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    Drug Delivery

    Biomaterial-Targeting Nanoparticle Delivery for Enhanced Drug Delivery

    (L-462) Biomaterial-Targeting Nanoparticle Delivery for Enhanced Drug Delivery

    Saturday, October 14, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row L - Poster # 462
    Introduction:: Drug delivery is widely used for tissue engineering applications to treat disease or injury. Drugs can be administered either systemically via the bloodstream, locally injected, or locally implanted as part of a drug-releasing biomaterial. Systemic drug administration is minimally invasive allowing for modifications in drug administration or redosing over time. However, systemic drug dosing is inefficient at accumulating in target tissues, resulting in drug accumulation in off-target organs, unwanted immune responses, and off-target effects that may increase patient risk and toxicity. Local drug delivery addresses toxicity issues by delivering drug directly to the intended tissue, but drug dosing cannot be modified once implanted and eventually the drug will become depleted. To overcome these challenges, we developed the BiomatErial Accumulating Carriers for an On-demand Nanotherapy (BEACON) platform which engineers our previously used poly(ethylene glycol) (PEG) tubes to serve as an implantable biomaterial that acts as a pro-regenerative scaffold and as a binding target for injected poly(lactic- co -glycolic acid)-b-polyethylene glycol (PLGA-PEG)  nanoparticles (NPs).(Ciciriello et al., 2022) The NPs are conjugated with a high affinity ligand for a receptor in the implanted biomaterial leading to local accumulation. The previous version of BEACON eliminated the need to rely on tissue-specific biomarkers but was inefficient at outperforming ligand-conjugated NP accumulation between control and receptor biomaterials but were capable of increasing NP retention. In this work, we re-engineer the BEACON ligand-receptor pairs to minimize blood protein aggregation and increase NP accumulation and retention in the biomaterial.

    Materials and Methods:: PEG microspheres were fabricated by using a water/oil emulsion technique (Fig. 1a). A final concentration of 20% w/v of 8-arm PEG maleimide with streptavidin maleimide in HEPES was homogenized at 4000rpm for 30s in 2% Tween-20 in silicone oil and cross-linked with 5 mM slow-degrading plasmid sensitive YKND cross-linking peptide. Microspheres were rinsed by centrifugation three times. Resulting microspheres were then packed into polydimethylsiloxane molds and exposed to ultraviolet light for 3 min to initiate free radical polymerization to generate streptavidin-PEG tubes. The tubes were rinsed three times, visually checked to ensure a hollow center, as well as evaluated by averaging 10 evenly spaced measurements from 3 tube samples using transmission electron microscopy technique. Streptavidin was quantified by a fluorescent assay using a Biotin-4-Fluorescien. Tubes were lyophilized and stored at -80˚C until use. PLGA-PEG and Biotin-PLGA-PEG NPs were fabricated using a nanoprecipitation technique (Fig. 1b). Polymer was suspended at 5 mg/ml in N,N-Dimethylformamide and added dropwise to 10ml distilled water with constant stirring at 900rpm and allowed to spin for 2 hours at room temperature. NPs were washed by centrifugation and resuspended at 5 mg/ml. NPs were analyzed by Dynamic Light Scatter (DLS) using a Malvern Zetasizer to determine size, polydispersity index (PDI) and zeta potential. NPs stability measured via DLS was tracked when stored at 4˚C and 37˚C at timepoint taken daily for 1 week. Biotin in NPs was quantified using a HABA Assay.

    Results, Conclusions, and Discussions::

    For the BEACON platform, the hydrogel tubes were modified to streptavidin-PEG-MAL, with streptavidin serving as a target receptor on the biomaterial. Fabricated tubes had a lumen with an inner diameter size of 258 ± 7 um, and a measured outer diameter of 732 ± 4 um. The streptavidin-PEG microspheres were comparable to PEG only microspheres in their size, morphological characteristics, and mechanical properties. PLGA-PEG NPs were conjugated with biotin to act as a ligand on the NP and attach to the streptavidin-PEG tubes. Biotin-PLGA-PEG NPs were then characterized using DLS (Fig. 1C) resulting in a Zave diameter of 50.5 ± 0.6 nm and a zeta potential of -25.4 ± 2.1 mV. NPs stability was evaluated at 4 and 37˚C over the course of 2 weeks. NPs stored at 4˚C were stable for a longer period of time than the NPs incubated at 37˚C, which showed a dramatic increase in Zave, PDI, and zeta potential after 24 h (Fig. 1D). BEACON was re-engineered with new high affinity ligand-receptor pairs and evaluated for NP characteristics, biomaterial properties, biomaterial-NP dynamics, and binding efficiency after blood fouling. Through our work, we hope demonstrated an increase in accumulation and retention of NPs in the receptor biomaterial following ligand/receptor concentration and composition optimization, which we will evaluate further in a model of spinal cord injury (SCI), as there are no currently approved therapies. We hope to demonstrate the utility of BEACON for local, on-demand drug delivery for SCI repair that could address existing clinical challenges in drug variability across patient groups.



    Acknowledgements (Optional): :

    References (Optional): :

    Ciciriello, A. J., Surnar, B., Medy, G. D., Su, X., Dhar, S., & Dumont, C. M. (2022). Biomaterial-targeted precision nanoparticle delivery to the injured spinal cord. Acta Biomaterialia, 152, 532–545. https://doi.org/10.1016/j.actbio.2022.08.077