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Bone tumor-homing nanotherapeutics for prolonged retention in tumor microenvironment and facilitated apoptotic process via mevalonate pathway inhibition
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- Authors
- Issue Date
- 2023-04
- Publisher
- Elsevier
- Citation
- Materials Today Bio, Vol.19, p. 100591
- Abstract
- Bone malignancy features a mineralized extracellular matrix primarily composed of hydroxyapatite, which in-terferes with the distribution and activity of antineoplastic agents. Herein, we report bone tumor-homing poly-meric nanotherapeutics consisting of alendronate-decorated chondroitin sulfate A-graft-poly(lactide-co-glycolide) and doxorubicin (DOX), named PLCSA-AD, which displayed a prolonged retention profile in the tumor micro -environment and augmented therapeutic efficacy via inhibition of the mevalonate pathway. PLCSA-AD exhibited a 1.72-fold lower IC50 value than free DOX and a higher affinity for hydroxyapatite than PLCSA in HOS/MNNG cell-based 2D bone tumor-mimicking models. The inhibition of the mevalonate pathway by PLCSA-AD in tumor cells was verified by investigating the cytosolic fraction of unprenylated proteins, where blank PLCSA-AD significantly increased the expression of cytosolic Ras and RhoA without changing their total cellular amounts. In a bone tumor-mimicking xenografted mouse model, AD-decorated nanotherapeutics significantly increased tumor accumulation (1.73-fold) compared with PLCSA, and higher adsorption to hydroxyapatites was observed in the histological analysis of the tumor. As a result, inhibition of the mevalonate pathway and improvement in tumor accumulation led to markedly enhanced therapeutic efficacy in vivo, suggesting that PLCSA-AD could be promising nanotherapeutics for bone tumor treatment.
- ISSN
- 2590-0064
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