Cisplatin-functionalized dual-functional bone substitute granules for bone defect treatment after bone tumor...

Area of Science:

• Biomaterials Science
• Oncology
• Orthopedic Surgery

Background:

• Invasive bone tumors present significant treatment challenges, including severe side effects from systemic chemotherapy, complex bone defects post-surgery, and high recurrence rates.
• Current therapeutic strategies often involve a combination of systemic chemotherapy and limb salvage surgery, which are limited by toxicity and efficacy.
• Novel approaches are needed to improve local tumor control and bone defect management after tumor resection.

Purpose of the Study:

• To develop dual-functional bone substitute biomaterials by functionalizing commercial bone substitutes with cisplatin for local delivery.
• To evaluate the physicochemical properties, anticancer efficacy, biosafety, and bone regenerative capacity of cisplatin-functionalized bone substitutes.
• To assess the potential of this local treatment strategy as an alternative to systemic cisplatin administration for bone tumor treatment.

Main Methods:

• Commercially available bone substitute granules (Bio-Oss® and MBCP®+) were functionalized with cisplatin.
• Physicochemical characterization (surface area, crystallinity) was performed to assess cisplatin adsorption and release.
• In vitro studies involved co-cultures of cancer cells (MDA-MB-231, PC3) and bone marrow stromal cells (hBMSCs) to evaluate cytotoxicity and mechanism of action (cell cycle arrest, apoptosis).
• In vivo studies utilized a rat femoral condyle defect model to assess bone tissue ingrowth and new bone formation.
• Systemic toxicity was evaluated by examining cisplatin accumulation and apoptotic damage in kidneys and livers.

Main Results:

• Cisplatin-functionalized Bio-Oss® granules exhibited enhanced cisplatin adsorption and release due to higher surface area and lower crystallinity compared to MBCP®+.
• In vitro, cisplatin-functionalized granules and their releasates demonstrated dose-dependent cytotoxicity against breast and prostate cancer cells, with minimal impact on hBMSCs.
• Cisplatin induced significant cell cycle arrest and apoptosis in cancer cells, but not in hBMSCs.
• In vivo, cisplatin-functionalized granules did not adversely affect bone tissue ingrowth or new bone formation in a rat model.
• Local application of cisplatin-functionalized granules resulted in negligible systemic cisplatin accumulation and no apoptotic damage in kidneys or livers.

Conclusions:

• Cisplatin-functionalized granular bone substitutes offer a dual function: local anticancer efficacy and bone regenerative capacity.
• This local delivery approach maintains a favorable balance between biosafety and therapeutic effect, avoiding systemic toxicity.
• Loading granular bone substitutes with cisplatin presents a promising, safe, and potentially more effective alternative for treating bone defects after bone tumor resections compared to systemic chemotherapy.