Development of a 3D printed particle embedded hydrogel mesh for localized delivery of iron-chelating agents




Chehri Chamchamali, Behnad

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By definition, cancer is a disease resulting from uncontrolled growth and division of abnormal cells, which aggregate to form various tumors in neoplasms. Of these neoplasms, glioblastoma (GBM) is one of the most prevalent and lethal type of brain tumor in humans. Only 5% of the patients survive five years after the primary diagnosis. Chemotherapeutics such as temozolomide (TMZ) are used to treat cancer patients with GBM. TMZ is an alkylating agent that can cross the blood-brain barrier (BBB) and minimize the possibility of the disease recurrence. TMZ treatment alone is not sufficient because too much exposure to TMZ causes health issues. Also, It has been shown that cancer cells develop resistance against TMZ. This necessitates using another approach to treat cancer cells. Targeting cancer cells metabolism to inhibit their growth and proliferation could be target of this new approach. Amongst various metabolite contributing in cell, Iron is one of the most necessary component. Iron is crucial for the replication and repair of DNA. Tumor cells often have a greater rate of proliferation than normal cells, which results in a much higher need for iron than that of normal cells. Therefore, removing iron helps in reducing cancer cells proliferation. Irom chelator are compounds that can remove intracellular iron hence induce apoptosis. Deferiprone (DFP) is amongst the most studied anti-cancer drugs with the ability to bypass the BBB and also be used to excrete the excess iron form the body. However, prolonged oral administration of this drug can be dangerous, which causes common side effects such as nausea, vomiting, infections. This brings up the need for a new method of drug delivery which leads to the usage of localized drug delivery systems. Due to the fact that, such techniques help to increase drug absorption at the tumor site and help reduce the dosage frequency and minimize side effects. Compared to systemic administration, local delivery to GBM includes several benefits such as avoiding the BBB and enhancing the local therapeutic bioavailability. As a result, much effort has been expended in developing novel therapeutic approaches capable of delivering an anticancer medication at the tumor site. This covers system architectures such as wafers, microspheres, CED, hydrogels and meshes. Microspheres constructed of biodegradable polymers have the ability to maintain the chemotherapeutic agent intact within the carrier and administer the medicine locally for a longer length of time whilst helping nutrients to still be delivered to the desired area with minimal obstructions. The use of polymeric particles may be challenging since the highlighted particles are transferred around the tissues and hence dislodge from their designated surface areas. Therefore ,the use of a hydrogel based mesh is introduced. Alginate is a naturally occurring hydrogel, which is appropriate for three-dimensional scaffolding materials. Alginate as a mesh substrate included desirable characteristics such as versatile characteristics with the placement of the mesh as well as prevention of the particles from transferring and dislocating inside the cerebral spinal fluid. In this thesis, two major methods of microparticle fabrication were used. Due to the nature of TMZ and DFP, oil-in-oil single emulsion and water-in-oil-in-water double emulsion were used in this study, respectively, to create PLGA based microparticles. After particle fabrication, they were embedded inside an alginate mesh substrate created using as 3D printer whilst implementing an extrusion-based 3D printing method, which provides the benefit of stationary particles.the resulting mesh were then placed in specific control media to measure the release of TMZ and DFP throughout the process. The data shown here depicts great potential in the use of a hydrogel-based particle embedded mesh for the deliverance of iron-alkylating agents.



Drug delivery systems, Microparticles, Glioblastoma, Iron-Chelating agents, Hydrogel, Polymer-based microparticles