Long-circulating ROS-responsive micelles for targeted eradication of cancer stem cells to inhibit tumor metastasis...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Ovarian cancer mortality is primarily driven by therapy-resistant ovarian cancer stem cells (OCSCs).
• OCSCs contribute to tumor metastasis, recurrence, and chemoresistance, which are not effectively addressed by conventional therapies.
• Current treatments struggle to overcome the inherent resistance and metastatic potential of OCSCs.

Purpose of the Study:

• To develop a targeted nanotherapeutic platform for co-delivery of paclitaxel (PTX) and curcumol (CC) to OCSCs.
• To engineer reactive oxygen species (ROS)-responsive micelles that exhibit a "stealth-to-sticky" transition for selective OCSC uptake.
• To investigate the synergistic effects of PTX and CC in combination with targeted delivery to overcome OCSC-mediated chemoresistance and malignant phenotypes.

Main Methods:

• Development of ROS-responsive thioketal (TK)-linked PEG5000 micelles (TK-NMs) incorporating a follicle-stimulating hormone β (FSHβ) targeting ligand.
• Utilizing tumor microenvironmental ROS to trigger PEG shedding and FSHβ exposure for FSH receptor (FSHR)-mediated OCSC targeting.
• Investigating the mechanism of enhanced intracellular drug accumulation and bypassing ATP-binding cassette (ABC) transporter efflux.
• Evaluating the synergistic anti-cancer effects of combined PTX and CC on OCSC apoptosis and stemness pathways (Wnt/β-catenin).
• Assessing the in vivo efficacy, metastasis reduction, recurrence delay, and systemic toxicity in ovarian cancer mouse models.

Main Results:

• TK-NMs demonstrated site-specific PEG shedding and FSHβ exposure in the tumor microenvironment, leading to selective OCSC uptake.
• The nanocarrier system established a positive feedback loop between ROS-responsive disassembly and drug-induced ROS generation, enhancing apoptosis.
• Co-delivery of PTX and CC synergistically inhibited the Wnt/β-catenin pathway, reversing chemoresistance and suppressing OCSC phenotypes.
• In vivo studies showed preferential tumor accumulation, significant anti-tumor efficacy, reduced lung metastasis, and delayed post-surgical recurrence with no observed systemic toxicity.

Conclusions:

• The developed ROS-responsive TK-NMs provide an effective platform for targeted co-delivery of PTX and CC to OCSCs.
• This nanotherapeutic approach successfully overcomes key limitations of current ovarian cancer treatments, including chemoresistance and metastasis.
• The modular design offers a promising strategy for developing advanced treatments against ovarian cancer stem cells.