Targeted delivery of liposomal senolytics to alleviate cellular senescence-induced bone loss
Rong Li1,2, Yaohua Wei2, Changhao Xiong2
1College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
Abstract:
The senescence of bone marrow-derived mesenchymal stem cells is involved in osteoporosis. The combination of dasatinib and quercetin has been explored to alleviate bone loss by efficiently reducing senescent cell populations. However, senolytic therapy by dasatinib and quercetin requires a precise ratio for better therapeutic effects, which is hard to achieve by oral administration. Meanwhile, the poor water solubility of these compounds limits their bioavailability, and their non-specific action could hamper effective penetration and targeting within relevant tissues. Herein, we developed alendronate-functionalized liposomes carrying dasatinib and quercetin (Aln-Lipo-DQ), focusing mainly on senescence-associated osteoporosis induced by chemotherapy or radiotherapy. Alendronate helps liposomes deliver dasatinib and quercetin to the femur and tibias, effectively removing senescent cells from bone tissue and increasing bone volume fraction from 5.05% to 11.95% in the chemotherapy-induced osteoporosis mouse model. We also found a 2.91-fold increase in bone volume fraction in Aln-Lipo-DQ treated groups compared to the control in radiotherapy models. This selectively targeting bone and reducing senescent cells holds great promise for cancer treatment-related and senescence-associated bone disorders.
Insights
New liposome delivery targets senescent cells in bone, effectively treating osteoporosis. This approach enhances bone volume and shows promise for bone disorders linked to cancer treatments.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Pharmacology
Background:
- Cellular senescence in bone marrow-derived mesenchymal stem cells contributes to osteoporosis.
- Senolytic therapy using dasatinib and quercetin shows potential for osteoporosis but faces challenges in precise dosing, bioavailability, and targeted delivery.
- Existing limitations hinder the therapeutic efficacy of senolytic agents for bone disorders.
Purpose of the Study:
- To develop an effective drug delivery system for senolytic therapy targeting bone disorders.
- To overcome the limitations of oral administration, poor water solubility, and non-specific action of dasatinib and quercetin.
- To investigate the efficacy of alendronate-functionalized liposomes carrying dasatinib and quercetin (Aln-Lipo-DQ) in treating senescence-associated osteoporosis.
Main Methods:
- Development of alendronate-functionalized liposomes encapsulating dasatinib and quercetin (Aln-Lipo-DQ).
- Administration of Aln-Lipo-DQ in mouse models of chemotherapy-induced osteoporosis (CIO) and radiotherapy-induced osteoporosis (RIO).
- Evaluation of bone volume fraction and senescent cell populations in treated bone tissues.
Main Results:
- Aln-Lipo-DQ significantly increased bone volume fraction from 5.05% to 11.95% in the CIO model.
- A 2.91-fold increase in bone volume fraction was observed in the RIO model compared to controls.
- The developed liposomes effectively delivered senolytic agents to bone tissue, reducing senescent cells.
Conclusions:
- Alendronate-functionalized liposomes provide targeted delivery of dasatinib and quercetin to bone, enhancing therapeutic outcomes.
- Aln-Lipo-DQ demonstrates significant potential for treating senescence-associated osteoporosis, particularly that induced by chemotherapy or radiotherapy.
- This targeted senolytic therapy offers a promising strategy for managing bone disorders associated with cancer treatments and aging.
