Investigation of a Dual siRNA/Chemotherapy Delivery System for Breast Cancer Therapy
Yongmei Zhao1, Tianqing Liu2, Aditya Ardana3
1School of Pharmacy, Nantong University, Nantong 226019 China.
Abstract:
Multidrug resistance (MDR) is a problem that is often associated with a poor clinical outcome in chemotherapeutic cancer treatment. MDR may potentially be overcome by utilizing synergistic approaches, such as combining siRNA gene therapy and chemotherapy to target different mechanisms of apoptosis. In this study, a strategy is presented for developing multicomponent nanomedicines using orthogonal and compatible chemistries that lead to effective nanotherapeutics. Hyperbranched polymers were used as drug carriers that contained doxorubicin (DOX), attached via a pH-sensitive hydrazone linkage, and ataxia-telangiectasia mutated (ATM) siRNA, attached via a redox-sensitive disulfide group. This nanomedicine also contained cyanine 5 (Cy5) as a diagnostic tracer as well as in-house developed bispecific antibodies that allowed targeting of the epidermal growth factor receptor (EGFR) present on tumor tissue. Highly efficient coupling of siRNA was achieved with 80% of thiol end-groups on the hyperbranched polymer coupling with siRNA. This attachment was reversible, with the majority of siRNA released in vitro under reducing conditions as desired. In cellular studies, the nanomedicine exhibited increased DNA damage and cancer cell inhibition compared to the individual treatments. Moreover, the nanomedicine has great potential to suppress the metabolism of cancer cells including both mitochondrial respiration and glycolytic activity, with enhanced efficacy observed when targeted to the cell surface protein EGFR. Our findings indicated that co-delivery of ATM siRNA and DOX serves as a more efficient therapeutic avenue in cancer treatment than delivery of the single species and offers a potential route for synergistically enhanced gene therapy.
Insights
This study developed a novel nanomedicine combining chemotherapy and gene therapy to overcome cancer multidrug resistance. The nanomedicine effectively delivered doxorubicin and ATM siRNA, showing enhanced cancer cell inhibition and suppressed metabolism.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Multidrug resistance (MDR) significantly limits chemotherapy efficacy and leads to poor clinical outcomes in cancer treatment.
- Synergistic approaches, combining gene therapy (siRNA) and chemotherapy, offer a promising strategy to overcome MDR by targeting multiple apoptosis pathways.
- Developing effective nanotherapeutics requires advanced strategies for precise drug and gene delivery.
Purpose of the Study:
- To design and synthesize a multicomponent nanomedicine for synergistic cancer therapy.
- To investigate the targeted delivery and controlled release of doxorubicin (DOX) and ataxia-telangiectasia mutated (ATM) siRNA.
- To evaluate the efficacy of the nanomedicine in inhibiting cancer cell growth and suppressing cancer cell metabolism.
Main Methods:
- Utilized hyperbranched polymers as drug carriers, functionalized with pH-sensitive hydrazone linkages for DOX and redox-sensitive disulfide groups for ATM siRNA.
- Incorporated cyanine 5 (Cy5) as a diagnostic tracer and bispecific antibodies for targeting the epidermal growth factor receptor (EGFR).
- Assessed siRNA coupling efficiency, *in vitro* siRNA release under reducing conditions, and cellular effects including DNA damage, cancer cell inhibition, and metabolic activity.
Main Results:
- Achieved highly efficient siRNA coupling (80%) with reversible attachment via disulfide bonds, enabling controlled *in vitro* release.
- Demonstrated enhanced DNA damage and cancer cell inhibition compared to individual treatments.
- Showed potential in suppressing cancer cell metabolism, including mitochondrial respiration and glycolytic activity, with enhanced efficacy upon EGFR targeting.
Conclusions:
- Co-delivery of ATM siRNA and doxorubicin via a multicomponent nanomedicine represents a potent strategy for synergistic cancer gene therapy.
- The developed nanomedicine effectively targets cancer cells, enhances therapeutic efficacy, and offers a promising approach to overcome multidrug resistance.
- This platform demonstrates the potential for advanced nanomedicine design using orthogonal chemistries for improved cancer treatment outcomes.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...