Publications by authors named "Bruno Sarmento"

302 Publications

Advances on Colorectal Cancer 3D models: the needed translational technology for nanomedicine screening.

Adv Drug Deliv Rev 2021 Jun 3. Epub 2021 Jun 3.

I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal. Electronic address:

Colorectal cancer (CRC) is a heterogeneous and molecularly complex disease, associated with high mortality worldwide, exposing the urgent need for novel therapeutic approaches. Their development and translation to the clinic have been hampered, partially due to the absence of reliable cellular models that resemble key features of the human disease. While traditional 2D models are not able to provide consistent and predictive responses about the in vivo efficiency of the formulation, animal models frequently fail to recapitulate cancer progression and to reproduce adverse effects. On its turn, multicellular 3D systems, by mimicking key genetic, physical and mechanical cues of the tumor microenvironment, constitute a promising tool in cancer research. In addition, they constitute more physiological and relevant environment for anticancer drugs screening and for predicting patient's response towards personalized approaches, bridging the gap between simplified 2D models and unrepresentative animal models. In this review, we provide an overview of CRC 3D models for translational research, with focus on their potential for nanomedicines screening.
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http://dx.doi.org/10.1016/j.addr.2021.06.001DOI Listing
June 2021

Graphene Oxide Topical Administration: Skin Permeability Studies.

Materials (Basel) 2021 May 25;14(11). Epub 2021 May 25.

i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-180 Porto, Portugal.

Nanostructured carriers have been widely used in pharmaceutical formulations for dermatological treatment. They offer targeted drug delivery, sustained release, improved biostability, and low toxicity, usually presenting advantages over conventional formulations. Due to its large surface area, small size and photothermal properties, graphene oxide (GO) has the potential to be used for such applications. Nanographene oxide (GOn) presented average sizes of 197.6 ± 11.8 nm, and a surface charge of -39.4 ± 1.8 mV, being stable in water for over 6 months. 55.5% of the mass of GOn dispersion (at a concentration of 1000 µg mL) permeated the skin after 6 h of exposure. GOn dispersions have been shown to absorb near-infrared radiation, reaching temperatures up to 45.7 °C, within mild the photothermal therapy temperature range. Furthermore, GOn in amounts superior to those which could permeate the skin were shown not to affect human skin fibroblasts (HFF-1) morphology or viability, after 24 h of incubation. Due to its large size, no skin permeation was observed for graphite particles in aqueous dispersions stabilized with Pluronic P-123 (Gt-P-123). Altogether, for the first time, Gon's potential as a topic administration agent and for delivery of photothermal therapy has been demonstrated.
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http://dx.doi.org/10.3390/ma14112810DOI Listing
May 2021

Electrospun fibers for vaginal administration of tenofovir disoproxil fumarate and emtricitabine in the context of topical pre-exposure prophylaxis.

J Control Release 2021 Jun 5;334:453-462. Epub 2021 May 5.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal. Electronic address:

Women are particularly vulnerable to sexual HIV-1 transmission. Oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is highly effective in avoiding new infections in men, but protection has only been shown to be moderate in women. Such differences have been associated, at least partially, to poor drug penetration of the lower female genital tract and the need for strict adherence to continuous daily oral intake of TDF/FTC. On-demand topical microbicide products could help circumvent these limitations. We developed electrospun fibers based on polycaprolactone (PCL fibers) or liposomes associated to poly(vinyl alcohol) (liposomes-in-PVA fibers) for the vaginal co-delivery of TDF and FTC, and assessed their pharmacokinetics in mice. PCL fibers and liposomes-in-PVA fibers were tested for morphological and physicochemical properties using scanning electron microscopy, differential scanning calorimetry and X-ray diffractometry. Fibers featured organoleptic and mechanical properties compatible with their suitable handling and vaginal administration. Fluorescent quenching of mucin in vitro - used as a proxy for mucoadhesion - was intense for PCL fibers, but mild for liposomes-in-PVA fibers. Both fibers were shown safe in vitro and able to rapidly release drug content (15-30 min) under sink conditions. Liposomes-in-PVA fibers allowed increasing genital drug concentrations after a single intravaginal administration when compared to continuous daily treatment for five days with 25-times higher oral doses. For instance, the levels of tenofovir and FTC in vaginal lavage were around 4- and 29-fold higher, respectively. PCL fibers were also superior to oral treatment, although to a minor extent (approximately 2-fold higher drug concentrations in lavage). Vaginal tissue drug levels were generally low for all treatments, while systemic drug exposure was negligible in the case of fibers. These data suggest that proposed fibers may provide an interesting alternative or an ancillary option to oral PrEP in women.
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http://dx.doi.org/10.1016/j.jconrel.2021.05.003DOI Listing
June 2021

Immunomodulatory nanomedicine for colorectal cancer treatment: a landscape to be explored?

Biomater Sci 2021 May;9(9):3228-3243

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. and INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal and CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal.

Colorectal cancer (CRC) is one of the deadliest cancers in the world mainly due to metastasis events. Despite improvements, the available treatment modalities for metastatic cases are limited, being generally associated with poor prognosis. As is well known, the immunosuppressive tumor microenvironment (TME) plays a key role in tumorigenesis, promoting cancer cell immune escape and disease progression. In addition, accumulating evidence indicates that the immunosuppressive microenvironment is a critical barrier for antitumor immunity in CRC, being extremely important to modulate the immune microenvironment to inhibit the tumor-promoting immune response. Therefore, new and effective cancer immunotherapeutic approaches demand a better control over the TME to reverse these immunosuppressive conditions. According to the features of different nanomedicines, nanoparticles can constitute a promising strategy, using different materials with the inherent ability to modulate TME and also with the potential to target immunosuppressive cells, to deliver antigens or immunomodulatory agents to eliminate this tumor. In this review, we summarize the importance of the TME in the progression and treatment response of CRC, exploring the potential of the nanotechnology for the development of immunomodulatory therapeutic strategies.
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http://dx.doi.org/10.1039/d1bm00137jDOI Listing
May 2021

Production and Characterization of Anti-CCR5 siRNA-Loaded Polycaprolactone Nanoparticles for Topical Pre-exposure Prophylaxis.

Methods Mol Biol 2021 ;2282:403-416

i3S-Instituto de Investigação e Inovação em Saúde & INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.

Topical posttranscriptional silencing of host factors involved in HIV-1 sexual transmission, such as CCR5, presents the potential to prevent new cases of infection. However, issues concerning proper engineering of safe and effective delivery systems for anti-CCR5 siRNA may impair the ability to yield suitable silencing at the mucosal level. Here we describe the production protocol of anti-CCR5 siRNA-loaded polycaprolactone-based nanoparticles (≈100 nm). Furthermore, we present data regarding the physicochemical and in vitro biological characterization of obtained nanosystems, which support their potential as microbicide candidates for topical pre-exposure prophylaxis of HIV-1 infection.
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http://dx.doi.org/10.1007/978-1-0716-1298-9_22DOI Listing
January 2021

Clofazimine functionalized polymeric nanoparticles for brain delivery in the tuberculosis treatment.

Int J Pharm 2021 Jun 27;602:120655. Epub 2021 Apr 27.

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde and Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal. Electronic address:

Central nervous system tuberculosis (CNS-TB) is the most severe form of the disease especially due to the inability of therapeutics to cross the blood-brain barrier (BBB). Clofazimine (CFZ) stands out for presenting high in vitro activity against multi-drug resistant strains of Mycobacterium tuberculosis, however, CFZ physicochemical and pharmacokinetics properties limit drug penetration into the CNS and, consequently, its clinical use. The aim of this work was to develop polymeric nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) loaded with CFZ and functionalized with a transferrin receptor (TfR)-binding peptide, aiming brain drug delivery for CNS-TB treatment by the intravenous route. The poor water solubility and high lipophilicity of CFZ was overcome through its entrapment into PLGA-PEG NPs manufactured by both conventional and microfluidic techniques using the nanoprecipitation principle. In vitro studies in brain endothelial hCMEC/D3 cells demonstrated that CFZ incorporation into the NPs was advantageous to reduce drug cytotoxicity. The TfR-binding peptide-functionalized NPs showed superior cell interaction and higher CFZ permeability across hCMEC/D3 cell monolayers compared to the non-functionalized NP control, thus indicating the efficacy of the functionalization strategy on providing CFZ transport through the BBB in vitro. The functionalized NPs demonstrate suitability for CFZ biological administration, suggested with low plasma protein binding, off-target biodistribution and precise delivery of CFZ towards the brain parenchyma.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120655DOI Listing
June 2021

Prevention of diabetes-associated fibrosis: Strategies in FcRn-targeted nanosystems for oral drug delivery.

Adv Drug Deliv Rev 2021 Apr 19. Epub 2021 Apr 19.

Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, 4585-116 Gandra, Portugal. Electronic address:

Diabetes mellitus is a chronic disease with an elevated risk of micro- and macrovascular complications, such as fibrosis. To prevent diabetes-associated fibrosis, the symptomatology of diabetes must be controlled, which is commonly done by subcutaneous injection of antidiabetic peptides. To minimize the pain and distress associated with such injections, there is an urgent need for non-invasive oral transmucosal drug delivery strategies. However, orally administered peptide-based drugs are exposed to harsh conditions in the gastrointestinal tract and poorly cross the selective intestinal epithelium. Thus, targeting of drugs to receptors expressed in epithelial cells, such as the neonatal Fc receptor (FcRn), may therefore enhance uptake and transport through mucosal barriers. This review compiles how in-depth studies of FcRn biology and engineering of receptor-binding molecules may pave the way for design of new classes of FcRn-targeted nanosystems. Tailored strategies may open new avenues for oral drug delivery and provide better treatment options for diabetes and, consequently, fibrosis prevention.
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http://dx.doi.org/10.1016/j.addr.2021.04.016DOI Listing
April 2021

Interface-Mediated Mechanism of Action-The Root of the Cytoprotective Effect of Immediate-Release Omeprazole.

J Med Chem 2021 04 13;64(8):5171-5184. Epub 2021 Apr 13.

LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.

Omeprazole is usually administered under an enteric coating. However, there is a Food and Drug Administration-approved strategy that enables its release in the stomach. When locally absorbed, omeprazole shows a higher efficacy and a cytoprotective effect, whose mechanism was still unknown. Therefore, we aimed to assess the effect of the absorption route on the gastric mucosa. 2D and 3D models of dipalmitoylphosphatidylcholine (DPPC) at different pH values (5.0 and 7.4) were used to mimic different absorption conditions. Several experimental techniques, namely, fluorescence studies, X-ray scattering methodologies, and Langmuir monolayers coupled with microscopy, X-ray diffraction, and infrared spectroscopy techniques, were combined with molecular dynamics simulations. The results showed that electrostatic and hydrophobic interactions between omeprazole and DPPC rearranged the conformational state of DPPC. Omeprazole intercalates among DPPC molecules, promoting domain formation with untilted phospholipids. Hence, the local release of omeprazole enables its action as a phospholipid-like drug, which can reinforce and protect the gastric mucosa.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00251DOI Listing
April 2021

In vitro model for predicting the access and distribution of drugs in the brain using hCMEC/D3 cells.

Eur J Pharm Biopharm 2021 Jun 8;163:120-126. Epub 2021 Apr 8.

INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal.

The BBB is a protective entity that prevents external substances from reaching the CNS but it also hinders the delivery of drugs into the brain when they are needed. The main objective of this work was to improve a previously proposed in vitro cell-based model by using a more physiological cell line (hCMEC/D3) to predict the main pharmacokinetic parameters that describe the access and distribution of drugs in the CNS: Kp, f, f and V. The hCMEC/D3 permeability of seven drugs was studied in transwell systems under different conditions (standard, modified with albumin and modified with brain homogenate). From the permeability coefficients of those experiments, the parameters mentioned above were calculated and four linear IVIVCs were established. The best ones were those that relate the in vitro and in vivo V and f (r = 0.961 and r = 0.940) which represent the binding rate of a substance to the brain tissue, evidencing the importance of using brain homogenate to mimic brain tissue when an in vitro brain permeability assay is done. This methodology could be a high-throughput screening tool in drug development to select the CNS promising drugs in three different in vitro BBB models (hCMEC/D3, MDCK and MDCK-MDR1).
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http://dx.doi.org/10.1016/j.ejpb.2021.04.002DOI Listing
June 2021

The effect of hypergravity in intestinal permeability of nanoformulations and molecules.

Eur J Pharm Biopharm 2021 Jun 27;163:38-48. Epub 2021 Mar 27.

INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central da Gandra, 137, 4585-116 Gandra, Portugal. Electronic address:

The oral administration of drugs remains a challenge due to rapid enzymatic degradation and minimal absorption in the gastrointestinal tract. Mechanical forces, namely hypergravity, can interfere with cellular integrity and drug absorption, and there is no study describing its influence in the intestinal permeability. In this work, it was studied the effect of hypergravity on intestinal Caco-2 cells and its influence in the intestinal permeability of different nanoformulations and molecules. It was shown that the cellular metabolic activity and integrity were maintained after exposure to different gravity-levels (g-levels). Expression of important drug transporters and tight junctions' proteins was evaluated and, most proteins demonstrated a switch of behavior in their expression. Furthermore, paracellular transport of FITC-Dextran showed to significantly increase with hypergravity, which agrees with the decrease of transepithelial electrical resistance and the increase of claudin-2 at higher g-levels. The diffusion of camptothecin released from polymeric micelles revealed a significant decrease, which agrees with the increased expression of the P-gp observed with the increase in g-levels, responsible for pumping this drug out. The neonatal Fc receptor-mediated transport of albumin-functionalized nanoparticles loaded with insulin showed no significant changes when increasing the g-levels. Thus, this study supports the effect of hypergravity on intestinal permeability is dependent on the molecule studied and the mechanism by which it is absorbed in the intestine.
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http://dx.doi.org/10.1016/j.ejpb.2021.03.013DOI Listing
June 2021

The potential of porcine ex vivo platform for intestinal permeability screening of FcRn-targeted drugs.

Eur J Pharm Biopharm 2021 May 23;162:99-104. Epub 2021 Mar 23.

Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal; Instituto de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal. Electronic address:

Conventionally, the intestinal permeability of drugs is evaluated using cell monolayer models that lack morphological, physiological and architectural features, as well as realistic neonatal Fc receptor (FcRn) expression. In addition, it is time-consuming, expensive and excessive to use a large number of mice for large-scale screening of FcRn-targeted candidates. For preclinical validation, it is critical to use suitable models that mimic the human intestine; the porcine ex vivo model is widely used for intestinal permeability studies, due to its physiological and anatomical similarities to humans. This study intended to analyze the potential to measure the intestinal permeability of FcRn-targeted substances using a porcine ex vivo platform, which is able to analyze 96 samples at the same time. In addition, the platform allows the screening of FcRn-targeting substances for transmucosal delivery, taking into consideration (cross-species) receptor-ligand binding kinetics. After analyzing the morphology of the porcine tissue, the FcRn expression across the gastrointestinal tract was verified. By studying the stomach, duodenum and jejunum, it was demonstrated that FcRn expression is maintained for up to 7 days. When evaluating the duodenum permeability of free engineered human albumin variants, it was shown that the variant with the mutation K573P (KP) is more efficiently transported. Given this, the porcine ex vivo platform was revealed to be a potential model for the screening of FcRn-targeted oral drug formulations.
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http://dx.doi.org/10.1016/j.ejpb.2021.03.009DOI Listing
May 2021

Quercetin-biapigenin nanoparticles are effective to penetrate the blood-brain barrier.

Drug Deliv Transl Res 2021 Mar 11. Epub 2021 Mar 11.

Centre of Molecular and Environmental Biology (CBMA), Biology Department, Department of Biology, University of Minho, 4710-057, Braga, Portugal.

Search for efficient therapeutic agents for central nervous system (CNS) disorders has been extensive. Nevertheless, blood-brain barrier (BBB) is an obstacle that prevents the majority of compounds to act in these diseases. It is, thus, of extreme relevance the BBB overcome, in order to deliver a drugs therapeutically active concentration to the action site, with the least losses and interaction with other organs, tissues, or cells. The present study aimed to investigate the potential protective effect of quercetin-biapigenin encapsulated into poly(Ɛ-polycaprolactone) (PCL) nanoparticles against t-BOOH-induced oxidative stress in several brain cell lines, as well as evaluate the permeability of those active molecules through an in vitro BBB model. The three cell lines under study (BV-2, hcmec/D3, and U87) presented different reactions to t-BOOH. In general, quercetin-biapigenin PCL-loaded nanoparticles were able to minimize compound toxicity they convey, regardless the cell line. Quercetin-biapigenin PCL-loaded nanoparticles (Papp of approximately 80 × 10-6 cm/s) revealed to be more permeable than free compounds (Papp of approximately 50 × 10-6 cm/s). As of our knowledge, this is the first report of quercetin-biapigenin PCL-loaded nanoparticle activity in brain cells. It is also the first determining its permeability through BBB, as an effective nanocarrier for brain delivery.
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http://dx.doi.org/10.1007/s13346-021-00917-6DOI Listing
March 2021

Clotrimazole-loaded N-(2-hydroxy)-propyl-3-trimethylammonium, O-palmitoyl chitosan nanoparticles for topical treatment of vulvovaginal candidiasis.

Acta Biomater 2021 04 24;125:312-321. Epub 2021 Feb 24.

i3S - Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; INEB - Institute of Biomedical Engineering, University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal. Electronic address:

Vulvovaginal candidiasis (VVC) represents a considerable health burden for women. Despite the availability of a significant array of antifungal drugs and topical products, the management of the infection is not always effective, and new approaches are needed. Here, we explored cationic N-(2-hydroxy)-propyl-3-trimethylammonium, O-palmitoyl chitosan nanoparticles (NPs) as carriers of clotrimazole (CLT) for the topical treatment of VVC. CLT-NPs with approximately 280 nm in diameter were obtained by self-assembly in water and subsequent stabilization by ionic crosslinking with tripolyphosphate. The nanosystem featured pH-independent sustained drug release up to 24 h, which affected both in vitro anti-Candida activity and cytotoxicity. The CLT-loaded nanostructured platform yielded favorable selectivity index values for a panel of standard strains and clinical isolates of Candida spp. and female genital tract cell lines (HEC-1-A, Ca Ski and HeLa), as compared to the free drug. CLT-NPs also improved in vitro drug permeability across HEC-1-A and Ca Ski cell monolayers, thus suggesting that the nanocarrier may provide higher mucosal tissue levels of the active compound. Overall, data support that CLT-NPs may be a valuable asset for the topical treatment of VVC. STATEMENT OF SIGNIFICANCE: Topical azoles such as clotrimazole (CLT) are first line antifungal drugs for the management of vulvovaginal candidiasis (VVC), but their action may be limited by issues such as toxicity and poor capacity to penetrate the genital mucosa. Herein, we report on the ability of a new cationic N-(2‑hydroxy)-propyl-3-trimethylammonium, O-dipalmitoyl chitosan derivative (DPCat35) to yield tripolyphosphate-reinforced micelle-like nanostructures that are suitable carriers for CLT. In particular, these nanosystems were able to improve the in vitro selectivity index of the drug and to provide enhanced epithelial drug permeability when tested in cell monolayer models. These data support that CLT-loaded DPCat35 nanoparticles feature favorable properties for the development of new nanomedicines for the topical management of VVC.
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http://dx.doi.org/10.1016/j.actbio.2021.02.029DOI Listing
April 2021

Antagonizing the spindle assembly checkpoint silencing enhances paclitaxel and Navitoclax-mediated apoptosis with distinct mechanistic.

Sci Rep 2021 Feb 18;11(1):4139. Epub 2021 Feb 18.

CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Rua Central da Gandra 1317, Gandra, 4585-116, Paredes, Portugal.

Antimitotic drugs arrest cells in mitosis through chronic activation of the spindle assembly checkpoint (SAC), leading to cell death. However, drug-treated cancer cells can escape death by undergoing mitotic slippage, due to premature mitotic exit. Therefore, overcoming slippage issue is a promising chemotherapeutic strategy to improve the effectiveness of antimitotics. Here, we antagonized SAC silencing by knocking down the MAD2-binding protein p31, to delay mitotic slippage, and tracked cancer cells treated with the antimitotic drug paclitaxel, over 3 days live-cell time-lapse analysis. We found that in the absence of p31, the duration of mitotic block was increased in cells challenged with nanomolar concentrations of paclitaxel, leading to an additive effects in terms of cell death which was predominantly anticipated during the first mitosis. As accumulation of an apoptotic signal was suggested to prevent mitotic slippage, when we challenged p31-depleted mitotic-arrested cells with the apoptosis potentiator Navitoclax (previously called ABT-263), cell fate was shifted to accelerated post-mitotic death. We conclude that inhibition of SAC silencing is critical for enhancing the lethality of antimitotic drugs as well as that of therapeutic apoptosis-inducing small molecules, with distinct mechanisms. The study highlights the potential of p31 as a target for antimitotic therapies.
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http://dx.doi.org/10.1038/s41598-021-83743-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893169PMC
February 2021

A nanoemulsion/micelles mixed nanosystem for the oral administration of hydrophobically modified insulin.

Drug Deliv Transl Res 2021 Apr 11;11(2):524-545. Epub 2021 Feb 11.

Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, Spain.

The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.
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http://dx.doi.org/10.1007/s13346-021-00920-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987602PMC
April 2021

In Vitro Assays for Nanoparticle-Cancer Cell Interaction Studies.

Adv Exp Med Biol 2021 ;1295:223-242

i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.

Nanotechnology is a rapid-growing field with an extreme potential to revolutionize cancer treatments. However, despite the rapid advances, the clinical translation is still scarce. One of the main hurdles contributing for this setback is the lack of reliable in vitro models for preclinical testing capable of predicting the outcomes in an in vivo setting. In fact, the use of 2D monolayers, considered the gold-standard in vitro technique, leads to the creation of misleading data that might not be completely observed in in vivo or clinical setting. Thus, there is the need to use more complex models capable of better mimicking the tumor microenvironment. For that purpose, the development and use of multicellular tumor spheroids, three-dimensional (3D) cell cultures which recapitulate numerous aspects of the tumors, represents an advantageous approach to test the developed anticancer therapies. In this chapter, we identify and discuss the advantages of the use of these 3D cellular models compared to the 2D models and how they can be utilized to study nanoparticle-cancer cell interaction in a more reliable way to predict the treatment outcome in vivo.
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http://dx.doi.org/10.1007/978-3-030-58174-9_10DOI Listing
February 2021

The Mad2-Binding Protein p31comet as a potential target for human cancer therapy.

Curr Cancer Drug Targets 2021 Jan 28. Epub 2021 Jan 28.

Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, CESPU, Gandra. Portugal.

The spindle assembly checkpoint (SAC) is a surveillance mechanism that prevents mitotic exit at the metaphase-to-anaphase transition until all chromosomes have established correct bipolar attachment to spindle microtubules. Activation of SAC relies on the assembly of the mitotic checkpoint complex (MCC), which requires conformational change from inactive open Mad2 (O-Mad2) to the active closed Mad2 (C-Mad2) at unattached kinetochores. The Mad2-binding protein p31comet plays a key role in controlling timely mitotic exit by promoting SAC silencing, through preventing Mad2 activation and promoting MCC disassembly. Besides, increasing evidences highlight the p31comet potential as target for cancer therapy. Here, we provide an updated overview of the functional significance of p31comet in mitotic progression, and discuss the potential of deregulated expression of p31comet in cancer and in therapeutic strategies.
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http://dx.doi.org/10.2174/1568009621666210129095726DOI Listing
January 2021

Third-generation solid dispersion combining Soluplus and poloxamer 407 enhances the oral bioavailability of resveratrol.

Int J Pharm 2021 Feb 21;595:120245. Epub 2021 Jan 21.

INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde and Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, 4585-116, Gandra, Portugal. Electronic address:

Resveratrol is a very promising anti-oxidant drug candidate with low oral bioavailability due to its intrinsic poor water solubility, intestinal efflux and metabolization mechanisms. Resveratrol solubility high-throughput screening with different carriers was performed showing an enhancement above 2000-fold with Soluplus® and Tween® 80. The former was selected as a carrier at the ratio of resveratrol: Soluplus® (1:2). Then, third-generation solid dispersions were developed with Gelucire® and poloxamer 407 at 5 and 15% to resveratrol: Soluplus® (1:2). All formulations enhanced solubility around 2-fold when compared to resveratrol: Soluplus® (1:2) solid dispersion. Caco-2 cells permeability studies showed that both surfactants increased drug permeability and the fraction recovered (2-fold) suggesting that these could reduce efflux mechanism and metabolism. Formulation with 15% poloxamer 407 demonstrated most promising results and was selected for further studies. In in vivo studies, resveratrol:Soluplus®: poloxamer 407 (1:2-15%) third generation solid dispersion presented an AUCo-t of 279 ± 54 ng.h/mL and a Cmax of 134 ± 78 ng/mL, 2.5 fold higher than solid dispersion without poloxamer 407. This work reports the development of third-generation solid dispersion that significantly improved resveratrol bioavailability. This was accomplished by an increased solubility and most probably by reducing intestinal efflux and metabolism mechanisms.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120245DOI Listing
February 2021

Polymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo.

J Control Release 2021 Mar 20;331:198-212. Epub 2021 Jan 20.

Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Zaragoza, Spain. Electronic address:

Colorectal cancer (CRC) is a highly prevalent disease worldwide. Patient survival is hampered by tumor relapse and the appearance of drug-resistant metastases, which are sustained by the presence of cancer stem cells (CSC). Specific delivery of anti-CSC chemotherapeutic drugs to tumors by using targeted drug delivery systems that can also target CSC sub-population might substantially improve current clinical outcomes. CD44v6 is a robust biomarker for advanced CRC and CSC, due to its functional role in tumorigenesis and cancer initiation process. Here, we show that CD44v6-targeted polymeric micelles (PM) loaded with niclosamide (NCS), a drug against CSC, is a good therapeutic strategy against colorectal CSC and circulating tumor cells (CTC) in vivo. HCT116 cells were sorted according to their CD44v6 receptor expression into CD44v6+ (high) and CDv44v6- (low) subpopulations. Accordingly, CD44v6+ cells presented stemness properties, such as overexpression of defined stemness markers (ALDH1A1, CD44v3 and CXCR4) and high capacity to form colonspheres in low attachment conditions. NCS-loaded PM functionalized with an antibody fragment against CD44v6 (Fab-CD44v6) presented adequate size, charge, and encapsulation efficiency. In addition, Fab-CD44v6 significantly increased PM internalization in CD44v6+ cells. Further, encapsulation of NCS improved its effectiveness in vitro, particularly against colonspheres, and allowed to increase its intravenous dosage in vivo by increasing the amount of NCS able to be administered without causing toxicity. Remarkably, functionalized PM accumulate in tumors and significantly reduce CTC in vivo. In conclusion, CD44v6 targeted PM meet the essential conditions to become an efficient anti-CSC therapy.
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http://dx.doi.org/10.1016/j.jconrel.2021.01.022DOI Listing
March 2021

Influence of Plasticizers on the pH-Dependent Drug Release and Cellular Interactions of Hydroxypropyl Methylcellulose/Zein Vaginal Anti-HIV Films Containing Tenofovir.

Biomacromolecules 2021 02 6;22(2):938-948. Epub 2021 Jan 6.

Departamento de Farmacia Galénica y Tecnología Alimentaria, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.

Vaginal films featuring the pH-dependent release of tenofovir (TFV) were developed for the prevention of sexual transmission of human immunodeficiency syndrome (HIV). Films based on hydroxypropyl methylcellulose and zein were prepared incorporating different plasticizers [oleic acid, lactic acid, glycerol, and polyethylene glycol 400 (PEG)] and evaluated for drug release in an acidic simulated vaginal fluid (pH 4.2) and a slightly alkaline mixture of simulated seminal and vaginal fluids (pH 7.5). Results revealed that optimal biphasic TFV release was possible with proper combination of plasticizers (PEG and oleic acid, 1:7 w/w) and by adjusting the plasticizer/matrix-forming material ratio. The films had similar or higher levels of TFV associated with genital epithelial cells (Ca Ski or HEC-1-A cells) but lower drug permeability compared to the free drug. These data confirm that films have the potential to achieve suitable mucosal levels of TFV with low systemic exposure. The films developed could protect women from HIV sexual transmission.
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http://dx.doi.org/10.1021/acs.biomac.0c01609DOI Listing
February 2021

Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity.

Int J Mol Sci 2020 Dec 29;22(1). Epub 2020 Dec 29.

OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal.

Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group recently reported that Tacrine, used to treat Alzheimer's Disease, inhibits the growth of breast cancer MCF-7 cells both alone and in combination with a reference drug. In this view, we have now coupled Tacrine with the model amphipathic cell-penetrating peptide (CPP) MAP, to ascertain whether coupling of the CPP might enhance the drug's antiproliferative properties. To this end, we synthesized MAP through solid-phase peptide synthesis, coupled it with Tacrine, and made a comparative evaluation of the parent drug, peptide, and the conjugate regarding their permeability across the blood-brain barrier (BBB), ability to inhibit acetylcholinesterase (AChE) in vitro, and antiproliferative activity on cancer cells. Both MAP and its Tacrine conjugate were highly toxic to MCF-7 and SH-SY5Y cells. In turn, BBB-permeability studies were inconclusive, and conjugation to the CPP led to a considerable loss of Tacrine function as an AChE inhibitor. Nonetheless, this work reinforces the potential of repurposing Tacrine for cancer and enhances the antiproliferative activity of this drug through its conjugation to a CPP.
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http://dx.doi.org/10.3390/ijms22010242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795729PMC
December 2020

Development of pH-sensitive vaginal films based on methacrylate copolymers for topical HIV-1 pre-exposure prophylaxis.

Acta Biomater 2021 02 14;121:316-327. Epub 2020 Dec 14.

Departamento de Farmacia Galénica y Tecnología Alimentaria, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040-Madrid, Spain.

Interest is growing in "smart" vaginal microbicides as a strategy to protect women from sexual transmission of human immunodeficiency virus (HIV). The concept is based on the development of products featuring low drug release in acidic media such as vaginal fluid but switch to a fast release profile when the medium becomes neutral or slightly alkaline. This mimics the surge in pH occurring in the vagina after sexual intercourse due to the seminal fluid. Semen is the main vehicle for HIV-1, and increasing antiretroviral drug levels in the vagina upon ejaculation may contribute to enhanced protection against viral sexual transmission. This work explores the use of different pharmaceutical-grade methacrylic acid-based polymers (Eudragit RL, RS, L and S) for developing vaginal films allowing the pH-dependant release of the antiretroviral drug tenofovir (TFV). Eudragit L 100 and Eudragit S 100, containing triethyl citrate as plasticiser, proved to be suitable for manufacturing films with optimal dual in vitro drug-release behaviour. TFV-release can be sustained for several days after film administration and all the drug is released in a few hours in conditions simulating ejaculation. The films' mechanical properties were also deemed suitable for comfortable vaginal administration. Two optimized films were further assessed using HEC-1-A and Ca Ski cell monolayer models and were found to possess favourable drug permeability profiles and drug levels associated to cell monolayer as compared to free TFV. Overall, pH-dependant films containing tenofovir may constitute promising candidates for "smart" vaginal microbicides to protect women from sexual HIV transmission.
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http://dx.doi.org/10.1016/j.actbio.2020.12.019DOI Listing
February 2021

The roles of vitamin D and cathelicidin in type 1 diabetes susceptibility.

Endocr Connect 2021 Jan;10(1):R1-R12

CEB - Centro de Engenharia Biológica, Universidade do Minho, Braga, Portugal.

Type 1 diabetes has an increasingly greater incidence and prevalence with no cure available. Vitamin D supplementation is well documented to reduce the risk of developing type 1 diabetes. Being involved in the modulation of cathelicidin expression, the question whether cathelicidin may be one of the underlying cause arises. Cathelicidin has been implicated in both the development and the protection against type 1 diabetes by mediating the interplay between the gut microbiome, the immune system and β cell function. While its potential on type 1 diabetes treatment seems high, the understanding of its effects is still limited. This review aims to contribute to a more comprehensive understanding of the potential of vitamin D and cathelicidin as adjuvants in type 1 diabetes therapy.
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http://dx.doi.org/10.1530/EC-20-0484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923048PMC
January 2021

Tissue-specific engineering: 3D bioprinting in regenerative medicine.

J Control Release 2021 Jan 28;329:237-256. Epub 2020 Nov 28.

Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, PR China. Electronic address:

Despite its complexity, the human body is composed of only four basic tissue types, namely epithelial, connective, muscular and nervous tissues. Notably, each tissue is an assemblage of similarly functional cells united in performing a specific function. Instead of mimicking functionality mechanically, three-dimensional (3D) bioprinting based on histological categories is a strategy designed with multiple materials and techniques, which is a versatile technology able to form functional organ structures in line with simplicity. This review aims to provide an overview of tissue-specific 3D bioprinting based on the biological characteristics of four tissue types, including the histological features, biomaterials and corresponding applications. It first briefly introduces the goals of tissue-specific bioprinting and then summarizes the major techniques and identification of particular material development. Moreover, its remarkable regenerative power in replacement therapy and novel outbreak in particular tissues are assembled by epithelial, connective, nerve and muscle tissues. Finally, we discuss challenges and future prospects of tissue-specific based 3D bioprinting in biomedicine, hoping to further inspire the development.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.044DOI Listing
January 2021

Lipid nanoparticles coated with chitosan using a one-step association method to target rifampicin to alveolar macrophages.

Carbohydr Polym 2021 Jan 24;252:116978. Epub 2020 Sep 24.

LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal. Electronic address:

This work proposes the development and characterization of solid lipid nanoparticles (SLNs) loaded with rifampicin (RIF) aiming to enhance mucoadhesion of the SLNs and consequently internalization by the alveolar macrophages (AMs). The lipid nanoparticles (NPs) were characterized and the results showed that the NPs obtained present a spherical or a starry shape with diameter around 250-500 nm, a monodisperse population, with zeta potential between -31 mV for uncoated SLNs and +33 mV for coated SLNs. The drug EE was approximately 90 % and the loading capacity (LC) 4.5 %. The SLNs coated with chitosan by the association method (aC-SLNs) show an effective mucoadhesive profile, verified by the turdimetry and surface loading method, corroborated with the cellular assays. The presence of chitosan in the aC-SLNs promotes higher mucoadhesive properties to the NPs and permeability in A549, suggesting that the safe aC-SLNs-RIF can be used as a promising drug delivery system for improving tuberculosis treatment.
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http://dx.doi.org/10.1016/j.carbpol.2020.116978DOI Listing
January 2021

Emerging trends in nano- and microencapsulation science: hallmarks of the 22 International Symposium on Microencapsulation.

Drug Deliv Transl Res 2020 12 23;10(6):1535-1536. Epub 2020 Oct 23.

i3S - Instituto de Investigação e Inovação em Saúde & INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal.

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http://dx.doi.org/10.1007/s13346-020-00865-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583686PMC
December 2020

Development of an Improved 3D Intestinal Model to Perform Permeability Studies of Paracellular Compounds.

Front Bioeng Biotechnol 2020 17;8:524018. Epub 2020 Sep 17.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.

The small intestine is the primary site of drug absorption following oral administration, making paramount the proper monitoring of the absorption process. tools to predict intestinal absorption are particularly important in preclinical drug development since they are less laborious and cost-intensive and raise less ethical considerations compared to studies. The Caco-2 model is considered the gold standard of intestinal models regarding the prediction of absorption of orally delivered compounds. However, this model presents several drawbacks, such as the expression of tighter tight junctions, not being suitable to perform permeability of paracellular compounds. Besides, cells are representative of only one intestinal cell type, without considering the role of non-absorptive cells on the absorption pathway of drugs. In the present study, we developed a new three-dimensional (3D) intestinal model that aims to bridge the gap between tools and animal studies. Our 3D model comprises a collagen layer with human intestinal fibroblasts (HIFs) embedded, mimicking the intestinal lamina propria and providing 3D support for the epithelium, composed of Caco-2 cells and mucus-producing HT29-MTX cells, creating a model that can better resemble, both in terms of composition and regarding the outcomes of drug permeability when testing paracellular compounds, the human small intestine. The optimization of the collagen layer with HIFs was performed, testing different collagen concentrations and HIF seeding densities in order to avoid collagen contraction before day 14, maintaining HIF metabolically active inside the collagen disks during time in culture. HIF morphology and extracellular matrix (ECM) deposition were assessed, confirming that fibroblasts presented a normal and healthy elongated shape and secreted fibronectin and laminin, remodeling the collagen matrix. Regarding the epithelial layer, transepithelial electrical resistance (TEER) values decreased when cells were in the 3D configuration, comparing with the 2D analogs (Caco-2 and coculture of Caco-2+HT29-MTX models), becoming more similar with values. The permeability assay with fluorescein isothiocyanate (FITC)-Dextran 4 kDa showed that absorption in the 3D models is significantly higher than that in the 2D models, confirming the importance of using a more biorelevant model when testing the paracellular permeability of compounds.
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http://dx.doi.org/10.3389/fbioe.2020.524018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527803PMC
September 2020

Building three-dimensional lung models for studying pharmacokinetics of inhaled drugs.

Adv Drug Deliv Rev 2021 03 22;170:386-395. Epub 2020 Sep 22.

i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; INEB, Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central da Gandra 1317, 4585-116 Gandra, Portugal. Electronic address:

Drug development is a critical step in the development pipeline of pharmaceutical industry, commonly performed in traditional cell culture and animal models. Though, those models hold critical gapsin the prediction and the translation of human pharmacokinetic (PK) and pharmacodynamics (PD) parameters. The advances in tissue engineering have allowed the combination of cell biology with microengineering techniques, offering alternatives to conventional preclinical models. Organ-on-a-chips and three-dimensional (3D) bioprinting models present the potentialityof simulating the physiological and pathological microenvironment of living organs and tissues, constituting this way,more realistic models for the assessment of absorption, distribution, metabolism and excretion (ADME) of drugs. Therefore, this review will focus on lung-on-a-chip and 3D bioprinting techniques for developing lung models that can be usedfor predicting PK/PD parameters.
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http://dx.doi.org/10.1016/j.addr.2020.09.008DOI Listing
March 2021

Advances on erythrocyte-mimicking nanovehicles to overcome barriers in biological microenvironments.

Adv Drug Deliv Rev 2021 03 15;170:312-339. Epub 2020 Sep 15.

I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal. Electronic address:

Although nanocarriers offer many advantages as drug delivery systems, their poor stability in circulation, premature drug release and nonspecific uptake in non-target organs have prompted biomimetic approaches using natural cell membranes to camouflage nanovehicles. Among them, erythrocytes, representing the most abundant blood circulating cells, have been extensively investigated for biomimetic coating on artificial nanocarriers due to their upgraded biocompatibility, biodegradability, non-immunogenicity and long-term blood circulation. Due to the cell surface mimetic properties combined with customized core material, erythrocyte-mimicking nanovehicles (EM-NVs) have a wide variety of applications, including drug delivery, imaging, phototherapy, immunomodulation, sensing and detection, that foresee a huge potential for therapeutic and diagnostic applications in several diseases. In this review, we summarize the recent advances in the biomedical applications of EM-NVs in cancer, infection, heart-, autoimmune- and CNS-related disorders and discuss the major challenges and opportunities in this research area.
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http://dx.doi.org/10.1016/j.addr.2020.09.001DOI Listing
March 2021