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pH-Responsive Nanoparticle-Coated Calcium Phosphate Granules for Bone Cancer Therapy
Lei He1, Jiaping Li2, Pamela Habibovic1
1Department of Instructive Biomaterials Engineering, MERLN Institute for Technology Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands.
Abstract:
Osteosarcoma (OS) remains the most prevalent malignant bone tumor, with stagnant survival rates and high recurrence risk due to residual tumor cells, and limited post-resection bone regeneration. Existing bifunctional bone graft substitutes integrating anticancer activity with osteogenesis are hindered by uncontrolled drug release and inefficient intracellular delivery. Here, we report a pH-sensitive nano-microparticle linking strategy, in which imine bonds are used as interfacial linkers between therapeutic nanoparticles and bone scaffolds to enable tumor microenvironment-triggered, on-demand nanotherapeutic release. In this study, we develop β-tricalcium phosphate (β-TCP) granules decorated with selenium (Se)-doped mesoporous silica nanoparticles (SeMIA@TCP), in which nanoparticles are functionalized with imine bonds for acidic pH-responsive detachment and alendronate for strong β-TCP binding. This design ensures stable nanoparticle immobilization under physiological conditions while enabling selective release within the mildly acidic OS microenvironment. In vitro, the SeMIA@TCP showed significant pH-dependent cytotoxicity toward OS cells, while maintaining low toxicity toward human mesenchymal stem cells (hMSCs) under physiological conditions, indicating a OS-targeting profile. Furthermore, the released nanoparticles enhanced alkaline phosphatase (ALP) expression and mineralization in hMSCs, underscoring their osteogenic potential. Collectively, these results demonstrate the potential of tumor microenvironment-responsive Se-doped MSN-assembled TCP granules as a design platform for bifunctional scaffolds in bone cancer treatment.
Insights
This study introduces novel pH-sensitive nanoparticles for bone cancer treatment. These nanoparticles target osteosarcoma cells in acidic tumor environments and promote bone regeneration, offering a promising bifunctional scaffold.
Area of Science:
- Biomaterials Science
- Oncology
- Nanotechnology
Background:
- Osteosarcoma (OS) is a prevalent bone cancer with poor survival rates and high recurrence.
- Current treatments face challenges with residual tumor cells and inadequate bone regeneration.
- Existing bifunctional bone grafts struggle with uncontrolled drug release and inefficient delivery.
Purpose of the Study:
- To develop a pH-sensitive nano-microparticle system for targeted osteosarcoma treatment and enhanced bone regeneration.
- To create a bifunctional bone scaffold that releases therapeutics on-demand within the tumor microenvironment.
- To improve intracellular delivery and control drug release for bone cancer therapy.
Main Methods:
- Fabrication of β-tricalcium phosphate (β-TCP) granules decorated with selenium (Se)-doped mesoporous silica nanoparticles (SeMIA@TCP).
- Functionalization of nanoparticles with imine bonds for pH-responsive release and alendronate for scaffold binding.
- In vitro evaluation of pH-dependent cytotoxicity against OS cells and toxicity toward human mesenchymal stem cells (hMSCs).
- Assessment of nanoparticle-induced osteogenic potential in hMSCs.
Main Results:
- SeMIA@TCP demonstrated pH-dependent cytotoxicity towards OS cells, with minimal toxicity to hMSCs at physiological pH.
- The system showed selective nanoparticle release in acidic tumor microenvironments.
- Released nanoparticles significantly enhanced alkaline phosphatase (ALP) expression and mineralization in hMSCs.
- Stable nanoparticle immobilization under physiological conditions was achieved.
Conclusions:
- Tumor microenvironment-responsive Se-doped MSN-assembled TCP granules represent a promising design for bifunctional scaffolds.
- This platform enables on-demand nanotherapeutic release, targeting osteosarcoma effectively.
- The developed scaffold holds potential for improving bone cancer treatment by combining anticancer activity with osteogenesis.
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