| Popis: |
Intra-articular injection of mesenchymal stem cells (MSCs) is an attractive treatment for osteoarthritis (OA) due to their ease of use in clinical settings, excellent safety profile, and remarkable spontaneous cartilage repair. However, significant challenges arise in relation to the control and induction of stem cell differentiation into the desired cartilaginous lineage. Kartogenin (KGN), a hydrophobic small molecule drug, may significantly promote chondrogenic differentiation of MSCs and induce cartilage regeneration in OA. However, low water solubility and poor bioavailability limits its biological application. In this report, we propose a new nano-drug delivery system based on multifunctional nanographene oxide (NGO) to efficiently load KGN molecules noncovalently via π–π stacking and hydrophobic interactions (PPG-KGN), which could quickly enter MSCs. Before intra-articular injection, MSCs are simply mixed and co-incubated with PPG-KGN to acquire KGN enhanced MSCs. This allows the efficient intracellular delivery of KGN, thereby promoting the chondrogenic differentiation potency of the MSCs. We investigated the effect of KGN-enhanced MSCs in the treatment of knee osteoarthritis. An in vitro study showed the PPG could be rapidly uptaken in the first 4 h after incubation, reaching saturation at 12 h, and accumulating in the lysosome and cytoplasm of MSCs. Thus, PPG-KGN could enhance the efficiency of the intracellular delivery of KGN, which showed remarkably high chondrogenic differentiation capacity of the MSCs. When applied to an OA model of cartilage injury in rats, MSCs were preconditioned with PPG-KGN before being injected into the knee joint. It demonstrated the PPG-KGN preconditioned MSCs contribute to protection from joint space narrowing, pathologic mineralization, osteoarthritis development, behavioral assessment of OA-induced pain, and tissue regeneration, as evidenced by radiographic, weight bearing, and histological analysis. Based on these findings, we propose the use of PPG for delivery of KGN to achieve enhanced MSC chondrogenic potential in osteoarthritis treatment. |
