In-situ crosslinking hydrogels for combinatorial delivery of chemokines and siRNA-DNA carrying microparticles to dendritic cells

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
Biomaterials (Impact Factor: 8.56). 07/2009; 30(28):5187-200. DOI: 10.1016/j.biomaterials.2009.06.001
Source: PubMed


Polymer-based, injectable systems that can simultaneously deliver multiple bioactive agents in a controlled manner could significantly enhance the efficacy of next generation therapeutics. For immunotherapies to be effective, both prophylactically or therapeutically, it is not only critical to drive the antigen (Ag)-specific immune response strongly towards either T helper type 1 (Th1) or Th2 phenotype, but also to promote recruitment of a high number of antigen-presenting cells (APCs) at the site of immunization. We have recently reported a microparticle-based system capable of simultaneously delivering siRNA and DNA to APCs. Here we present an in-situ crosslinkable, injectable formulation containing dendritic cell (DC)-chemo-attractants and dual-mode DNA-siRNA loaded microparticles to attract immature DCs and simultaneously deliver, to the migrated cells, immunomodulatory siRNA and plasmid DNA antigens. These low crosslink density hydrogels were designed to degrade within 2-7 days in vitro and released chemokines in a sustained manner. Chemokine carrying gels attracted 4-6 folds more DCs over a sustained period in vitro, compared to an equivalent bolus dose. Interestingly, migrated DCs were able to infiltrate the hydrogels and efficiently phagocytose the siRNA-DNA carrying microparticles. Hydrogel embedded microparticles co-delivering Interleukin-10 siRNA and plasmid DNA antigens exhibited efficient Interleukin-10 gene knockdown in migrated primary DCs in vitro.

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    • "For example, they can be coated with chemoattractants (e.g. CCL19, CCL20, CCL21) that specifically stimulate DC accumulation to the area of administration in vivo [60] [61], and once taken up, the microparticle can release its tolerogenic payload with or without the provision of antigens. Finally, microparticles can also be programmed to release their various contents at different times after in vivo injection. "
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    ABSTRACT: We have developed novel antisense oligonucleotide-formulated microspheres that can reverse hyperglycemia in newly-onset diabetic mice. Dendritic cells taking up the microspheres adopt a restrained co-stimulation ability and migrate to the pancreatic lymph nodes when injected into an abdominal region that is drained by those lymph nodes. Furthermore, we demonstrate that the absolute numbers of antigen-specific Foxp3+ T regulatory cells are increased only in the lymph nodes draining the site of administration and that these T-cells proliferate independently of antigen supply in the microspheres. Taken together, our data add to the emerging model where antigen supply may not be a requirement in "vaccines" for autoimmune disease, but the site of administration - subserved by lymph nodes draining the target organ - is in fact critical to foster the generation of antigen-specific regulatory cells. The implications of these observations on "vaccine" design for autoimmunity are discussed and summarized. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Clinical Immunology
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    • "With the developed hydrogel depot being sensitive to the pharmaceutical substance novobiocin, the repetitive delivery of a vaccine could be drastically simplified by the simple oral intake of a tablet containing the stimulus molecule. In contrast to other innovative polymer-based vaccination methods2627 and remote-controlled delivery strategies such as implanted microchips which have recently been shown to deliver therapeutic proteins in a pulse-like fashion in human28, our system based on an orally available stimulus allows for simple handling and therefore represents a highly attractive alternative for the simplification of vaccination regimes especially in developing countries. This hydrogel depot may further be suitable for the externally controlled delivery of numerous other vaccines and biopharmaceuticals. "
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    ABSTRACT: The simplification of current vaccine administration regimes is of crucial interest in order to further sustain and expand the high impact of vaccines for public health. Most vaccines including the vaccine against hepatitis B need several doses to achieve protective immunization. In order to reduce the amount of repetitive injections, depot-based approaches represent a promising strategy. We present the application of novobiocin-sensitive biohybrid hydrogels as a depot for the pharmacologically controlled release of a vaccine against hepatitis B. Upon subcutaneous implantation of the vaccine depot into mice, we were able to release the vaccine by the oral administration of the stimulus molecule novobiocin resulting in successful immunization of the mice. This material-based vaccination regime holds high promises to replace classical vaccine injections conducted by medical personnel by the simple oral uptake of the stimulus thereby solving a major obstacle in increasing hepatitis B vaccination coverage.
    Full-text · Article · Sep 2013 · Scientific Reports
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    • "DEX-HEMA, previously reported by Hennink [13], is a biodegradable and biocompatible polymer [16] [17], The covalent crosslinks formed following photopolymerization under low level UV light contain ester linkages that can degrade in aqueous media. Biomaterial swelling and degradation rate are important for (1) the transport of oxygen and nutrients to and the removal of waste products from incorporated cells, (2) providing space for new tissue formation in tissue engineering applications, and (3) controlling the release of bioactive molecules [18] [19] such as siRNA. These parameters can be tailored by varying the degree of methacrylation [20] [21], size of crosslinker [22] and hydrogel macromer concentration [17]. "
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    ABSTRACT: Currently, the most severe limitation to applying RNA interference technology is delivery, including localizing the molecules to a specific site of interest to target a specific cell population and sustaining the presentation of these molecules for a controlled period of time. In this study, we engineered a functionalized, biodegradable system created by covalent incorporation of cationic linear polyethyleneimine (LPEI) into photocrosslinked dextran (DEX) hydrogels through a biodegradable ester linkage. The key innovation of this system is that control over the sustained release of short interference RNA (siRNA) was achieved, as LPEI could electrostatically interact with siRNA to maintain siRNA within the hydrogels and degradation of the covalent ester linkages between the LPEI and the hydrogels led to tunable release of LPEI/siRNA complexes over time. The covalent conjugation of LPEI did not affect the swelling or degradation properties of the hydrogels, and the addition of siRNA and LPEI had minimal effect on their mechanical properties. These hydrogels exhibited low cytotoxicity against human embryonic kidney 293 cells (HEK293). The release profiles could be tailored by varying DEX (8 and 12% w/w) and LPEI (0, 5, 10μg/100μl gel) concentrations with nearly 100% cumulative release achieved at day 9 (8% w/w gel) and day 17 (12% w/w gel). The released siRNA exhibited high bioactivity with cells surrounding and inside the hydrogels over an extended time period. This controllable and sustained siRNA delivery hydrogel system that permits tailored siRNA release profiles may be valuable to guide cell fate for regenerative medicine and other therapeutic applications such as cancer treatment.
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