Preparation and development of new bioactive resorbable polymeric systems loaded with bemiparin for drug delivery and tissue engineering

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Orgánica. Fecha de lectura: 22-07-201

Successes and Challenges: Inhaled Treatment Approaches Using Magnetic Nanoparticles in Cystic Fibrosis

Magnetic nanoparticles have been largely applied to increase the e cacy of antibiotics due to passive accumulation provided by enhancing permeability and retention, which is essential for the treatment of lung infections. Recurring lung infections such as in the life-shortening genetic disease cystic fibrosis (CF) are a major problem. The recent advent of the CF modulator drug ivacaftor, alone or in combination with lumacaftor or tezacaftor, has enabled systemic treatment of the majority of patients. Magnetic nanoparticles (MNPs) show unique properties such as biocompatibility and biodegradability as well as magnetic and heat-medicated characteristics. These properties make them suitable to be used as drug carriers and hyperthermia-based agents. Hyperthermia is a promising approach for the thermal activation therapy of several diseases, including pulmonary diseases. The benefits of delivering CF drugs via inhalation using MNPs as drug carriers a ord application of su cient therapeutic dosages directly to the primary target site, while avoiding potential suboptimal pharmacokinetics/pharmacodynamics and minimizing the risks of systemic toxicity. This review explores the multidisciplinary approach of using MNPs as vehicles of drug delivery. Additionally, we highlight advantages such as increased drug concentration at disease site, minimized drug loss and the possibility of specific cell targeting, while addressing major challenges for this emerging field.University of MelbourneNational Health and Medical Research Council of Australi

Ocular development after highly effective modulator treatment early in life

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered

Hyperthermia-Triggered Doxorubicin Release from Polymer-Coated Magnetic Nanorods

In this paper, it is proposed that polymer-coated magnetic nanorods (MNRs) can be used with the advantage of a double objective: first, to serve as magnetic hyperthermia agents, and second, to be used as magnetic vehicles for the antitumor drug doxorubicin (DOX). Two di erent synthetic methodologies (hydrothermal and co-precipitation) were used to obtain MNRs of maghemite and magnetite. They were coated with poly(ethyleneimine) and poly(sodium 4-styrenesulfonate), and loaded with DOX, using the Layer-by-Layer technique. Evidence of the polymer coating and the drug loading was justified by ATR-FTIR and electrophoretic mobility measurements, and the composition of the coated nanorods was obtained by a thermogravimetric analysis. The nanorods were tested as magnetic hyperthermia agents, and it was found that they provided sufficiently large heating rates to be used as adjuvant therapy against solid tumors. DOX loading and release were determined by UV-visible spectroscopy, and it was found that up to 50% of the loaded drug was released in about 5 h, although the rate of release could be regulated by simultaneous application of hyperthermia, which acts as a sort of external release-trigger. Shape control offers another physical property of the particles as candidates to interact with tumor cells, and particles that are not too elongated can easily find their way through the cell membrane.This research work is supported by Junta de Andalucía (PE2012-FQM694); Feder Funds UE; and MINECO Ramón y Cajal programme (RYC-2014-16901)

Advantages and Disadvantages of Using Magnetic Nanoparticles for the Treatment of Complicated Ocular Disorders

Nanomaterials provide enormous opportunities to overcome the limitations of conventional ocular delivery systems, such as low therapeutic efficacy, side effects due to the systemic exposure, or invasive surgery. Apart from the more common ocular disorders, there are some genetic diseases, such as cystic fibrosis, that develop ocular disorders as secondary effects as long as the disease progresses. These patients are more difficult to be pharmacologically treated using conventional drug routes (topically, systemic), since specific pharmacological formulations can be incompatible, display increased toxicity, or their therapeutic efficacy decreases with the administration of different kind of chemical molecules. Magnetic nanoparticles can be used as potent drug carriers and magnetic hyperthermia agents due to their response to an external magnetic field. Drugs can be concentrated in the target point, limiting the damage to other tissues. The other advantage of these magnetic nanoparticles is that they can act as magnetic resonance imaging agents, allowing the detection of the exact location of the disease. However, there are some drawbacks related to their use in drug delivery, such as the limitation to maintain efficacy in the target organ once the magnetic field is removed from outside. Another disadvantage is the difficulty in maintaining the therapeutic action in three dimensions inside the human body. This review summarizes all the application possibilities related to magnetic nanoparticles in ocular diseases.This work was funded from Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI2020) Fellowship supported by Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía co-funded by Fondo Social Europeo de Andalucía 2014–2020. Portions of this work were supported by the NHMRC Fellowship Scheme (APP1157287).Ye

Modulation of the Magnetic Hyperthermia Response Using Different Superparamagnetic Iron Oxide Nanoparticle Morphologies

Financial support from the Spanish Institutions: Mineco, (RyC-2014-16901), Ministerio de Ciencia, Innovación y Universidades (PGC2018-098770-B-I00), and Junta de Andalucía (Programa Operativo Feder 2014-2020, grants BF-FQM-141-UGR18, A1-FQM-34-UGR-18, C-FQM- 497-UGR18) is gratefully acknowledged.The use of magnetic nanoparticles in hyperthermia, that is, heating induced by alternating magnetic fields, is gaining interest as a non-invasive, free of side effects technique that can be considered as a co-adjuvant of other cancer treatments. Having sufficient control on the field characteristics, within admissible limits, the focus is presently on the magnetic material. In the present contribution, no attempt has been made of using other composition than superparamagnetic iron oxide nanoparticles (SPION), or of applying surface functionalization, which opens a wider range of choices. We have used a hydrothermal synthesis route that allows preparing SPION nanoparticles in the 40 nm size range, with spherical, cuboidal or rod-like shapes, by minor changes in the synthesis steps. The three kinds of particles (an attempt to produce star-shaped colloids yielded hematite) were demonstrated to have the magnetite (or maghemite) crystallinity. Magnetization cycles showed virtually no hysteresis and demonstrated the superparamagnetic nature of the particles, cuboidal ones displaying saturation magnetization comparable to bulk magnetite, followed by rods and spheres. The three types were used as hyperthermia agents using magnetic fields of 20 kA/m amplitude and frequency in the range 136-205 kHz. All samples demonstrated to be able to raise the solution temperature from room values to 45 degrees C in a mere 60 s. Not all of them performed the same way, though. Cuboidal magnetic nanoparticles (MNPs) displayed the maximum heating power (SAR or specific absorption rate), ranging in fact among the highest reported with these geometries and raw magnetite composition.Mineco RyC-2014-16901Ministerio de Ciencia, Innovacion y Universidades PGC2018-098770-B-I00Junta de Andalucia BF-FQM-141-UGR18 A1-FQM-34-UGR-18 C-FQM-497-UGR1

Hyperthermia-Triggered Gemcitabine Release from Polymer-Coated Magnetite Nanoparticles

In this work a combined, multifunctional platform, which was devised for the simultaneous application of magnetic hyperthermia and the delivery of the antitumor drug gemcitabine, is described and tested in vitro. The system consists of magnetite particles embedded in a polymer envelope, designed to make them biocompatible, thanks to the presence of poly (ethylene glycol) in the polymer shell. The commercial particles, after thorough cleaning, are provided with carboxyl terminal groups, so that at physiological pH they present negative surface charge. This was proved by electrophoresis, and makes it possible to electrostatically adsorb gemcitabine hydrochloride, which is the active drug of the resulting nanostructure. Both electrophoresis and infrared spectroscopy are used to confirm the adsorption of the drug. The gemcitabine-loaded particles are tested regarding their ability to release it while heating the surroundings by magnetic hyperthermia, in principle their chances as antitumor agents. The release, with first-order kinetics, is found to be faster when carried out in a thermostated bath at 43 ºC than at 37 ºC, as expected. But, the main result of this investigation is that while the particles retain their hyperthermia response, with reasonably high heating power, they release the drug faster and with zeroth-order kinetics when they are maintained at 43 ºC under the action of the alternating magnetic field used for hyperthermia.This research work is supported by MINECO Ramón y Cajal programme (RYC-2014-16901); Junta de Andalucía (PE2012-FQM694) and Feder Funds UE

Bioactive bilayered dressing for compromised epidermal tissue regeneration with sequential activity of complementary agents

The article deals with the design, preparation, and evaluation of a new bilayered dressing for application in the healing of compromised wounds. The system is based on the sequential release of two complementary bioactive components to enhance the activation of the regeneration of dermal tissue. The internal layer is a highly hydrophilic and biodegradable film of gelatin and hyaluronic acid (HG), crosslinked with the natural compound genipin, which reacts with the amine groups of gelatin. This film is loaded with the proangiogenic, anti-inflammatory, and antibacterial peptide, proadrenomedullin N-terminal 20 peptide (PAMP), that is released slowly in the wound site. The external layer, more stable and less hydrophilic, is constituted by a biodegradable polyurethane derived from poly(caprolactone) and pluronic L61. This layer is loaded with resorbable nanoparticles of bemiparin (a fractionated low molecular weight heparin), which promotes the activation of growth factors, FGF and VEGF, and provides a good biomechanical stability and controlled permeability of the bilayered dressing. Experiments carried out in mice demonstrate the excellent angiogenic effect of the HG film in the dermal tissue. Application of the bilayered dressing in the wound healing rabbit ear model shows an improved cicatrization of the wound in both ischemic and non-ischemic defects, favoring epithelialization and reducing noticeably the contraction and the inflammation.This work was supported by the CIBER-BBN and a Grant from Spain’s Ministry of Science and Education (SAF2009-13240-C02-01).Peer Reviewe

Chitosan-tripolyphosphate Nanoparticles As Arrabidaea Chica Standardized Extract Carrier: Synthesis, Characterization, Biocompatibility, And Antiulcerogenic Activity.

Natural products using plants have received considerable attention because of their potential to treat various diseases. Arrabidaea chica (Humb. & Bonpl.) B. Verlot is a native tropical American vine with healing properties employed in folk medicine for wound healing, inflammation, and gastrointestinal colic. Applying nanotechnology to plant extracts has revealed an advantageous strategy for herbal drugs considering the numerous features that nanostructured systems offer, including solubility, bioavailability, and pharmacological activity enhancement. The present study reports the preparation and characterization of chitosan-sodium tripolyphosphate nanoparticles (NPs) charged with A. chica standardized extract (AcE). Particle size and zeta potential were measured using a Zetasizer Nano ZS. The NP morphological characteristics were observed using scanning electron microscopy. Our studies indicated that the chitosan/sodium tripolyphosphate mass ratio of 5 and volume ratio of 10 were found to be the best condition to achieve the lowest NP sizes, with an average hydrodynamic diameter of 150±13 nm and a zeta potential of +45±2 mV. Particle size decreased with AcE addition (60±10.2 nm), suggesting an interaction between the extract's composition and polymers. The NP biocompatibility was evaluated using human skin fibroblasts. AcE-NP demonstrated capability of maintaining cell viability at the lowest concentrations tested, stimulating cell proliferation at higher concentrations. Antiulcerogenic activity of AcE-NP was also evaluated with an acute gastric ulcer experimental model induced by ethanol and indomethacin. NPs loaded with A. chica extract reduced the ulcerative lesion index using lower doses compared with the free extract, suggesting that extract encapsulation in chitosan NPs allowed for a dose reduction for a gastroprotective effect. The AcE encapsulation offers an approach for further application of the A. chica extract that could be considered a potential candidate for ulcer-healing pharmaceutical systems.103897-390