Response of murine fibroblasts or human keratinocytes to micro- and nano-scale titanium particles: the permeability of particles across keratinocytes' monolayers Catarina Pacheco, Redouane Messous, Rui P Moura, Andreia Almeida, Patrícia Silva, et al. Clinical Oral Investigations, 2025 Purpose The aim of this study was to evaluate the cytocompatibility of micro- and nano-scale commercially pure Titanium (cpTi) particles in contact with fibroblasts and keratinocytes and the penetration of cpTi particles across keratinocytes' layers. Method Commercially pure titanium (cp-Ti) particles with 50-nm or 1-µm size were chemically and morphologically characterized using a Field Emission Guns Electron Microscopy (FEGSEM), Scanning Transmission Electron Microscope (STEM), and Energy Dispersion Spectrometry (EDAX). Then, the cytotoxic profile of the particles was monitored in contact with murine L929 fibroblasts and TR146 keratinocytes for 1, 4, and 7 days. Further permeability assays were performed across a TR146 monolayer via TranswellTM model. Results Physicochemical characterization of cpTi nano-scale particles (cpTi NPs) revealed a mean size at 70 nm and a specific surface area at around ~ 17.2 m2/g, while micro-scale particles (cpTi MP) size ranged from 0.3 up to 5.3 μm with a mean size of 1.4 μm at dry conditions. The optimized de-agglomeration of nanoparticles resulted in an increased specific surface area up to 57.3 m2/g. The metabolic activity of fibroblasts decreased against 50 or 100 µg/ml cpTi over 3 days cell culture while keratinocytes were not affected. Moreover, cpTi NP were internalized and steadily translocated into keratinocyte monolayers, showing an apparent permeability coefficient of 6.65 × 10−6 cm/s for 50 µg/mL and 3.96 × 10−6 cm/s for 100 µg/mL. Conclusions Altogether, nano-scale titanium particles decreased the viability of fibroblasts although a significant viability of keratinocytes has been detected by standard cell culture assays. However, nano-scale titanium particles were found into keratinocytes and even trespassed the cells' layers that could reach other cells and blood vessels in an in vivo scenario. Thus, toxicity of titanium particles depends on their particle size, exposure time, content, and interaction with the surrounding media. Graphical Abstract
Bioengineered Nanomedicines Targeting the Intestinal Fc Receptor Achieve the Improved Glucoregulatory Effect of Semaglutide in a Type 2 Diabetic Mice Model Soraia Pinto, Juliana Viegas, Cecília Cristelo, Catarina Pacheco, Sofia Barros, et al. ACS Nano, 2024 The oral administration of the glucagon-like peptide-1 analogue, semaglutide, remains a hurdle due to its limited bioavailability. Herein, neonatal Fc receptor (FcRn)-targeted nanoparticles (NPs) were designed to enhance the oral delivery of semaglutide. The nanocarriers were covalently linked to the FcRn-binding peptide FcBP or the affibody molecule ZFcRn that specifically binds to the human FcRn (hFcRn) in a pH-dependent manner. These FcRn-targeted ligands were selected over the endogenous ligands of the receptor (albumin and IgG) due to their smaller size and simpler structure, which could facilitate the transport of functionalized NPs through the tissues. The capacity of FcRn-targeted semaglutide-NPs in controlling the blood glucose levels was evaluated in an hFcRn transgenic mice model, where type 2 diabetes mellitus (T2DM) was induced via intraperitoneal injection of nicotinamide followed by streptozotocin. The encapsulation of semaglutide into FcRn-targeted NPs was translated in an improved glucoregulatory effect in T2DM-induced mice when compared to the oral free semaglutide or nontargeted NP groups, after daily oral administrations for 7 days. Notably, a similar glucose-lowering response was observed between both FcRn-targeted NPs and the subcutaneous semaglutide groups. An increase in insulin pancreatic content and a recovery in β cell mass were visualized in the mice treated with FcRn-targeted semaglutide-NPs. The biodistribution of fluorescently labeled NPs through the gastrointestinal tract demonstrated that the nanosystems targeting the hFcRn are retained longer in the ileum and colorectum, where the expression of FcRn is more prevalent, than nontargeted NPs. Therefore, FcRn-targeted nanocarriers proved to be an effective platform for improving the pharmacological effect of semaglutide in a T2DM-induced mice model.
Stimuli-Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood-to-Brain Trafficking and Tumor Targeting Cláudia Martins, Marco Araújo, Alessio Malfanti, Catarina Pacheco, Stuart J. Smith, et al. Small, 2023 Minimal therapeutic advances have been achieved over the past two decades for glioblastoma (GBM), which remains an unmet clinical need. Here, hypothesis-driven stimuli-responsive nanoparticles (NPs) for docetaxel (DTX) delivery to GBM are reported, with multifunctional features that circumvent insufficient blood-brain barrier (BBB) trafficking and lack of GBM targeting-two major hurdles for anti-GBM therapies. NPs are dual-surface tailored with a i) brain-targeted acid-responsive Angiopep-2 moiety that triggers NP structural rearrangement within BBB endosomal vesicles, and ii) L-Histidine moiety that provides NP preferential accumulation into GBM cells post-BBB crossing. In tumor invasive margin patient cells, the stimuli-responsive multifunctional NPs target GBM cells, enhance cell uptake by 12-fold, and induce three times higher cytotoxicity in 2D and 3D cell models. Moreover, the in vitro BBB permeability is increased by threefold. A biodistribution in vivo trial confirms a threefold enhancement of NP accumulation into the brain. Last, the in vivo antitumor efficacy is validated in GBM orthotopic models following intratumoral and intravenous administration. Median survival and number of long-term survivors are increased by 50%. Altogether, a preclinical proof of concept supports these stimuli-responsive multifunctional NPs as an effective anti-GBM multistage chemotherapeutic strategy, with ability to respond to multiple fronts of the GBM microenvironment.
Rational design of anticancer multidrug nanosystems and their adaptation for glioblastoma treatment C Pacheco, F Baltazar, BM Costa, B Sarmento Drug Delivery and Translational Research, 1-19 , 2025 2025
Nanocarrier-based intranasal drug delivery for enhanced neurological disorders treatment E Morim, B Sarmento, C Pacheco Drug Delivery and Translational Research, 1-19 , 2025 2025 Citations: 5
Multimodal nanoparticles co-delivering bevacizumab and dichloroacetate for dual targeting of neoangiogenesis and hyperglycolysis in glioblastoma treatment C Pacheco, O de Dios, MA Ramiréz-González, C Martins, SL Fialho, ... Journal of Controlled Release, 113931 , 2025 2025 Citations: 7
Co-delivery of antioxidants and siRNA-VEGF: promising treatment for age-related macular degeneration MF Dias, ELC Cruz-Cazarim, F Pittella, A Baião, AC Pacheco, B Sarmento, ... Drug Delivery and Translational Research, 1-29 , 2025 2025 Citations: 9
Bioengineered Nanomedicines Targeting the Intestinal Fc Receptor Achieve the Improved Glucoregulatory Effect of Semaglutide in a Type 2 Diabetic Mice Model S Pinto, J Viegas, C Cristelo, C Pacheco, S Barros, ST Buckley, J Garousi, ... ACS nano , 2024 2024 Citations: 17
Tissue-based in vitro and ex vivo models for blood–brain barrier permeability studies RP Moura, C Pacheco, P Faria, B Sarmento Concepts and Models for Drug Permeability Studies, 233-249 , 2024 2024
Nanomedicine approaches for treating glioblastoma C Martins, C Pacheco, P Faria, B Sarmento Nanomedicine 18 (18), 1135-1138 , 2023 2023 Citations: 1
Multifunctional nanomedicine strategies to manage brain diseases P Faria, C Pacheco, RP Moura, B Sarmento, C Martins Drug Delivery and Translational Research 13 (5), 1322-1342 , 2023 2023 Citations: 19
Stimuli‐Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood‐to‐Brain Trafficking and Tumor Targeting C Martins, M Araújo, A Malfanti, C Pacheco, SJ Smith, B Ucakar, ... Small, 2300029 , 2023 2023 Citations: 46
Recent advances in long-acting drug delivery systems for anticancer drug C Pacheco, A Baiao, T Ding, W Cui, B Sarmento Advanced Drug Delivery Reviews, 114724 , 2023 2023 Citations: 193
The effect of glioblastoma microenvironment on therapeutic, diagnostic, or theranostic systems C Martins, C Pacheco, B Sarmento New Insights Into Glioblastoma, 729-747 , 2023 2023
Glioblastoma immuno-endothelial multicellular microtissue as a 3D in vitro evaluation tool of anti-cancer nano-therapeutics C Martins, C Pacheco, C Moreira-Barbosa, A Marques-Magalhaes, S Dias, ... Journal of Controlled Release 353, 77-95 , 2023 2023 Citations: 24
Nanomedicine internalization and penetration: why should we use spheroids? B Pinto, C Pacheco, P Silva, J Carvalho-Tavares, B Sarmento, H Bousbaa Scientific Letters 1 (1), 3-3 , 2022 2022 Citations: 6
Glioblastoma Vasculature: From its Critical Role in Tumor Survival to Relevant in Vitro Modelling C Pacheco, C Martins, J Monteiro, F Baltazar, BM Costa, B Sarmento Frontiers in Drug Delivery 2, 823412 , 2022 2022 Citations: 35
Bringing vascularization into glioblastoma in vitro models C Pacheco, F Baltazar, BM Costa, B Sarmento Trends in Molecular Medicine 28 (2), 84-86 , 2022 2022 Citations: 6
Implantable and long-lasting drug delivery systems for cancer treatment C Pacheco, A Baião, F Sousa, B Sarmento Long-Acting Drug Delivery Systems, 129-162 , 2022 2022 Citations: 4
Lipid nanocapsules to enhance drug bioavailability to the central nervous system RP Moura, C Pacheco, AP Pêgo, A des Rieux, B Sarmento Journal of Controlled Release 322, 390-400 , 2020 2020 Citations: 80
Chitosan-based nanomedicine for brain delivery: Where are we heading? C Pacheco, F Sousa, B Sarmento Reactive and Functional Polymers 146, 104430 , 2020 2020 Citations: 52
MOST CITED SCHOLAR PUBLICATIONS
Recent advances in long-acting drug delivery systems for anticancer drug C Pacheco, A Baiao, T Ding, W Cui, B Sarmento Advanced Drug Delivery Reviews, 114724 , 2023 2023 Citations: 193
Lipid nanocapsules to enhance drug bioavailability to the central nervous system RP Moura, C Pacheco, AP Pêgo, A des Rieux, B Sarmento Journal of Controlled Release 322, 390-400 , 2020 2020 Citations: 80
Chitosan-based nanomedicine for brain delivery: Where are we heading? C Pacheco, F Sousa, B Sarmento Reactive and Functional Polymers 146, 104430 , 2020 2020 Citations: 52
Stimuli‐Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood‐to‐Brain Trafficking and Tumor Targeting C Martins, M Araújo, A Malfanti, C Pacheco, SJ Smith, B Ucakar, ... Small, 2300029 , 2023 2023 Citations: 46
Glioblastoma Vasculature: From its Critical Role in Tumor Survival to Relevant in Vitro Modelling C Pacheco, C Martins, J Monteiro, F Baltazar, BM Costa, B Sarmento Frontiers in Drug Delivery 2, 823412 , 2022 2022 Citations: 35
Glioblastoma immuno-endothelial multicellular microtissue as a 3D in vitro evaluation tool of anti-cancer nano-therapeutics C Martins, C Pacheco, C Moreira-Barbosa, A Marques-Magalhaes, S Dias, ... Journal of Controlled Release 353, 77-95 , 2023 2023 Citations: 24
Multifunctional nanomedicine strategies to manage brain diseases P Faria, C Pacheco, RP Moura, B Sarmento, C Martins Drug Delivery and Translational Research 13 (5), 1322-1342 , 2023 2023 Citations: 19
Bioengineered Nanomedicines Targeting the Intestinal Fc Receptor Achieve the Improved Glucoregulatory Effect of Semaglutide in a Type 2 Diabetic Mice Model S Pinto, J Viegas, C Cristelo, C Pacheco, S Barros, ST Buckley, J Garousi, ... ACS nano , 2024 2024 Citations: 17
Co-delivery of antioxidants and siRNA-VEGF: promising treatment for age-related macular degeneration MF Dias, ELC Cruz-Cazarim, F Pittella, A Baião, AC Pacheco, B Sarmento, ... Drug Delivery and Translational Research, 1-29 , 2025 2025 Citations: 9
Multimodal nanoparticles co-delivering bevacizumab and dichloroacetate for dual targeting of neoangiogenesis and hyperglycolysis in glioblastoma treatment C Pacheco, O de Dios, MA Ramiréz-González, C Martins, SL Fialho, ... Journal of Controlled Release, 113931 , 2025 2025 Citations: 7
Nanomedicine internalization and penetration: why should we use spheroids? B Pinto, C Pacheco, P Silva, J Carvalho-Tavares, B Sarmento, H Bousbaa Scientific Letters 1 (1), 3-3 , 2022 2022 Citations: 6
Bringing vascularization into glioblastoma in vitro models C Pacheco, F Baltazar, BM Costa, B Sarmento Trends in Molecular Medicine 28 (2), 84-86 , 2022 2022 Citations: 6
Nanocarrier-based intranasal drug delivery for enhanced neurological disorders treatment E Morim, B Sarmento, C Pacheco Drug Delivery and Translational Research, 1-19 , 2025 2025 Citations: 5
Implantable and long-lasting drug delivery systems for cancer treatment C Pacheco, A Baião, F Sousa, B Sarmento Long-Acting Drug Delivery Systems, 129-162 , 2022 2022 Citations: 4
Nanomedicine approaches for treating glioblastoma C Martins, C Pacheco, P Faria, B Sarmento Nanomedicine 18 (18), 1135-1138 , 2023 2023 Citations: 1
Rational design of anticancer multidrug nanosystems and their adaptation for glioblastoma treatment C Pacheco, F Baltazar, BM Costa, B Sarmento Drug Delivery and Translational Research, 1-19 , 2025 2025
Tissue-based in vitro and ex vivo models for blood–brain barrier permeability studies RP Moura, C Pacheco, P Faria, B Sarmento Concepts and Models for Drug Permeability Studies, 233-249 , 2024 2024
The effect of glioblastoma microenvironment on therapeutic, diagnostic, or theranostic systems C Martins, C Pacheco, B Sarmento New Insights Into Glioblastoma, 729-747 , 2023 2023
