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Yeast microcapsule-mediated oral delivery of IL-1? shRNA for post-traumatic osteoarthritis therapy

ABSTRACT: Post-traumatic osteoarthritis is a prevalent debilitating joint disease. However, there is no FDA-approved disease-modifying osteoarthritis drug currently. Gene therapy can improve disease progression but lacks an effective delivery system. Here, we constructed an oral drug delivery system by non-virus-mediated interleukin-1? (IL-1?) short hairpin RNA (shRNA) and non-pathogenic yeast to evaluate its effect on osteoarthritis therapy. After recombinant IL-1? shRNA/yeast therapy, yeast microcapsule-mediated oral delivery of IL-1? shRNA greatly reduced the IL-1? expression in intestine macrophage, bone marrow macrophage, and articular cartilage, systematically regulate the inflammatory response. The degeneration of articular cartilage was significantly inhibited in the medial femoral condyle and medial tibial plateau of the knee joint. And the expression of osteoarthritis markers Col X and MMP13 was reduced in the knee joint. Thus, yeast microcapsule-mediated oral delivery of IL-1? shRNA may serve as a novel gene therapy strategy for treating joint degeneration through immunomodulation of the mononuclear phagocyte system from the intestine to subchondral bone marrow and ultimately preserving the articular cartilage joint. Graphical Abstract Zhang et al. present a novel and efficient shRNA delivery system mediated by yeast microcapsule for post-traumatic osteoarthritis therapy and immunomodulation via orally administered method.

SUBMITTER: Zhang L

PROVIDER: S-EPMC7779538 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Project description:Targeted therapy via the patient-friendly oral route remains the holy grail of chemotherapy for cancer. Herein we report a yeast-derived platform for targeted oral delivery of cisplatin (CDDP) that is one of the most effective drugs for chemotherapy of various types of cancers. Methods: The optimal conditions were first established to fabricate yeast microcapsules (YCs) with desirable loading capability. Then, CDDP-derived precursor nanoparticles (PreCDDP) were prepared and packaged into YC to produce orally deliverable PreCDDP/YC. The physiochemical properties, in vitro drug release profiles, in vitro antitumor activity, oral targeting capability, in vivo pharmacokinetics, and in vivo efficacy of the YC-based biomimetic delivery system were examined. Results: YCs obtained under the optimized condition showed desirable loading efficiency for quantum dots that were used as a model nanocargo. In vitro experiments demonstrated rapid endocytosis and prolonged retention of YC in macrophages. By electrostatic force-mediated self-deposition, PreCDDP was efficiently loaded into YC. PreCDDP/YC showed potent cytotoxicity in different tumor cells, indicating that PreCDDP loaded in YC maintained its antitumor activity after intracellular release. As compared to CDDP and PreCDDP, orally administered PreCDDP/YC displayed significantly higher bioavailability. Post oral delivery, YC could accumulate in A549 human lung carcinoma xenografts in mice, achieving by monocyte/macrophage-mediated translocation via the lymphatic system. Through this targeting effect, orally administered PreCDDP/YC showed desirable efficacy in A549 xenograft-bearing mice, which was comparable to that of free CDDP administered by intravenous injection. Orally administered free CDDP, however, did not afford antitumor effects. Furthermore, oral treatment with PreCDDP/YC displayed better safety than free CDDP administered via the oral or intravenous route. Conclusions: This biomimetic approach can serve as an effective strategy to develop targeted oral chemotherapies based on CDDP or its derivatives.

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Yeast microcapsule-mediated oral delivery of IL-1? shRNA for post-traumatic osteoarthritis therapy

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