TY - JOUR AB - Plasma protein binding (PPB) is closely related to pharmacokinetics, pharmacodynamics and drug toxicity. Existing models for predicting PPB often suffer from low prediction accuracy and poor interpretability, especially for high PPB compounds, and are most often not experimentally validated. Here, we carried out a strict data curation protocol, and applied consensus modeling to obtain a model with a coefficient of determination of 0.90 and 0.91 on the training set and the test set, respectively. This model (available on the OCHEM platform https://ochem.eu/article/29) was further retrospectively validated for a set of 63 poly-fluorinated molecules and prospectively validated for a set of 25 highly diverse compounds, and its performance for both these sets was superior to that of the other previously reported models. Furthermore, we identified the physicochemical and structural characteristics of high and low PPB molecules for further structural optimization. Finally, we provide practical and detailed recommendations for structural optimization to decrease PPB binding of lead compounds. AU - Han, Z.* AU - Xia, Z. AU - Xia, J.* AU - Tetko, I.V. AU - Wu, S.* C1 - 72219 C2 - 56493 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands TI - The state-of-the-art machine learning model for plasma protein binding prediction: Computational modeling with OCHEM and experimental validation. JO - Eur. J. Pharm. Sci. VL - 204 PB - Elsevier PY - 2025 SN - 0928-0987 ER - TY - JOUR AB - The development of biomimetic in vitro lung models as an alternative to animal studies is urgent to improve the predictability of the pharmacokinetics of potential new drugs. For pharmacokinetics studies, advanced in vitro lung models such as lung-chips should mimic a functional air-blood barrier. Unlike in vivo conditions, stem/primary cells and cell lines do not necessarily form a functional and tight barrier when cultured in vitro. Here, we explore the two gold standard techniques for monitoring barrier integrity: transepithelial electrical resistance (TEER) and permeability. We discuss the advantages and limitations of these methods, provide recommendations for methodological improvements, and we elude on possible future directions. AU - Doryab, A. AU - Schmid, O. C1 - 66328 C2 - 53135 TI - Towards a gold standard functional readout to characterize In Vitro lung barriers. JO - Eur. J. Pharm. Sci. VL - 179 PY - 2022 SN - 0928-0987 ER - TY - JOUR AB - Inhalation therapy plays an important role in management or treatment of respiratory diseases such asthma and chronic obstructive pulmonary diseases (COPDs). For decades, pressurized metered dose inhalers (pMDIs) have been the most popular and prescribed drug delivery devices for inhalation therapy. The main objectives of the present computational work are to study flow structure inside a pMDI, as well as transport and deposition of micron-sized particles in a model of human tracheobronchial airways and their dependence on inhalation air flow rate and characteristic pMDI parameters. The upper airway geometry, which includes the extrathoracic region, trachea, and bronchial airways up to the fourth generation in some branches, was constructed based on computed tomography (CT) images of an adult healthy female. Computational fluid dynamics (CFD) simulation was employed using the k-ω model with low-Reynolds number (LRN) corrections to accomplish the objectives. The deposition results of the present study were verified with the in vitro deposition data of our previous investigation on pulmonary drug delivery using a hollow replica of the same airway geometry as used for CFD modeling. It was found that the flow structure inside the pMDI and extrathoracic region strongly depends on inhalation flow rate and geometry of the inhaler. In addition, regional aerosol deposition patterns were investigated at four inhalation flow rates between 30 and 120 L/min and for 60 L/min yielding highest deposition fractions of 24.4% and 3.1% for the extrathoracic region (EX) and the trachea, respectively. It was also revealed that particle deposition was larger in the right branches of the bronchial airways (right lung) than the left branches (left lung) for all of the considered cases. Also, optimization of spray characteristics showed that the optimum values for initial spray velocity, spray cone angle and spray duration were 100 m/s, 10∘ and 0.1 sec, respectively. Moreover, spray cone angle, more than any other of the investigated pMDI parameters can change the deposition pattern of inhaled particles in the airway model. In conclusion, the present investigation provides a validated CFD model for particle deposition and new insights into the relevance of flow structure for deposition of pMDI-emitted pharmaceutical aerosols in the upper respiratory tract. AU - Ahookhosh, K.* AU - Saidi, M.* AU - Mohammadpourfard, M.* AU - Aminfar, H.* AU - Hamishehkar, H.* AU - Farnoud, A. AU - Schmid, O. C1 - 62337 C2 - 50796 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands TI - Flow structure and particle deposition analyses for optimization of a pressurized metered dose inhaler (pMDI) in a model of tracheobronchial airway. JO - Eur. J. Pharm. Sci. VL - 164 PB - Elsevier PY - 2021 SN - 0928-0987 ER - TY - JOUR AB - Multifunctional LUV liposomes (mf-LIPs) were developed, having a curcumin-lipid ligand (TREG) with affinity towards amyloid species, together with ligands to target the transferrin and the LDL receptors of the blood-brain-barrier (BBB), on their surface. mf-LIPs were evaluated for their brain targeting, on hCMEC/D3 monolayers, and for their ability to inhibit Aβ-peptide aggregation. The transport of mf-LIP across hCMEC/D3 monolayers was similar to that of BBB-LIPs, indicating that the presence of TREG on their surface does not reduce their brain targeting potential. Likewise, mf-LIP inhibitory effect on Aβ aggregation was similar to that of LIPs functionalized only with TREG, proving that the presence of brain targeting ligands does not reduce the functionality of the amyloid-specific ligand. Addition of the curcumin-lipid in some liposome types was found to enhance their integrity and reduce the effect of serum proteins on their interaction with brain endothelial cells. Finally, preliminary in vivo results confirm the in vitro findings. Concluding, the current results reveal the potential of the specific curcumin-lipid derivative as a component of multifunctional LIPs with efficient brain targeting capability, intended to act as a theragnostic system for AD. AU - Papadia, K.* AU - Markoutsa, E.* AU - Mourtas, S.* AU - Giannou, A.D.* AU - La Ferla, B.* AU - Nicotra, F.* AU - Salmona, M.* AU - Klepetsanis, P.* AU - Stathopoulos, G.T. AU - Antimisiaris, S.G.* C1 - 50646 C2 - 42755 CY - Amsterdam SP - 140-148 TI - Multifunctional LUV liposomes decorated for BBB and amyloid targeting. A. In vitro proof-of-concept. JO - Eur. J. Pharm. Sci. VL - 101 PB - Elsevier Science Bv PY - 2017 SN - 0928-0987 ER - TY - JOUR AB - Multifunctional liposomes (mf-LIPs) having a curcumin-lipid ligand (to target amyloids) together with two ligands to target the transferrin, and the low-density apolipoprotein receptor of the blood-brain-barrier (BBB) on their surface, were previously studied (in vitro) as potential theranostic systems for Alzheimer's disease (AD) (Papadia et al., 2017, Eur. J. Pharm. Sciences; 101:140-148). Herein, the targeting potential of mf-LIPs was compared to that of BBB-LIPs (liposomes having only the two BBB-specific ligands) in FVB mice (normal), as well as in double transgenic mice (APP/PS1) and their corresponding littermates (WT), by live-animal (in vivo) and explanted organ (ex vivo) imaging. In FVB mice, the head-signals of mf-LIPs and BBB-LIPs are either similar, or signals from mf-LIP are higher, suggesting that the co-presence of the curcumin derivative on the liposome surface does not disturb the functionality of the BBB-specific ligands. Higher brain/liver+spleen ratios (ex vivo) were calculated post-injection of mf-LIP, compared to those found after BBB-LIP injection, due to the reduced distribution of mf-LIPs in the liver and spleen; showing that the curcumin ligand increases the stealth properties of liposomes by reducing their uptake by liver and spleen. The later effect is more pronounced when the density of the BBB-specific ligands on the mf-LIPs is 0.1mol%, compared to 0.2%, highlighting the importance of this parameter. When a high lipid dose (4mg/mouse) is injected in WT and APP/PS1 mice, the head-signals of mf-LIPs are significantly higher than those of BBB-LIPs, but no differences are observed between WT and APP/PS1 mice. However, after administration of a low liposome dose (0.05mg/mouse) of mf-LIPs, significant differences in the head-signals are found between WT and transgenic mice, highlighting the AD theranostic potential of the multifunctional liposomes, as well as the importance of the experimental parameters used in such in vivo screening studies. AU - Papadia, K.* AU - Giannou, A.D. AU - Markoutsa, E.* AU - Bigot, C.* AU - Vanhoute, G.* AU - Mourtas, S.* AU - der Linden, A.V.* AU - Stathopoulos, G.T. AU - Antimisiaris, S.G.* C1 - 50703 C2 - 42465 CY - Amsterdam SP - 180-187 TI - Multifunctional LUV liposomes decorated for BBB and amyloid targeting - B. In vivo brain targeting potential in wild-type and APP/PS1 mice. JO - Eur. J. Pharm. Sci. VL - 102 PB - Elsevier Science Bv PY - 2017 SN - 0928-0987 ER - TY - JOUR AB - Lipophilicity is a crucial parameter in drug development since it impacts both ADME properties and target affinity of drug candidates. In early drug discovery stage, accurate tools for logP prediction are highly desired. Many calculation methods were developed to aid pharmaceutical scientists in drug research; however almost all suffer from insufficient accuracy and variation of performance in several regions of the chemical space associated with new chemical entities. The low predictive power of existing software packages can be explained by limited availability and/or variable quality of experimental logP values associated with training set used, which stem from various protocols and poorly cover chemical space. In this study, a dataset of 1000 diverse test compounds out of 4.5 million was generated; logP values of 759 purchasable compounds (46% non-ionizable, 30% basic, 17% acidic, 0.5% zwitterionic and 6.5% ampholytes) from this selected set were experimentally determined by UHPLC followed by UV detection or MS detection when necessary. Finally, a data collection of 707 validated logP values ranging from 0.30 to 7.50 is now available for benchmarking of existing and development of new approaches to predict octanol/water partition coefficients of chemical compounds. AU - Martel, S.* AU - Gillerat, F.* AU - Carosati, E.* AU - Maiarelli, D.* AU - Tetko, I.V. AU - Mannhold, R.* AU - Carrupt, P.A.* C1 - 11844 C2 - 30831 SP - 21-29 TI - Large, chemically diverse dataset of logP measurements for benchmarking studies. JO - Eur. J. Pharm. Sci. VL - 48 IS - 1-2 PB - Elsevier Science PY - 2013 SN - 0928-0987 ER -