Mitochondria-targeting graphene oxide nanocomposites for fluorescence imaging-guided synergistic phototherapy of drug-resistant osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor occurring in children and young adults. Drug-resistant osteosarcoma often results in chemotherapy failure. Therefore, new treatments aimed at novel therapeutic targets are urgently needed for the treatment of drug-resistant osteosarcoma. Mitochondria-targeted phototherapy, i.e., synergistic photodynamic/photothermal therapy, has emerged as a highly promising strategy for treating drug-resistant tumors. This study proposed a new nano-drug delivery system based on near-infrared imaging and multifunctional graphene, which can target mitochondria and show synergistic phototherapy, with preferential accumulation in tumors. METHODS AND RESULTS: Based on our previous study, (4-carboxybutyl) triphenyl phosphonium bromide (TPP), a mitochondria-targeting ligand, was conjugated to indocyanine green (ICG)-loaded, polyethylenimine-modified PEGylated nanographene oxide sheets (TPP-PPG@ICG) to promote mitochondrial accumulation after cellular internalization. Thereafter, exposure to a single dose of near-infrared irradiation enabled synergistic photodynamic and photothermal therapy, which simultaneously inhibited adenosine triphosphate synthesis and mitochondrial function. Induction of intrinsic apoptosis assisted in surmounting drug resistance and caused tumor cell death. After fluorescence imaging-guided synergistic phototherapy, the mitochondria-targeting, multifunctional graphene-based, drug-delivery system showed highly selective anticancer efficiency in vitro and in vivo, resulting in marked inhibition of tumor progression without noticeable toxicity in mice bearing doxorubicin-resistant MG63 tumor cells. CONCLUSION: The mitochondria-targeting TPP-PPG@ICG nanocomposite constitutes a new class of nanomedicine for fluorescence imaging-guided synergistic phototherapy and shows promise for treating drug-resistant osteosarcoma.

Subtrochanteric shortening osteotomy during cementless total hip arthroplasty in young patients with severe developmental dysplasia of the hip.

BACKGROUND: This retrospective study was designed to determine complications, functional and radiographic results of transverse subtrochanteric osteotomy during cementless, modular total hip arthroplasty (THA) in a series of active patients younger than 45 years with Crowe Type-III or IV developmental dysplasia of the hip (DDH). METHODS: We followed 49 patients (56 hips) with DDH who were treated with cementless THA, where the acetabular cup was positioned in the anatomic hip center and where a simultaneous transverse femoral osteotomy was performed. Complication rate evaluation and clinical outcomes were measured by validated clinical scores and radiographic evaluation were performed at a mean follow up of 10 years (range, 4.8-14.3 years). RESULTS: The mean limb-length discrepancy was reduced from 4.2 cm to 1.1 cm (P < 0.01). The mean Harris hip score (HSS) significantly improved from 40.6 points to 87.4 points (P < 0.01). Similarly, severity of low back pain, modified MAP, HOOS, and SF-12 also showed significant improvement (P < 0.01). There were 3 cases of postoperative dislocation, 3 cases of transient nerve palsy, 2 cases of nonunion, and 4 cases of intraoperative fracture. At 10 years follow-up, the estimated survival rate with any component revision as end points was 92%. CONCLUSION: The cementless THA combined with transverse subtrochanteric osteotomy is a reliable technique with restoration of a more normal limb, satisfactory clinical outcomes, and mid-term survival of components.

Carbon dots enhance extracellular matrix secretion for dentin-pulp complex regeneration through PI3K/Akt/mTOR pathway-mediated activation of autophagy.

Pulp injury is one of the most common clinical diseases, and severe cases are usually associated with the functional loss of the tooth, while the current clinical treatment modality is only a cavity filling procedure without the regeneration of the dentin-pulp complex, thus leading to a devitalized and brittle tooth. In this study, carbon dots (CDots) with excellent biocompatibility are prepared from ascorbic acid and polyethyleneimine via a hydrothermal method. The as-prepared CDots can enhance extracellular matrix (ECM) secretion of human dental pulp stem cells (DPSCs), giving rise to increased cell adhesion on ECM and a stronger osteogenic/odontogenic differentiation capacity of DPSCs. Further, the mechanism underlying CDots-enhanced ECM secretion is revealed by the transcriptome analysis, Western blot assay and molecular dynamics simulation, identifying that the pharmacological activities of CDots are originated from a reasonable activation of the autophagy, which is mediated by regulating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Based on the abundant CDots-induced ECM and thereby the reinforcement of the cell-ECM adhesion, an intact dental pulp stem cell sheet can be achieved, which in return promote in vivo the efficient regeneration of dentin-pulp complex as well as blood vessels.

Near-Infrared Light-Controllable Multifunction Mesoporous Polydopamine Nanocomposites for Promoting Infected Wound Healing.

The successful treatment of infected wounds requires strategies with effective antimicrobial, anti-inflammatory, and healing-promoting properties. Accordingly, the use of Cu2+ and tetracycline (TC), which can promote angiogenesis, re-epithelialization, and collagen deposition, also antibacterial activity, at the wound site, has shown application prospects in promoting infected wound repair. However, realizing controllable release to prolong action time and avoid potential toxicities is critical. Moreover, near-infrared light (NIR)-activated mesoporous polydopamine nanoparticles (MPDA NPs) reportedly exert anti-inflammatory effects by eliminating the reactive oxygen species generated during inflammatory responses. In this study, we assess whether Cu2+ and TC loaded in MPDA NPs can accelerate infected wound healing in mice. In particular, Cu2+ is chelated and immobilized on the surface of MPDA NPs, while a thermosensitive phase-change material (PCM; melting point: 39-40 °C), combined with antibiotics, was loaded into the MPDA NPs as a gatekeeper (PPMD@Cu/TC). Results show that PPMD@Cu/TC exhibits significant great photothermal properties with NIR irradiation, which induces the release of Cu2+, while inducing PCM melting and, subsequent, TC release. In combination with anti-inflammatory therapy, NIR-triggered Cu2+ and TC release enables the nanocomposite to eradicate bacterial wound infections and accelerate healing. Importantly, negligible damage to primary organs and satisfactory biocompatibility were observed in the murine model. Collectively, these findings highlight the therapeutic potential of this MPDA-based platform for controlling bacterial infection and accelerating wound healing.

Designing Highly Luminescent Cellulose Nanocrystals with Modulated Morphology for Multifunctional Bioimaging Materials.

Spherical cellulose nanocrystals (SCNs) and rod-shaped cellulose nanocrystals (RCNs) were extracted from different cellulose materials. The two shape forms of cellulose nanocrystals (CNs) were designed with a combination of isothiocyanate (FITC), and both the obtained FITC-SCNs and FITC-RCNs exhibited high fluorescence brightness. The surfaces of SCNs and RCNs were subjected to a secondary imino group by a Schiff reaction and then covalently bonded to the isothiocyanate group of FITC through a secondary imino group to obtain fluorescent cellulose nanocrystals (FITC-CNs). The absolute ζ-potential and dispersion stability of FITC-CNs (FITC-SCNs and FITC-RCNs) were improved, which also promoted the increase in the fluorescence quantum yield. FITC-RCNs had a fluorescence quantum yield of 30.7%, and FITC-SCNs had a morphological advantage (better dispersion, etc.), resulting in a higher fluorescence quantum yield of 35.9%. Cell cytotoxicity experiments demonstrated that the process of FITC-CNs entering mouse osteoblasts (MC3T3) did not destroy the cell membrane, showing good biocompatibility. On the other hand, FITC-CNs with good dispersibility can significantly enhance poly(vinyl alcohol) (PVA) and poly(lactic acid) (PLA); their mechanical properties were improved (the highest sample reached to 243%) and their fluorescent properties were imparted. This study provides a simple surface functionalization method to produce high-luminance fluorescent materials for bioimaging, multifunctional nanoenhancement/dispersion marking, and anticounterfeiting materials.