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Apoptotic tumor cell-derived microparticles loading Napabucasin inhibit CSCs and synergistic immune therapy
Boping Jing1,2,3, Feng Guo4, Rui An3,5
1Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Background:
Cancer stem cells (CSCs) are crucial for the growth, metastasis, drug resistance, recurrence, and spread of tumors. Napabucasin (NAP) could effectively inhibit CSC, but its mechanism has not been fully explained. Additionally, NAP also has the drawbacks of poor water solubility and low utilization. Therefore, this study not only elaborated the new mechanism of NAP inhibiting CSCs, but also built NAP-loaded nanoprobes using apoptotic tumor-derived microparticles (TMPs) as carriers to combine diagnose and treat of colon cancer and lessen the adverse effects of NAP.
Results:
The study discovered a new mechanism for NAP inhibiting tumors. NAP, in addition to inhibiting STAT3, may also inhibit STAT1, thereby inhibiting the expression of CD44, and the stemness of colon cancer. N3-TMPs@NAP was successfully synthesized, and it possessed a lipid bilayer with a particle size of 220.13 ± 4.52 nm, as well as strong tumor binding ability and anti-tumor effect in vitro. In static PET/CT imaging studies, the tumor was clearly visible and showed higher uptake after N3-TMPs@NAP injection than after oral administration. The average tumor volume and weight of the N3-TMPs@NAP group on day 14 of the treatment studies were computed to be 270.55 ± 107.59 mm3 and 0.30 ± 0.12 g, respectively. These values were significantly lower than those of the other groups. Additionally, N3-TMPs@NAP might prevent colon cancer from spreading to the liver. Furthermore, due to TMPs' stimulation of innate immunity, N3-TMPs@NAP might stimulate anti-tumor.
Conclusions:
As a combined diagnostic and therapeutic nanoprobe, N3-TMPs@NAP could successfully conduct PET/CT imaging, suppress CSCs, and synergistically stimulate anticancer immune responses. Additionally, this nanoprobe might someday be employed in clinical situations because TMPs for it can be produced from human tissue and NAP has FDA approval.
Insights
This study reveals Napabucasin (NAP) inhibits colon cancer stem cells (CSCs) by targeting STAT1 and STAT3. A novel nanoprobe, N3-TMPs@NAP, enhances diagnosis and treatment, improving efficacy and reducing side effects.
Area of Science:
- Oncology
- Nanomedicine
- Cancer Stem Cell Biology
Background:
- Cancer stem cells (CSCs) drive tumor growth, metastasis, and drug resistance.
- Napabucasin (NAP) shows potential against CSCs, but its mechanism and delivery are limited by poor solubility and low utilization.
- Apoptotic tumor-derived microparticles (TMPs) offer a promising carrier for targeted drug delivery and combination therapy.
Purpose of the Study:
- To elucidate the novel mechanism of NAP in inhibiting colon CSCs.
- To develop a NAP-loaded nanoprobe using TMPs for combined diagnosis and treatment of colon cancer.
- To improve NAP's efficacy and reduce its adverse effects.
Main Methods:
- Investigated NAP's effect on STAT1, STAT3, CD44 expression, and colon CSC stemness.
- Synthesized N3-TMPs@NAP nanoprobes using apoptotic TMPs as carriers.
- Evaluated the in vitro anti-tumor effects and in vivo PET/CT imaging capabilities of N3-TMPs@NAP.
- Assessed the therapeutic efficacy and potential anti-metastatic effects of N3-TMPs@NAP in colon cancer models.
Main Results:
- Discovered NAP inhibits CSCs by targeting STAT1 and STAT3, reducing CD44 expression and stemness.
- Successfully synthesized N3-TMPs@NAP (220.13 nm) with strong tumor-binding and in vitro anti-tumor activity.
- N3-TMPs@NAP demonstrated superior tumor visibility and uptake via PET/CT imaging compared to oral NAP.
- Significantly reduced tumor volume and weight, with potential to inhibit liver metastasis, and stimulated anti-tumor immune responses.
Conclusions:
- N3-TMPs@NAP functions as a theranostic nanoprobe for PET/CT imaging, CSC suppression, and immune stimulation.
- The nanoprobe shows potential for clinical application due to the use of human-derived TMPs and FDA-approved NAP.
- This approach offers a promising strategy for enhanced colon cancer diagnosis and treatment.
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