ABSTRACT
Although the pathogenesis of osteoarthritis (OA) is unclear, inflammatory cytokines are related to its occurrence. However, few studies focused on the therapeutic strategies of regulating joint homeostasis by simultaneously remodeling the anti-inflammatory and immunomodulatory microenvironments. Fibroblast growth factor 18 (FGF18) is the only disease-modifying OA drug (DMOAD) with a potent ability and high efficiency in maintaining the phenotype of chondrocytes within cell culture models. However, its potential role in the immune microenvironment remains unknown. Besides, information on an optimal carrier, whose interface and chondral-biomimetic microenvironment mimic the native articular tissue, is still lacking, which substantially limits the clinical efficacy of FGF18. Herein, to simulate the cartilage matrix, chondroitin sulfate (ChS)-based nanoparticles (NPs) are integrated into poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PLEL) hydrogels to develop a bionic thermosensitive sustainable delivery system. Electrostatically self-assembled ChS and ε-poly-l-lysine (EPL) NPs are prepared for the bioencapsulation of FGF18. This bionic delivery system suppressed the inflammatory response in interleukin-1ß (IL-1ß)-mediated chondrocytes, promoted macrophage M2 polarization, and inhibited M1 polarization, thereby ameliorating cartilage degeneration and synovitis in OA. Thus, the ChS-based hydrogel system offers a potential strategy to regulate the chondrocyte-macrophage crosstalk, thus re-establishing the anti-inflammatory and immunomodulatory microenvironment for OA therapy.
ABSTRACT
Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single-component dual-functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)-generated HOCl. A representative prodrug (DHU-CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU-CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU-CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase-2 (COX-2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX-2. Downstream prostaglandins E2 and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU-CBA2 promotes infiltration and function of CD8+ T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single-component dual-functional prodrug activated by TME-specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX-2 inhibitor.
Subject(s)
Lung Neoplasms , Photochemotherapy , Prodrugs , Spinal Neoplasms , Humans , Photosensitizing Agents/therapeutic use , Lung Neoplasms/drug therapy , Cyclooxygenase 2 , CD8-Positive T-Lymphocytes , Spinal Neoplasms/drug therapy , Indomethacin , Tumor MicroenvironmentABSTRACT
BACKGROUND: Surgery is often indicated for patients with massively prolapsed intervertebral disc herniation. The interlaminar endoscopic spine system (iLESSYS) Delta 6-mm working channel endoscope has advantages over other systems. The aim of this study was to explore the benefits and complications of using the iLESSYS Delta for the treatment of massively prolapsed intervertebral disc herniation. AIM: To explore the clinical benefits of treating massively prolapsed lumbar intervertebral disc herniation with the iLESSYS Delta endoscope. METHODS: In this study, the data of 37 patients who underwent surgery with the iLESSYS Delta endoscope at The Affiliated Hospital of Qingdao University were retrospectively analyzed. Intraoperative blood loss, operation time, and complications were collected. The visual analog scale (VAS), oswestry disability index (ODI), and modified MacNab criteria were determined before and at 1 d, 3 mo, and 6 mo after surgery. RESULTS: The mean intraoperative blood loss was 20.4 ± 1.2 mL. The mean operation time was 97.3 ± 12.4 min. The VAS scores for leg and back pain decreased from 68.0 ± 7.3, 34.4 ± 8.5 before operation to 2.5 ± 1.7, 5.5 ± 1.9 at 6 mo after surgery, respectively. The ODI also decreased from 60.2 ± 7.3 to 17.9 ± 3.4 at 6 mo after surgery. The improvement rate of the MacNab score was 86.4%, which was considered excellent. No spinal dural injury, nerve root injury, secondary protrusion of intervertebral disc, or myeloid hypertension was found during follow-up. CONCLUSION: The iLESSYS Delta 6-mm working channel endoscope has several advantages in terms of clinical and functional benefits, complications, and low risk of residual vertebral pulp in treating patients with massively prolapsed intervertebral disc herniation.
