Enzyme Powered Nanomotors Towards Biomedical Applications

[eng] The advancements in nanotechnology enabled the development of new diagnostic tools and drug delivery systems based on nanosystems, which offer unique features such as large surface area to volume ratio, cargo loading capabilities, increased circulation times, as well as versatility and multifunctionality. Despite this, the majority of nanomedicines do not translate into clinics, in part due to the biological barriers present in the body. Synthetic nano- and micromotors could be an alternative tool in nanomedicine, as the continuous propulsion force and potential to modulate the medium may aid tissue penetration and drug diffusion across biological barriers. Enzyme-powered motors are especially interesting for biomedical applications, owing to their biocompatibility and use of bioavailable substrates as fuel for propulsion. This thesis aims at exploring the potential applications of urease-powered nanomotors in nanomedicine. In the first work, we evaluated these motors as drug delivery systems. We found that active urease- powered nanomotors showed active motion in phosphate buffer solutions, and enhanced in vitro drug release profiles in comparison to passive nanoparticles. In addition, we observed that the motors were more efficient in delivering drug to cancer cells and caused higher toxicity levels, due to the combination of boosted drug release and local increase of pH produced by urea breakdown into ammonia and carbon dioxide. One of the major goals in nanomedicine is to achieve localized drug action, thus reducing side-effects. A commonly strategy to attain this is the use moieties to target specific diseases. In our second work, we assessed the ability of urease-powered nanomotors to improve the targeting and penetration of spheroids, using an antibody with therapeutic potential. We showed that the combination of active propulsion with targeting led to a significant increase in spheroid penetration, and that this effect caused a decrease in cell proliferation due to the antibody’s therapeutic action. Considering that high concentrations of nanomedicines are required to achieve therapeutic efficiency; in the third work we investigated the collective behavior of urease-powered nanomotors. Apart from optical microscopy, we evaluated the tracked the swarming behavior of the nanomotors using positron emission tomography, which is a technique widely used in clinics, due to its noninvasiveness and ability to provide quantitative information. We showed that the nanomotors were able to overcome hurdles while swimming in confined geometries. We observed that the nanomotors swarming behavior led to enhanced fluid convection and mixing both in vitro, and in vivo within mice’s bladders. Aiming at conferring protecting abilities to the enzyme-powered nanomotors, in the fourth work, we investigated the use of liposomes as chassis for nanomotors, encapsulating urease within their inner compartment. We demonstrated that the lipidic bilayer provides the enzymatic engines with protection from harsh acidic environments, and that the motility of liposome-based motors can be activated with bile salts. Altogether, these results demonstrate the potential of enzyme-powered nanomotors as nanomedicine tools, with versatile chassis, as well as capability to enhance drug delivery and tumor penetration. Moreover, their collective dynamics in vivo, tracked using medical imaging techniques, represent a step-forward in the journey towards clinical translation.[spa] Recientes avances en nanotecnología han permitido el desarrollo de nuevas herramientas para el diagnóstico de enfermedades y el transporte dirigido de fármacos, ofreciendo propiedades únicas como encapsulación de fármacos, el control sobre la biodistribución de estos, versatilidad y multifuncionalidad. A pesar de estos avances, la mayoría de nanomedicinas no consiguen llegar a aplicaciones médicas reales, lo cual es en parte debido a la presencia de barreras biológicas en el organismo que limitan su transporte hacia los tejidos de interés. En este sentido, el desarrollo de nuevos micro- y nanomotores sintéticos, capaces de autopropulsarse y causar cambios locales en el ambiente, podrían ofrecer una alternativa para la nanomedicina, promoviendo una mayor penetración en tejidos de interés y un mejor transporte de fármacos a través de las barreras biológicas. En concreto, los nanomotores enzimáticos poseen un alto potencial para aplicaciones biomédicas gracias a su biocompatibilidad y a la posibilidad de usar sustancias presentes en el organismo como combustible. Los trabajos presentados en esta tesis exploran el potenical de nanomotores, autopropulsados mediante la enzima ureasa, para aplicaciones biomédicas, y investigan su uso como vehículos para transporte de fármacos, su capacidad para mejorar penetración de tejidos diana, su versatilidad y movimiento colectivo. En conjunto, los resultados presentados en esta tesis doctoral demuestran el potencial del uso de nanomotores autopropulsados mediante enzimas como herramientas biomédicas, ofreciendo versatilidad en su diseño y una alta capacidad para promover el transporte de fármacos y la penetración en tumores. Por último, su movimiento colectivo observado in vivo mediante técnicas de imagen médicas representan un significativo avance en el viaje hacia su aplicación en medicina

Magnetically Assisted Capsule Endoscopy: A Viable Alternative to Conventional Flexible Endoscopy of the Stomach?

INTRODUCTION: Oesophagogastroduodenoscopy is the investigation of choice to identify mucosal lesions of the upper gastrointestinal tract, but it is poorly tolerated by patients. A simple non-invasive technique to image the upper gastrointestinal tract, which could be made widely available, would be beneficial to patients. Capsule endoscopy is well tolerated by patients but the stomach has proved difficult to visualise accurately with capsule technology due to its’ capacious nature and mucosal folds, which can obscure pathology. MiroCam Navi (Intromedic Ltd, Seoul, Korea) is a capsule endoscope containing a small amount of magnetic material which has been made available with a handheld magnet which might allow a degree of control. This body of work aims to address whether this new technology could be a feasible alternative to conventional flexible endoscopy of the stomach. METHODS: Four studies were conducted to test this research question. The first explores the feasibility of magnetically assisted capsule endoscopy of the stomach and operator learning curve in an ex vivo porcine model. This was followed by a randomised, blinded trial comparing magnetically assisted capsule endoscopy to conventional flexible endoscopy in ex vivo porcine stomach models. Subsequently a prospective, single centre randomised controlled trial in humans examined whether magnetically assisted capsule endoscopy could enhance conventional small bowel capsule endoscopy by reducing gastric transit time. Finally a blinded comparison of diagnostic yield of magnetically assisted capsule endoscopy compared to oesophagogastroduodenoscopy was performed in patients with recurrent or refractory iron deficiency anaemia. RESULTS: In the first study all stomach tags were identified in 87.2% of examinations and a learning curve was demonstrated (mean examination times for the first 23 and second 23 procedures 10.28 and 6.26 minutes respectively (p<0.001). In the second study the difference in sensitivities between oesophagogastroduodenoscopy and conventional flexible endoscopy for detecting beads within an ex vivo porcine stomach model was 1.11 (95% CI 0.06, 28.26) proving magnetically assisted capsule endoscopy to be non-inferior to flexible endoscopy. In the first human study, although there was no significant difference in gastric transit time or capsule endoscopy completion rate between the two groups (p=0.12 and p=0.39 respectively), the time to first pyloric image was significantly shorter in the intervention group (p=0.03) suggesting that magnetic control hastens capsular transit to the gastric antrum but cannot impact upon duodenal passage. In the last study, a total of 38 pathological findings were identified in this comparative study of magnetically assisted capsule endoscopy and conventional endoscopy. Of these, 16 were detected at both procedures, while flexible endoscopy identified 14 additional lesions not seen at magnetically assisted capsule endoscopy and magnetically assisted capsule endoscopy detected 8 abnormalities not seen by oesophagogastroduodenoscopy. No adverse events occurred in either of the human trials. Finally magnetically steerable capsule endoscopy induced less procedural pain, discomfort and distress than oesophagogastroduodenoscopy (p=0.0009, p=0.001 and p=0.006 respectively). CONCLUSION: Magnetically assisted capsule endoscopy is safe, well tolerated and a viable alternative to conventional endoscopy. Further research to develop and improve this new procedure is recommended

Current status and advances in esophageal drug delivery technology:influence of physiological, pathophysiological and pharmaceutical factors

Diseases affecting the esophagus are common. However, targeted drug delivery to the esophagus is challenging due to the anatomy and physiology of this organ. Current pharmacological treatment for esophageal diseases predominantly relies on the off-label use of drugs in various dosage forms, including those for systemic drug delivery (e.g. oral tablets, sublingual tablets, and injections) and topical drug delivery (e.g. metered dose inhaler, viscous solution or suspension, and endoscopic injection into the esophagus). In general, systemic therapy has shown the most efficacy but requires the use of high drug doses to achieve effective concentrations in the esophagus, which increases the risk of adverse effects and toxicity. Topical drug delivery has enormous potential in improving the way we treat patients with acute and chronic esophageal diseases, especially those requiring drugs that have low therapeutic index and/or significant adverse effects to non-targeted organs and tissues. This review will address the physiological, pathophysiological, and pharmaceutical considerations influencing topical drug delivery in the esophagus. The main conventional (e.g. liquid formulations, orodispersible tablets, lozenges, pastilles, troches, chewing gum) and innovative (e.g. stent-based, film-based, nanoparticulate-based) drug delivery approaches will be comprehensively discussed, along with the developments to improve their effectiveness for topical esophageal drug delivery. The translational challenges and future clinical advances of this research will also be discussed.</p

Nanoprobes for Tumor Theranostics

This book reports cutting-edge technology in nanoprobes or nanobiomaterials used for the accurate diagnosis and therapy of tumors, involving a multidisciplinary of chemistry, materials science, oncology, biology, and medicine

New Techniques in Gastrointestinal Endoscopy

As result of progress, endoscopy has became more complex, using more sophisticated devices and has claimed a special form. In this moment, the gastroenterologist performing endoscopy has to be an expert in macroscopic view of the lesions in the gut, with good skills for using standard endoscopes, with good experience in ultrasound (for performing endoscopic ultrasound), with pathology experience for confocal examination. It is compulsory to get experience and to have patience and attention for the follow-up of thousands of images transmitted during capsule endoscopy or to have knowledge in physics necessary for autofluorescence imaging endoscopy. Therefore, the idea of an endoscopist has changed. Examinations mentioned need a special formation, a superior level of instruction, accessible to those who have already gained enough experience in basic diagnostic endoscopy. This is the reason for what these new issues of endoscopy are presented in this book of New techniques in Gastrointestinal Endoscopy

6th Iberian Meeting of Colloids and Interfaces - RIC16: book of abstracts

info:eu-repo/semantics/publishedVersio

Current status and advances in esophageal drug delivery technology: influence of physiological, pathophysiological and pharmaceutical factors

Diseases affecting the esophagus are common. However, targeted drug delivery to the esophagus is challenging due to the anatomy and physiology of this organ. Current pharmacological treatment for esophageal diseases predominantly relies on the off-label use of drugs in various dosage forms, including those for systemic drug delivery (e.g. oral tablets, sublingual tablets, and injections) and topical drug delivery (e.g. metered dose inhaler, viscous solution or suspension, and endoscopic injection into the esophagus). In general, systemic therapy has shown the most efficacy but requires the use of high drug doses to achieve effective concentrations in the esophagus, which increases the risk of adverse effects and toxicity. Topical drug delivery has enormous potential in improving the way we treat patients with acute and chronic esophageal diseases, especially those requiring drugs that have low therapeutic index and/or significant adverse effects to non-targeted organs and tissues. This review will address the physiological, pathophysiological, and pharmaceutical considerations influencing topical drug delivery in the esophagus. The main conventional (e.g. liquid formulations, orodispersible tablets, lozenges, pastilles, troches, chewing gum) and innovative (e.g. stent-based, film-based, nanoparticulate-based) drug delivery approaches will be comprehensively discussed, along with the developments to improve their effectiveness for topical esophageal drug delivery. The translational challenges and future clinical advances of this research will also be discussed

Progenitor cells in auricular cartilage demonstrate promising cartilage regenerative potential in 3D hydrogel culture

The reconstruction of auricular deformities is a very challenging surgical procedure that could benefit from a tissue engineering approach. Nevertheless, a major obstacle is presented by the acquisition of sufficient amounts of autologous cells to create a cartilage construct the size of the human ear. Extensively expanded chondrocytes are unable to retain their phenotype, while bone marrow-derived mesenchymal stromal cells (MSC) show endochondral terminal differentiation by formation of a calcified matrix. The identification of tissue-specific progenitor cells in auricular cartilage, which can be expanded to high numbers without loss of cartilage phenotype, has great prospects for cartilage regeneration of larger constructs. This study investigates the largely unexplored potential of auricular progenitor cells for cartilage tissue engineering in 3D hydrogels

Inflammatory Bowel Disease

This book is dedicated to inflammatory bowel disease, and the authors discuss the advances in the pathogenesis of inflammatory bowel disease, as well as several new parameters involved in the etiopathogeny of Crohn's disease and ulcerative colitis, such as intestinal barrier dysfunction and the roles of TH 17 cells and IL 17 in the immune response in inflammatory bowel disease. The book also focuses on several relevant clinical points, such as pregnancy during inflammatory bowel disease and the health-related quality of life as an end point of the different treatments of the diseases. Finally, advances in management of patients with inflammatory bowel disease are discussed, especially in a complete review of the recent literature