KGN and HGC, respectively. These marine compounds therefore have potential for development as treatments for female reproductive cancers

3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors

Mass Spectrometry Imaging (MSI) is a widespread technique used to qualitatively describe in two dimensions the distribution of endogenous or exogenous compounds within tissue sections. Absolute quantification of drugs using MSI is a recent challenge that just in the last years has started to be addressed. Starting from a two dimensional MSI protocol, we developed a three-dimensional pipeline to study drug penetration in tumors and to develop a new drug quantification method by MALDI MSI. Paclitaxel distribution and concentration in different tumors were measured in a 3D model of Malignant Pleural Mesothelioma (MPM), which is known to be a very heterogeneous neoplasm, highly resistant to different drugs. The 3D computational reconstruction allows an accurate description of tumor PTX penetration, adding information about the heterogeneity of tumor drug distribution due to the complex microenvironment. The use of an internal standard, homogenously sprayed on tissue slices, ensures quantitative results that are similar to those obtained using HPLC. The 3D model gives important information about the drug concentration in different tumor sub-volumes and shows that the great part of each tumor is not reached by the drug, suggesting the concept of pseudo-resistance as a further explanation for ineffective therapies and tumors relapse