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Multifunctional polyamidoamine-modified selenium nanoparticles dual-delivering siRNA and cisplatin to A549/DDP cells
Wenjing Zheng1, Chengwen Cao1, Yanan Liu2
1Department of Chemistry, Jinan University, Guangzhou 510632, China.
Abstract:
Multidrug resistance (MDR) is a major barrier against effective cancer treatment. Dual-delivering a therapeutic small interfering RNA (siRNA) and chemotherapeutic agents has been developed to reverse drug resistance in tumor cells. In this study, amine-terminated generation 5 polyamidoamine (PAMAM) dendrimers (G5.NH2)-modified selenium nanoparticles (G5@Se NP) were synthesized for the systemic dual-delivery of mdr1 siRNA and cisplatin (cis-diamminedichloroplatinum-(II), DDP), which was demonstrated to enhance siRNA loading, releasing efficiency and gene-silencing efficacy. When the mdr1 siRNA was conjugated with G5@Se NP via electrostatic interaction, a significant down-regulation of P-glycoprotein and multidrug resistance-associated protein expression was observed; G5@Se-DDP-siRNA arrested A549/DDP cells at G1 phase and led to enhanced cytotoxicity in A549/DDP cells through induction of apoptosis involving the AKT and ERK signaling pathways. Interestingly, G5@Se-DDP NP were much less reactive than DDP in the reactions with both MT and GSH, indicating that loading of DDP in a nano-delivery system could effectively prevent cell detoxification. Furthermore, animal studies demonstrated that the new delivery system of G5@Se-DDP-siRNA significantly enhanced the anti-tumor effect on tumor-bearing nude mice, with no appreciable abnormality in the major organs. These results suggest that G5@Se NP could be a potential platform to combine chemotherapy and gene therapy technology in the treatment of human disease.
Insights
This study developed a novel nanoparticle system for dual delivery of chemotherapy and gene therapy to combat multidrug resistance in cancer. The system effectively enhanced anti-tumor effects in mice with no major organ damage.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Multidrug resistance (MDR) significantly hinders effective cancer treatment.
- Dual-delivery systems combining chemotherapy and gene therapy show promise for overcoming drug resistance.
Purpose of the Study:
- To synthesize and evaluate amine-terminated generation 5 polyamidoamine (PAMAM) dendrimers (G5.NH2)-modified selenium nanoparticles (G5@Se NP) for dual delivery of mdr1 siRNA and cisplatin (DDP).
- To assess the enhanced siRNA loading, release efficiency, gene-silencing efficacy, and anti-tumor activity of the G5@Se-DDP-siRNA system.
Main Methods:
- Synthesis of G5.NH2-modified selenium nanoparticles (G5@Se NP).
- Conjugation of mdr1 siRNA and cisplatin (DDP) to G5@Se NP via electrostatic interaction.
- In vitro evaluation of gene silencing, cell cycle arrest, apoptosis induction, and cytotoxicity in A549/DDP cells.
- In vitro assessment of DDP reactivity with cellular thiols (MT and GSH).
- In vivo anti-tumor efficacy studies in tumor-bearing nude mice.
Main Results:
- G5@Se NP enhanced siRNA loading, release, and gene silencing, down-regulating P-glycoprotein and multidrug resistance-associated protein.
- G5@Se-DDP-siRNA induced apoptosis and enhanced cytotoxicity in A549/DDP cells via AKT and ERK pathways, arresting cells in G1 phase.
- Cisplatin (DDP) loading in G5@Se NP reduced its reactivity with MT and GSH, preventing cellular detoxification.
- The G5@Se-DDP-siRNA system demonstrated significant anti-tumor effects in vivo with no observable toxicity in major organs.
Conclusions:
- G5@Se NP serves as an effective platform for the dual delivery of siRNA and chemotherapy drugs.
- This combined chemo-gene therapy approach shows significant potential for overcoming multidrug resistance in cancer treatment.
- The G5@Se NP platform holds promise for developing advanced therapeutic strategies for various human diseases.
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