Poly propyl ether imine (PETIM) dendrimer: A novel non-toxic dendrimer for sustained drug delivery

In the present study, an attempt was made to study the acute and sub-acute toxicity profile of G3-COOH Poly (propyl ether imine) PETIM] dendrimer and its use as a carrier for sustained delivery of model drug ketoprofen. Drug-dendrimer complex was prepared and characterized by FTIR, solubility and in vitro drug release study. PETIM dendrimer was found to have significantly less toxicity in A541 cells compared to Poly amido amine (PAMAM) dendrimer. Further, acute and 28 days sub-acute toxicity measurement in mice showed no mortality, hematological, biochemical or histopathological changes up to 80 mg/kg dose of PETIM dendrimer. The results of study demonstrated that G3-COOH PETIM dendrimer can be used as a safe and efficient vehicle for sustained drug delivery. (C) 2010 Elsevier Masson SAS. All rights reserved.

Punctal plug: a medical device to treat dry eye syndrome and for sustained drug delivery to the eye

Punctal plugs (PPs) are miniature medical implants that were initially developed for the treatment of dry eyes. Since their introduction in 1975, many PPs made from different materials and designs have been developed. PPs, albeit generally successful, suffer from drawbacks such as epiphora and suppurative canaliculitis. To overcome these issues intelligent designs of PPs were proposed (e.g. SmartPLUG™ and Form Fit™). PPs are also gaining interest among pharmaceutical scientists for sustaining drug delivery to the eye. This review aims to provide an overview of PPs for dry eye treatment and drug delivery to treat a range of ocular diseases. It also discusses current challenges in using PPs for ocular diseases.

Novel particulate antibiotic-loaded platforms as sustained drug delivery systems for bone infection treatment

Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2015

Cell-responsive nanogels for anticancer drug delivery

One of the main goals in Nanomedicine is to create innovative drug delivery systems (DDS) capable of delivering drugs into a specific location with high efficiency. In the development of DDS, some essential properties are desired, such as biocompatibility and biodegradability. Furthermore, an ideal DDS should be able to deliver a drug in a controlled manner and minimize its side effects. These two objectives are still a challenge for researchers all around the world. Nanogels are an excellent vehicle to use in drug delivery and several other applications due to their biocompatibility. They are polymer-based networks, chemically or physically crosslinked, with at least 80-90% water in their composition. Their properties can be tuned, like the nanogel size, multifunctionality and degradability. Nanogels are capable of carrying in their interior bioactive molecules and deliver them into cells. The main objective of this project was to produce nanogels for the delivery of anticancer drugs with the ability of responding to existent stimuli inside cells (cellresponsiveness nanogels) and/or of controlled drug delivery. The nanogels were mainly based on alginate (AG), a natural biopolymer, and prepared using emulsion approaches. After their synthesis, they were used to encapsulate doxorubicin (Dox) which was chosen as a model drug. In the first part of the experimental work, disulfide-linked AG nanogels were prepared and, as expected, were redox-sensitive to a reducing environment like the intracellular medium. In the second part, AG nanogels crosslinked with both calcium ions and cationic poly(amidoamine) dendrimers were developed with improved sustained drug delivery. The prepared nanogels were characterized in terms of size, chemical composition, morphology, and drug delivery behavior (under redox/pH stimuli). The in vitro cytotoxicity of the nanogels was also tested against CAL-72 cells (an osteosarcoma cell line).

PROTEIN-TRIGGERED SUSTAINED DRUG RELEASE CONTROLLED BY APTAMERS BOUND TO OLIGOMER-CROSSLINKED ALGINATE

Sustained drug release systems provide many advantages over traditional delivery methods such as extending the time in which the drug is found to be within an effective concentration within the therapeutic window, which decreases the frequency of administration of the drug, and increases patient compliance. Research using polyacrylamide crosslinked by oligomers containing an aptamer sequence, has demonstrated a pulsatile release over 50 minutes triggered by a 2 mM target adenosine concentration. This thesis aims to build off this concept by designing a system that delivers in a sustained manner when triggered by micromolar target concentrations reflective of disease in vivo, using macromolecular targets. For example, the disease wet age related macular degeneration (wet AMD) is associated with increased concentrations of the protein vascular endothelial growth factor (VEGF-A) – a macromolecule. Patients with wet AMD would benefit from the implantation of devices or microspheres that release drugs in a sustained manner in response to local VEGF concentrations. In this thesis, we hypothesize that the protein lysozyme, used to demonstrate proof-of-concept, could trigger the increased release of drugs from oligomer-crosslinked alginate. The objectives are to (i) demonstrate sustained release from alginate, (ii) design oligomer crosslinked alginate that degrades in response to lysozyme, and then (iii) use these systems to control the release of FITC-dextran with and without lysozyme. A series of control experiments and analyses were used to optimize the crosslinking of alginate by annealed oligomers. The cumulative release of FITC-dextran (MW 20,000) from oligomer crosslinked alginate increased by 3.4 μg when lysozyme (3 μM) was introduced at 48 hours, as opposed to controls which released only 0.2 μg. FITC-loaded alginate microspheres coated by oligomer-crosslinked alginate released 15% more FITC-dextran over 120 hours when placed into 3 μM of lysozyme than without lysozyme. Controls of alginate crosslinked with PEG or control oligomers (without a lysozyme aptamer sequence) had no changes in release with lysozyme. The incorporation of a lysozyme aptamer onto oligomers used to crosslink alginate disks or alginate coatings on microspheres resulted in different diffusion and release of FITC-dextran into PBS with or without lysozyme. This approach could be adapted for the delivery of drugs to diseases with specific protein profiles such as wet AMD.

Mussel-inspired porous SiO2 scaffolds with improved mineralization and cytocompatibility for drug delivery and bone tissue engineering

Porous SiO2 scaffolds with mesopore structure (named as MS scaffolds) have been proposed as suitable for bone tissue engineering due to their excellent drug-delivery ability; however, the mineralization and cytocompatibility of MS scaffolds are far from optimal for bone tissue engineering, and it is also unclear how the delivery of drugs from MS scaffolds affects osteoblastic cells. The aims of the present study were to improve the mineralization and cytocompatibility of MS scaffolds by coating mussel-inspired polydopamine on the pore walls of scaffolds. The effects of polydopamine modification on MS scaffolds was investigated with respect to apatite mineralization and the attachment, proliferation and differentiation of bone marrow stromal cells (BMSCs), as was the release profile of the drug dexamethasone (DEX). Our results show that polydopamine can readily coat the pore walls of MS scaffolds and that polydopamine-modified MS scaffolds have a significantly improved apatite-mineralization ability as well as better attachment and proliferation of BMSCs in the scaffolds, compared to controls. Polydopamine modification did not alter the release profile of DEX from MS scaffolds but the sustained delivery of DEX significantly improved alkaline phosphatase (ALP) activity of BMSCs in the scaffolds. These results suggest that polydopamine modification is a viable option to enhance the bioactivity of bone tissue engineering scaffolds and, further, that DEX-loaded polydopamine MS scaffolds have potential uses as a release system to enhance the osteogenic properties of bone tissue engineering applications.

Synthesis of an erodible biomimetic hydrogel for drug delivery using native chemical ligation

Hydrogels are hydrophilic, three dimensional polymers that imbibe large quantities of water while remaining insoluble in aqueous solutions due to chemical or physical cross-linking. The polymers swell in water or biological fluids, immobilizing the bioactive agent, leading to drug release in a well-defined specific manner. Thus the hydrogels’ elastic properties, swellability and biocompatibility make them excellent formulations for drug delivery. Currently, many drug potencies and therapeutic effects are limited or otherwise reduced because of the partial degradation that occurs before the administered drug reaches the desired site of action. On the other hand, sustained release medications release drugs continually, rather than providing relief of symptoms and protection solely when necessary. In fact, it would be much better if drugs could be administered in a manner that precisely matches physiological needs at desired times and at the desired site (site specific targeting). There is therefore an unmet need to develop controlled drug delivery systems especially for delivery of peptide and protein bound drugs. The purpose of this project is to produce hydrogels for structural drug delivery and time-dependent sustained release of drugs (bioactive agents). We use an innovative polymerisation strategy based on native chemical ligation (NCL) to covalently cross-link polymers to form hydrogels. When mixed in aqueous solution, four armed (polyethylene glycol) amine (PEG-4A) end functionalised with thioester and four branched Nterminal cysteine peptide dendrimers spontaneously conjugated to produce biomimetic hydrogels. These hydrogels showed superior resistance to shear stress compared to an equivalent PEG macromonomer system and were shown to be proteolytically degradable with concomitant release of a model payload molecule. This is the first report of a peptide dendrimers/PEG macromonomer approach to hydrogel production and opens up the prospect of facile hydrogel synthesis together with tailored payload release.

Intravitreal drug delivery in retinal disease : are we out of our depth?

Introduction With the ever-increasing global burden of retinal disease, there is an urgent need to vastly improve formulation strategies that enhance posterior eye delivery of therapeutics. Despite intravitreal administration having demonstrated notable superiority over other routes in enhancing retinal drug availability, there still exist various significant physical/biochemical barriers preventing optimal drug delivery into the retina. A further complication lies with an inability to reliably translate laboratory-based retinal models into a clinical setting. Several formulation approaches have recently been evaluated to improve intravitreal therapeutic outcomes, and our aim in this review is to highlight strategies that hold the most promise. Areas covered We discuss the complex barriers faced by the intravitreal route and examine how formulation strategies including implants, nanoparticulate carriers, viral vectors and sonotherapy have been utilized to attain both sustained delivery and enhanced penetration through to the retina. We conclude by highlighting the advances and limitations of current in vitro, ex vivo and in vivo retinal models in use by researchers globally. Expert opinion Various nanoparticle compositions have demonstrated the ability to overcome the retinal barriers successfully; however, their utility is limited to the laboratory setting. Optimization of these formulations and the development of more robust experimental retinal models are necessary to translate success in the laboratory into clinically efficacious outcomes.

Characterization of Ion-Exchange Fibers for Controlled Drug Delivery

Increasing attention has been focused on methods that deliver pharmacologically active compounds (e.g. drugs, peptides and proteins) in a controlled fashion, so that constant, sustained, site-specific or pulsatile action can be attained. Ion-exchange resins have been widely studied in medical and pharmaceutical applications, including controlled drug delivery, leading to commercialisation of some resin based formulations. Ion-exchangers provide an efficient means to adjust and control drug delivery, as the electrostatic interactions enable precise control of the ion-exchange process and, thus, a more uniform and accurate control of drug release compared to systems that are based only on physical interactions. Unlike the resins, only few studies have been reported on ion-exchange fibers in drug delivery. However, the ion-exchange fibers have many advantageous properties compared to the conventional ion-exchange resins, such as more efficient compound loading into and release from the ion-exchanger, easier incorporation of drug-sized compounds, enhanced control of the ion-exchange process, better mechanical, chemical and thermal stability, and good formulation properties, which make the fibers attractive materials for controlled drug delivery systems. In this study, the factors affecting the nature and strength of the binding/loading of drug-sized model compounds into the ion-exchange fibers was evaluated comprehensively and, moreover, the controllability of subsequent drug release/delivery from the fibers was assessed by modifying the conditions of external solutions. Also the feasibility of ion-exchange fibers for simultaneous delivery of two drugs in combination was studied by dual loading. Donnan theory and theoretical modelling were applied to gain mechanistic understanding on these factors. The experimental results imply that incorporation of model compounds into the ion-exchange fibers was attained mainly as a result of ionic bonding, with additional contribution of non-specific interactions. Increasing the ion-exchange capacity of the fiber or decreasing the valence of loaded compounds increased the molar loading, while more efficient release of the compounds was observed consistently at conditions where the valence or concentration of the extracting counter-ion was increased. Donnan theory was capable of fully interpreting the ion-exchange equilibria and the theoretical modelling supported precisely the experimental observations. The physico-chemical characteristics (lipophilicity, hydrogen bonding ability) of the model compounds and the framework of the fibrous ion-exchanger influenced the affinity of the drugs towards the fibers and may, thus, affect both drug loading and release. It was concluded that precisely controlled drug delivery may be tailored for each compound, in particularly, by choosing a suitable ion-exchange fiber and optimizing the delivery system to take into account the external conditions, also when delivering two drugs simultaneously.

Surface modification and paclitaxel drug delivery of folic acid modified polyethylene glycol functionalized hydroxyapatite nanoparticles

Nanoparticles are used for a number of biomedical applications. In this work we report the synthesis of folic acid (FA) modified polyethylene glycol (PEG) functionalized hydroxyapatite (HAp) nanoparticles. The anticancer drug, paclitaxel, is attached to the folic acid modified polyethylene glycol functionalized hydroxyapatite nanoparticles and the in vitro drug release is analyzed. The surface modification and functionalization is confirmed by Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA) and UV spectroscopy. The importance of the paper is the investigation of the release behavior of paclitaxel conjugated folic acid modified polyethylene glycol functionalized hydroxyapatite nanoparticles. The results show an initial rapid release and then a sustained release. (C) 2012 Elsevier B.V. All rights reserved.