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Nanosystem Delivers Senescence Activators and Immunomodulators to Combat Liver Cancer
Ke Gong1, Juyang Jiao2, Zhihua Wu1
1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, P. R. China.
Abstract:
CD47 blockade has emerged as a promising immunotherapy against liver cancer. However, the optimization of its antitumor effectiveness using efficient drug delivery systems or combinations of therapeutic agents remains largely incomplete. Here, patients with liver cancer co-expressing CD47 and CDC7 (cell division cycle 7, a negative senescence-related gene) are found to have the worst prognosis. Moreover, CD47 is highly expressed, and senescence is inhibited after the development of chemoresistance, suggesting that combination therapy targeting CD47 and CDC7 to inhibit CD47 and induce senescence may be a promising strategy for liver cancer. The efficacy of intravenously administered CDC7 and CD47 inhibitors is limited by low uptake and short circulation times. Here, inhibitors are coloaded into a dual-targeted nanosystem. The sequential release of the inhibitors from the nanosystem under acidic conditions first induces cellular senescence and then promotes immune responses. In an in situ liver cancer mouse model and a chemotherapy-resistant mouse model, the nanosystem effectively inhibited tumor growth by 90.33% and 85.15%, respectively. Overall, the nanosystem in this work achieved the sequential release of CDC7 and CD47 inhibitors in situ to trigger senescence and induce immunotherapy, effectively combating liver cancer and overcoming chemoresistance.
Insights
A novel nanosystem delivers CD47 and CDC7 inhibitors to combat liver cancer. This dual-targeted approach induces senescence and immunotherapy, significantly inhibiting tumor growth and overcoming chemoresistance.
Area of Science:
- Oncology
- Immunotherapy
- Nanomedicine
Background:
- CD47 blockade shows promise for liver cancer immunotherapy but requires optimization.
- Co-expression of CD47 and CDC7 correlates with poor prognosis in liver cancer patients.
- Chemoresistance in liver cancer involves high CD47 expression and inhibited senescence.
Purpose of the Study:
- To develop an optimized drug delivery system for CD47 and CDC7 inhibitors.
- To investigate the potential of combined CD47 and CDC7 inhibition for liver cancer treatment.
- To induce cellular senescence and enhance immunotherapy in chemoresistant liver cancer.
Main Methods:
- Coloading of CDC7 and CD47 inhibitors into a dual-targeted nanosystem.
- Sequential drug release from the nanosystem under acidic conditions.
- Evaluation of the nanosystem's efficacy in in situ liver cancer and chemoresistant mouse models.
Main Results:
- The nanosystem demonstrated significant tumor growth inhibition (90.33% in liver cancer, 85.15% in chemoresistant models).
- Sequential release of inhibitors effectively induced cellular senescence and promoted immune responses.
- The dual-targeted nanosystem overcame limitations of intravenous administration, such as low uptake and short circulation times.
Conclusions:
- The developed nanosystem offers a promising strategy for liver cancer treatment by sequentially delivering CDC7 and CD47 inhibitors.
- This approach effectively induces senescence and immunotherapy, combating liver cancer and overcoming chemoresistance.
- The dual-targeted nanosystem represents an advancement in nanomedicine for cancer therapy.
