Nano-Based Drug Delivery Systems: Potential Developments in the Therapy of Metastatic Osteosarcoma-A Narrative Review.

Osteosarcoma, a predominant malignant bone tumor, poses significant challenges due to its high metastatic and recurrent nature. Although various therapeutic strategies are currently in use, they often inadequately target osteosarcoma metastasis. This review focuses on the potential of nanoscale drug delivery systems to bridge this clinical gap. It begins with an overview of the molecular mechanisms underlying metastatic osteosarcoma, highlighting the limitations of existing treatments. The review then transitions to an in-depth examination of nanoscale drug delivery technologies, emphasizing their potential to enhance drug bioavailability and reduce systemic toxicity. Central to this review is a discussion of recent advancements in utilizing nanotechnology for the potential intervention of metastatic osteosarcoma, with a critical analysis of several preclinical studies. This review aims to provide insights into the potential applications of nanotechnology in metastatic osteosarcoma therapy, setting the stage for future clinical breakthroughs and innovative cancer treatments.

Clinical evaluation of the three-dimensional printed strut-type prosthesis combined with autograft reconstruction for giant cell tumor of the distal femur.

Propose: This study aimed to describe the design and surgical techniques of a three-dimensional (3D) printed strut-type prosthesis with a porous titanium surface for distal femur giant cell tumors of bone (GCTB) and evaluate the short-term clinical outcomes. Methods: From June 2018 to January 2021, 9 consecutive patients with grade I or II GCTB in the distal femur underwent extended intralesional curettage followed by 3D-printed strut-type prosthesis combined with autograft reconstruction were retrospectively reviewed to assess their clinical and radiographic outcomes. Results: All patients were followed up for 30.8 ± 7.5 months (18-42 months) after surgery. The mean affected subchondral bone percentage and the mean subchondral bone thickness before surgery was 31.8% ± 9.6% (range, 18.2% ~50.2%) and 2.2 ± 0.8 mm (range, 1.2-4.0 mm), respectively. At the final follow-up, all the patients were alive without local recurrence; no postoperative complications were observed. Patients had significant improvements in postoperative MSTS-93 score [(26.7 ± 2.4) vs. (18.8 ± 3.7), P < 0.05], and ROM [(122.8° ± 9.1°) vs. (108.3° ± 6.1°), P < 0.05] compared with their preoperative statuses. Furthermore, the mean subchondral bone thickness has increased to 10.9 ± 1.3 mm (range, 9.1-12.1 mm). Conclusion: 3D-printed strut-type prosthesis combined with autograft reconstruction provides acceptable early functional and radiographic outcomes in patients with grade I or II GCTB in distal femur due to the advantages of the prosthesis such as good biocompatibility, osseointegration capacity, and subchondral bone protection. If our early outcomes can be further validated in studies with more patients and sufficient follow-up, this method may be evaluated as an alternative for the treatment of grade I or II GCTB in the distal femur.

Advances of Osteosarcoma Models for Drug Discovery and Precision Medicine.

The management of osteosarcoma (OS) patients presents a significant clinical challenge. Despite progress in conventional and targeted therapies, the survival rate of OS patients remains limited largely due to therapy resistance and the high metastatic potential of the disease. OS models that accurately reflect the fundamental characteristics are vital to the innovation and validation of effective therapies. This review provides an insight into the advances and challenges in OS drug development, focusing on various preclinical models, including cell lines, 3D culture models, murine models, and canine models. The relevance, strengths, and limitations of each model in OS research are explored. In particular, we highlight a range of potential therapeutics identified through these models. These instances of successful drug development represent promising pathways for personalized OS treatment.

The Roles of Exosomes in Metastasis of Sarcoma: From Biomarkers to Therapeutic Targets.

Sarcoma is a heterogeneous group of mesenchymal neoplasms with a high rate of lung metastasis. The cellular mechanisms responsible for sarcoma metastasis remain poorly understood. Furthermore, there are limited efficacious therapeutic strategies for treating metastatic sarcoma. Improved diagnostic and therapeutic modalities are of increasing importance for the treatment of sarcoma due to their high mortality in the advanced stages of the disease. Recent evidence demonstrates that the exosome, a type of extracellular vesicle released by virtually all cells in the body, is an important facilitator of intercellular communication between the cells and the surrounding environment. The exosome is gaining significant attention among the medical research community, but there is little knowledge about how the exosome affects sarcoma metastasis. In this review, we summarize the multifaceted roles of sarcoma-derived exosomes in promoting the process of metastasis via the formation of pre-metastatic niche (PMN), the regulation of immunity, angiogenesis, vascular permeability, and the migration of sarcoma cells. We also highlight the potential of exosomes as innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma metastasis.

Exosomes in sarcoma: Prospects for clinical applications.

Sarcoma is a group of rare and heterogeneous mesenchymal tumors, prone to late diagnosis and poor prognosis. Exosomes are cell-derived small extracellular vesicles found in most body fluids and contain nucleic acids, proteins, lipids, and other molecules. Qualitative and quantitative changes of exosomes and the contents are associated with sarcoma progression, exhibiting their potential as biomarkers. Exosomes possess the capacity of evading immune responses, bioactivity for trafficking, tumor tropism, and lesion residence. Thus, exosomes could be engineered as tumor-specific vehicles in drugs and RNA delivery systems. Exosomes might also serve as therapeutic targets in targeted therapy and immunotherapy and be involved in chemotherapy resistance. Here, we provide a comprehensive summary of exosome applications in liquid biopsy-based diagnosis and explore their implications in the delivery system, targeted therapy, and chemotherapy resistance of sarcoma. Moreover, challenges in exosome clinical applications are raised and some future research directions are proposed.

Cementless curved endoprosthesis stem for distal femoral reconstruction in a Chinese population: a combined anatomical & biomechanical study.

BACKGROUND: The endoprosthetic knee reconstruction using a current universal femoral stem might not be suitable for local population due to the anatomical difference between Chinese and Western populations. We measured the anatomical parameters of Chinese femurs as reference for stem design, and proposed a cementless, curved, short endoprosthesis stem for the reconstruction of distal femur. This study analyzed the biomechanical performance of the newly designed stem aimed at the identification of better operative strategy. METHODS: The CT-scanning data of femurs derived from 96 healthy Chinese volunteers were imported into the Mimics software, and a segmental measurement strategy was applied to evaluate the radius of curvature (ROC) of the femoral medullary cavity. Then, 4 kinds of endoprosthetic replacement models were created based on the measurement results. Model A: the distal tumor resected femora + straight stem A; Model B: the distal tumor resected femora + curved stem B; Model C: the distal tumor resected femora + curved stem C; Model D: the distal tumor resected femora + curved stem D. Finally, the mechanical difference among these models were compared by finite element analysis. RESULTS: The mean femoral ROC of Segment1, 2, 3, 4, 5 measured in the present study was 724.5 mm, 747.5 mm, 1016.5 mm, 1286.5 mm, and 1128 mm, respectively. Based on the femoral ROC of Segment2, the stem ROC of the curved stem B, C, and D was designed as 475 mm, 700 mm, and 1300 mm, respectively. Generally, all endoprosthetic replacement models showed a normal-like stress distribution on the femurs. However, compared to the straight stem, the biomimetic curved stem showed better biomechanical performance both in terms of reducing the extent of the stress shielding of the femur and in terms of minimizing the stress distribution of the implant. CONCLUSIONS: The uncemented, curved, short stem with suitable ROC can perfectly match the Chinese femoral canal morphology which has better mechanical properties than the conventional femoral stem. Thus, this newly designed femoral stem might be an optimized method for treatment of malignant femoral tumours in the Chinese populations in the case that the numerical results are supported by future experimental studies.

Exosomal Long Non-Coding RNA ANCR Mediates Drug Resistance in Osteosarcoma.

Osteosarcoma (OS) is rare cancer with bimodal age distribution with peaks observed in children and young adults. Typically, OS is treated with pre-surgery neoadjuvant therapy, surgical excision, and post-surgery chemotherapy. However, the efficacy of treatment on disease prognosis and objective response is not currently optimal, often resulting in drug resistance; in turn, highlighting the need to understand mechanisms driving resistance to therapy in OS patients. Using Doxycycline (Dox)-sensitive and resistant variants of OS cells lines KHOS and U2OS, we found that the resistant variants KHOS-DR and U2OS-DR have significantly higher in vitro proliferation. Treating the Dox-sensitive KHOS/U2OS cells with exosomes isolated from KHOS-DR/U2OS-DR made them resistant to treatment with Dox in vitro and in vivo and enhanced tumor growth and progression, while decreasing overall survival. Expression of the long non-coding RNA (lncRNA) ANCR was significantly higher in the KHOS-DR and U2OS-DR variants. SiRNA-mediated knockdown of ANCR decreased in vitro proliferation, while increasing sensitivity to Dox treatment in the KHOS-DR/U2OS-DR cells. Expression of the exosomal lncRNA ANCR was critical for drug resistance and OS tumor progression in xenografts and was correlated to resistance to Adriamycin and overall survival is patients with OS. These results establish lncRNA ANCR as a critical mediator of resistance to therapy in OS patients, highlighting it as a potential therapeutic target in OS patients.