Drug delivery of paclitaxel for an intraperitoneal chemotherapy

Peritoneal carcinomatosis (PC) is a frequent phenomenon in the course of gastroinstestinal and ovarian cancer and is responsible for a high mortality. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has been introduced as an alternative treatment. An interesting drug for HIPEC is paclitaxel. However, the use of paclitaxel is hampered by its poor solubility and the currently used formulation vehicle (Cremophor EL(R)/ethanol). Therefore, the objective of this research project was to develop a tensioactive- and solvent-free paclitaxel formulation suitable for HIPEC. A second objective was to evaluate this novel formulation on cell lines for its efficiency in comparison to Taxol(R). A third objective was an in vivo evaluation of the toxicity, bioavailability and tumour growth delay (TGD) of both formulations (Taxo(R) and Pac/RAME-beta-CD). The formulation study yielded the following formulation: 1/20 (mol/mol) complex of paclitaxel and randomly-methylated-beta-cyclodextrins (Pac/RAME-beta-CD) dissolved in phosphate buffered saline (PBS) supplemented with 0.1% (w/v) hydroxypropylmethylcellulose (HPMC). This formulation showed sufficient physical stability at room temperature and under HIPEC conditions. Initially, both formulations showed similar (<= 10% difference) cytotoxic activity on two cancer cell lines (CC531s and CaCo-2) and no influence of the addition of hyperthermia was seen. Increasing the cell concentration and reducing the contact time resulted in a loss of equipotency. This loss was explained by the presence of multi drug resistant (MDR) cells. Resensitization of these MDR cells was achieved via the addition HPPP, a non-selective glucosylceramide synthase inhibitor. In vivo evaluation showed that the toxicity of both formulations was similar (maximum tolerated dose (MTD) of 0.24 mg/ml for both). Bioavailability, however, was significantly increased for Pac/RAME-beta-CD (i.e. 40-fold increase for the area under the curve). Preliminary results from the TGD study allowed to establish the study protocol for a future in-depth TGD study. In conclusion, this project has shown that it is possible to formulate paclitaxel using beta-cyclodextrins without loosing its activity on cancer cell lines. In vivo evaluation between Taxol(R) and Pac/RAME-betal-CD has shown a similar toxicity profile but a significant difference in bioavailability, which might, according to the TGD study, have implications on their TGD

Sizing nanomatter in biological fluids by fluorescence single particle tracking

Accurate sizing of nanoparticles in biological media is important for drug delivery and biomedical imaging applications since size directly influences the nanoparticle processing and nanotoxicity in vivo. Using fluorescence single particle cracking we have succeeded for the first time in following the aggregation of drug delivery nanoparticles in real time in undiluted whole blood. We demonstrate that, by using a suitable surface functionalization, nanoparticle aggregation in the blood circulation is prevented to a large extent

Fluorescence single particle tracking for sizing of nanoparticles in undiluted biological fluids

While extremely relevant to many life science fields, such as biomedical diagnostics and drug delivery, studies on the size of nanoparticulate matter dispersed in biofluids are missing due to a lack of suitable methods. Here we report that fluorescence single particle tracking (fSPT) with maximum entropy analysis is the first technique suited for accurate sizing of nanoparticles dispersed in biofluids, such as whole blood. After a thorough validation, the fSPT sizing method was applied to liposomes that have been under investigation for decades as nanocarriers for drugs. The tendency of these liposomes to form aggregates in whole blood was tested in vitro and in vivo. In addition, we have demonstrated that the fSPT sizing technique can be used for identifying and sizing natural cell-derived microparticles directly in plasma. fSPT sizing opens up the possibility to systematically study the size and aggregation of endogenous or exogenous nanoparticles in biofluids

Development of a Nanocrystalline Paclitaxel Formulation for Hipec Treatment

To develop a nanocrystalline paclitaxel formulation with a high paclitaxel-to-stabilizer ratio which can be used for hyperthermic intraperitoneal chemotherapy (HIPEC). Paclitaxel (PTX) nanocrystals were prepared via wet milling using Pluronic F127(A (R)) as stabilizer. The suitability of paclitaxel nanosuspensions for HIPEC treatment was evaluated by analyzing the cytotoxicity of both stabilizer and formulation, and by determining the maximum tolerated dose (MTD) and bioavailability. The effect on tumor growth was evaluated by magnetic resonance imaging (MRI) at day 7 and 14 after HIPEC treatment in rats with peritoneal carcinomatosis of ovarian origin. Monodisperse nanosuspensions (+/- 400 nm) were developed using Pluronic F127(A (R)) as single additive. The cytotoxicity and MTD of this nanocrystalline formulation was similar compared to Taxol(A (R)), while its bioavailability was higher. MRI data after HIPEC treatment with a PTX nanocrystalline suspension showed a significant reduction of tumor volume compared to the non-treated group. Although no significant differences on tumor volume were observed between Taxol(A (R)) and the nanosuspension, the rats treated with the nanosuspension recovered faster following the HIPEC procedure. Nanosuspensions with a high paclitaxel-to-stabilizer ratio are of interest for the treatment of peritoneal carcinomatosis of ovarian origin via HIPEC

Measurement of inclusive π0\pi^{0} production in hadronic Z0Z^{0} decays

An analysis is presented of inclusive \pi^0 production in Z^0 decays measured with the DELPHI detector. At low energies, \pi^0 decays are reconstructed by \linebreak using pairs of converted photons and combinations of converted photons and photons reconstructed in the barrel electromagnetic calorimeter (HPC). At high energies (up to x_p = 2 \cdot p_{\pi}/\sqrt{s} = 0.75) the excellent granularity of the HPC is exploited to search for two-photon substructures in single showers. The inclusive differential cross section is measured as a function of energy for {q\overline q} and {b \bar b} events. The number of \pi^0's per hadronic Z^0 event is N(\pi^0)/ Z_{had}^0 = 9.2 \pm 0.2 \mbox{(stat)} \pm 1.0 \mbox{(syst)} and for {b \bar b}~events the number of \pi^0's is {\mathrm N(\pi^0)/ b \overline b} = 10.1 \pm 0.4 \mbox{(stat)} \pm 1.1 \mbox{(syst)} . The ratio of the number of \pi^0's in b \overline b events to hadronic Z^0 events is less affected by the systematic errors and is found to be 1.09 \pm 0.05 \pm 0.01. The measured \pi^0 cross sections are compared with the predictions of different parton shower models. For hadronic events, the peak position in the \mathrm \xi_p = \ln(1/x_p) distribution is \xi_p^{\star} = 3.90^{+0.24}_{-0.14}. The average number of \pi^0's from the decay of primary \mathrm B hadrons is found to be {\mathrm N} (B \rightarrow \pi^0 \, X)/\mbox{B hadron} = 2.78 \pm 0.15 \mbox{(stat)} \pm 0.60 \mbox{(syst)}

Measurements of the leptonic branching fractions of the τ\tau

Data collected with the DELPHI detector from 1993 to 1995 combined with previous DELPHI results for data from 1991 and 1992 yield the branching fractions B({\tau \rightarrow \mbox{\rm e} \nu \bar{\nu}}) = (17.877 \pm 0.109_{stat} \pm 0.110_{sys} )\% and $B({\tau \rightarrow \mu \nu \bar{\nu}}) = (17.325 \pm 0.095_{stat} \pm 0.077_{sys} )\%$