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Published on: March 18, 2014
Dual-Responsive Micelles Co-delivering All-Trans Retinoic Acid and Paclitaxel for Enhanced Eradication of
Zhiyu Chen1, Junhong Chen1, Shuang Liu2
1Department of Orthopaedic Surgery, Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Orthopaedic Research Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P. R. China.
Abstract:
Osteosarcoma is the most prevalent primary bone cancer affecting children and adolescents, characterized by its high invasiveness and the challenges in treatment posed by multidrug resistance. Cancer stem cells significantly contribute to poor clinical outcomes; however, current targeted therapies remain limited in their effectiveness. In this study, we developed a novel dual-responsive nanomedicine designed to target the microenvironment of osteosarcoma cancer stem cells (OCSCs) and osteosarcoma itself, which selectively releases all-trans retinoic acid and paclitaxel, termed mPCDAP. Our findings indicate that mPCDAP rapidly releases all-trans retinoic acid to suppress stemness under conditions of elevated glutathione, subsequently increasing intracellular reactive oxygen species levels in tumor cells. This mechanism further facilitates the release of paclitaxel under conditions of highly reactive oxygen species, thereby inducing apoptosis in osteosarcoma cells. Additionally, mPCDAP was effectively internalized by both osteosarcoma cells and OCSCs, with in vitro and in vivo results demonstrating significant synergistic antitumor effects, promoting apoptosis and markedly reducing tumor stemness. This study presents a novel approach and promising prospects for targeted therapy of osteosarcoma and OCSCs.
Insights
A novel nanomedicine, mPCDAP, targets osteosarcoma cancer stem cells (OCSCs) by releasing drugs in response to the tumor microenvironment. This approach effectively suppresses OCSC stemness and induces apoptosis in osteosarcoma cells.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanotechnology
Background:
- Osteosarcoma is a primary bone cancer in children and adolescents.
- Multidrug resistance and cancer stem cells (CSCs) complicate osteosarcoma treatment.
- Current targeted therapies for osteosarcoma and OCSCs are limited.
Purpose of the Study:
- To develop a dual-responsive nanomedicine for targeting osteosarcoma and its cancer stem cells.
- To investigate the drug release mechanism and synergistic effects of the nanomedicine.
Main Methods:
- Development of a dual-responsive nanomedicine (mPCDAP) releasing all-trans retinoic acid and paclitaxel.
- Evaluation of mPCDAP's drug release triggered by glutathione and reactive oxygen species (ROS).
- In vitro and in vivo studies assessing mPCDAP's internalization, anti-tumor effects, and impact on stemness.
Main Results:
- mPCDAP releases all-trans retinoic acid under high glutathione, reducing stemness and increasing ROS.
- Subsequent paclitaxel release under high ROS induces osteosarcoma cell apoptosis.
- mPCDAP demonstrated significant synergistic anti-tumor effects, reducing stemness and promoting apoptosis in vitro and in vivo.
Conclusions:
- mPCDAP offers a novel targeted therapy approach for osteosarcoma.
- The dual-responsive nanomedicine effectively targets both osteosarcoma cells and OCSCs.
- This strategy shows promising prospects for overcoming multidrug resistance and improving osteosarcoma treatment outcomes.
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