Browsing by Author "Ma, Yutian"

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    Engineering Biocoatings To Prolong Drug Release from Supraparticles
    (American Chemical Society, 2019-08) Ma, Yutian; Cortez-Jugo, Christina; Li, Jianhua; Lin, Zhixing; Richardson, Rachael; Han, Yiyuan; Zhou, Jiajing; Björnmalm, Mattias; Feeney, Orlagh; Zhong, Qi-Zhi; Porter, Christopher; Wise, Andrew; Caruso, Frank
    Supraparticles (SPs) assembled from smaller colloidal nanoparticles can serve as depots of therapeutic compounds and are of interest for long-term, sustained drug release in biomedical applications. However, a key challenge to achieving temporal control of drug release from SPs is the occurrence of an initial rapid release of the loaded drug (i.e., "burst" release) that limits sustained release and potentially causes burst release-associated drug toxicity. Herein, a biocoating strategy is presented for silica-SPs (Si-SPs) to reduce the extent of burst release of the loaded model protein lysozyme. Specifically, Si-SPs were coated with a fibrin film, formed by enzymatic conversion of fibrinogen into fibrin. The fibrin-coated Si-SPs, (F)Si-SPs, which could be loaded with 7.9 +/- 0.9 mug of lysozyme per SP, released >60% of cargo protein over a considerably longer period of time of >20 days when compared with the uncoated Si-SPs that released the same amount of the cargo protein, however, within the first 3 days. Neurotrophins that support the survival and differentiation of neurons could also be loaded at approximately 7.3 mug per SP, with fibrin coating also delaying neurotrophin release (only 10% of cargo released over 21 days compared with 60% from Si-SPs). In addition, the effects of incorporating a hydrogel-based system for surgical delivery and the opportunity to control drug release kinetics were investigated-an alginate-based hydrogel scaffold was used to encapsulate (F)Si-SPs. The introduction of the hydrogel further extended the initial release of the encapsulated lysozyme to approximately 40 days (for the same amount of cargo released). The results demonstrate the increasing versatility of the SP drug delivery platform, combining large loading capacity with sustained drug release, that is tailorable using different modes of controlled delivery approaches.
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    Gel-Mediated Electrospray Assembly of Silica Supraparticles for Sustained Drug Delivery
    (ACS Publications, 2018-09) Ma, Yutian; Björnmalm, Mattias; Wise, Andrew; Cortez-Jugo, Christina; Revalor, Eve; Ju, Yi; Feeney, Orlagh; Richardson, Rachael; Hanssen, Eric; Shepherd, Robert; Porter, Christopher; Caruso, Frank
    Supraparticles (SPs) composed of smaller colloidal particles provide a platform for the long-term, controlled release of therapeutics in biomedical applications. However, current synthesis methods used to achieve high drug loading and those involving biocompatible materials are often tedious and low throughput, thereby limiting the translation of SPs to diverse applications. Herein, we present a simple, effective, and automatable alginate-mediated electrospray technique for the assembly of robust spherical silica SPs (Si-SPs) for long-term (>4 months) drug delivery. The Si-SPs are composed of either porous or nonporous primary Si particles within a decomposable alginate matrix. The size and shape of the Si-SPs can be tailored by controlling the concentrations of alginate and silica primary particles used and key electrospraying parameters, such as flow rate, voltage, and collector distance. Furthermore, the performance (including drug loading kinetics, loading capacity, loading efficiency, and drug release) of the Si-SPs can be tuned by changing the porosity of the primary particles and through the retention or removal (via calcination) of the alginate matrix. The structure and morphology of the Si-SPs were characterized by electron microscopy, dynamic light scattering, N2 adsorption-desorption analysis, and X-ray photoelectron spectroscopy. The cytotoxicity and degradability of the Si-SPs were also examined. Drug loading kinetics and loading capacity for six different types of Si-SPs, using a model protein drug (fluorescently labeled lysozyme), demonstrate that Si-SPs prepared from primary silica particles with large pores can load significant amounts of lysozyme (∼10 μg per SP) and exhibit sustained, long-term release of more than 150 days. Our experiments show that Si-SPs can be produced through a gel-mediated electrospray technique that is robust and automatable (important for clinical translation and commercialization) and that they present a promising platform for long-term drug delivery.
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    New molecular therapies for the treatment of hearing loss
    (Elsevier, Inc., 2019-05) Ma, Yutian; Wise, Andrew; Shepherd, Robert; Rachael, Richardson
    An estimated 466 million people suffer from hearing loss worldwide. Sensorineural hearing loss is characterized by degeneration of key structures of the sensory pathway in the cochlea such as the sensory hair cells, the primary auditory neurons and their synaptic connection to the hair cells - the ribbon synapse. Various strategies to protect or regenerate these sensory cells and structures are the subject of intensive research. Yet despite recent advances in our understandings of the capacity of the cochlea for repair and regeneration there are currently no pharmacological or biological interventions for hearing loss. Current research focusses on localized cochlear drug, gene and cell-based therapies. One of the more promising drug-based therapies is based on neurotrophic factors for the repair of the ribbon synapse after noise exposure, as well as preventing loss of primary auditory neurons and regrowth of the auditory neuron fibers after severe hearing loss. Drug therapy delivery technologies are being employed to address the specific needs of neurotrophin and other therapies for hearing loss that include the need for high doses, long-term delivery, localised or cell-specific targeting and techniques for their safe and efficacious delivery to the cochlea. Novel biomaterials are enabling high payloads of drugs to be administered to the cochlea with subsequent slow-release properties that are proving to be beneficial for treating hearing loss. In parallel, new gene therapy technologies are addressing the need for cell specificity and high efficacy for the treatment of both genetic and acquired hearing loss with promising reports of hearing recovery. Some biomaterials and cell therapies are being used in conjunction with the cochlear implant ensuring therapeutic benefit to the primary neurons during electrical stimulation. This review will introduce the auditory system, hearing loss and the potential for repair and regeneration in the cochlea. Drug delivery to the cochlea will then be reviewed, with a focus on new biomaterials, gene therapy technologies, cell therapy and the use of the cochlear implant as a vehicle for drug delivery. With the current pre-clinical research effort into therapies for hearing loss, including clinical trials for gene therapy, the future for the treatment for hearing loss is looking bright.
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    A radiolab ele d drug tracing method to study neurotrophin-3 retention and distribution in the cochlea after nano-based local delivery
    (Elsevier B.V., 2020-09) Lam, Patrick; Gunewardene, Niliksha; Ma, Yutian; Caruso, Frank; Nguyen, Trung; Flynn, Brianna; Wise, Andrew; Richardson, Rachael
    Hearing loss is the most common sensory deficit worldwide with no approved therapeutics for treatment. Local neurotrophin delivery into the cochlea has shown great potential in protecting and repairing the sensory cells important for hearing. However, delivery of these factors into the inner ear at therapeutic levels over a sustained period of time has remained a challenge restricting clinical translation. We have developed a method to test the pharmacokinetics of neurotrophin released from porous silica particles called ‘supraparticles’ that can provide sustained release of neurotrophins to the inner ear. This report describes a radiolabeling method to examine neurotrophin retention and distribution in the cochlea. The neurotrophin was labeled with a radioactive tracer (iodine 125: 125I) and delivered into the cochlea via the supraparticle system. Gamma counts reveal drug levels and clearance in the intact cochlea, as well as accumulation in off-target organs (safety test). Autoradiography analyses using film and emulsion permit quantification and visualization of drug distribution at the cellular level. The method has a detection limit of 0.8 pg of radiolabeled neurotrophin-3 in cochlear sections exposed to film. The tracer 125I with a half-life of 59.4 days can be used to label other drugs/substances with a tyrosine residue and therefore be broadly applicable for long-term pharmacokinetic studies in other systems.