Multifunctional nanoparticles co-delivering EZH2 siRNA and etoposide for synergistic therapy of orthotopic
Zhi-Qiang Yuan1, Wei-Liang Chen1, Ben-Gang You1
1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Abstract:
Malignant proliferation and metastasis in non-small cell lung carcinoma (NSCLC) are great challenges for effective clinical treatment through conventional chemotherapy. The combinational therapy strategy of RNA interfering (RNAi) technology and chemotherapeutic agents have been reported to be promising for effective cancer therapy. In this study, based on multifunctional nanoparticles (NPs), the simultaneous delivery of etoposide (ETP) and anti-Enhancer of Zeste Homologue 2 (EZH2) siRNA for the effective treatment of orthotopic lung tumor was achieved. The NPs exhibited pH/redox dual sensitivity verified by particle size changes, morphological changes, and in vitro release of drugs. Confocal microscopy analysis confirmed that the NPs exhibited endosomal escape property and on-demand intracellular drug release behavior, which can protect siRNA from degradation and facilitate the chemotherapeutic effect respectively. In vitro tumor cell motility study demonstrated that EZH2 siRNA loaded in NPs can decrease the migration and invasion capabilities of tumor cells by downregulating the expression of EZH2 mRNA and protein. In particular, an antiproliferation study revealed that the co-delivery of siRNA and ETP in the multifunctional NPs can induce a synergistic therapeutic effect on NSCLC. In vivo targeting evaluation showed that cRGDyC-PEG modification on NPs exhibited a low distribution in normal organs and an obvious accumulation in orthotopic lung tumor. Furthermore, targeted NPs co-delivering siRNA and ETP showed superior inhibition on tumor growth and metastasis and produced minimal systemic toxicity. These findings indicated that multifunctional NPs can be utilized as a co-delivery system, and that the combination of EZH2 siRNA and ETP can effectively treat NSCLC.
Insights
Multifunctional nanoparticles simultaneously deliver etoposide (chemotherapy) and Enhancer of Zeste Homologue 2 (EZH2) siRNA to effectively treat non-small cell lung carcinoma (NSCLC) by inhibiting tumor growth and metastasis with minimal toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Non-small cell lung carcinoma (NSCLC) presents significant challenges in treatment due to malignant proliferation and metastasis.
- Conventional chemotherapy often has limitations in effectively treating advanced NSCLC.
- Combination therapy using RNA interference (RNAi) and chemotherapy shows promise for enhanced cancer treatment.
Purpose of the Study:
- To develop multifunctional nanoparticles (NPs) for the simultaneous delivery of etoposide (ETP) and anti-Enhancer of Zeste Homologue 2 (EZH2) siRNA.
- To evaluate the efficacy of this dual-delivery system in treating orthotopic lung tumors.
- To investigate the synergistic therapeutic effect and targeted delivery of the NPs.
Main Methods:
- Fabrication of pH/redox dual-sensitive multifunctional NPs for co-delivery of ETP and EZH2 siRNA.
- In vitro characterization including particle size, morphology, drug release, endosomal escape, and cell motility assays.
- In vivo studies involving targeted delivery evaluation and assessment of tumor growth and metastasis inhibition in orthotopic lung tumor models.
- Assessment of systemic toxicity.
Main Results:
- NPs demonstrated pH/redox dual sensitivity, controlled drug release, and effective endosomal escape.
- EZH2 siRNA significantly reduced tumor cell migration and invasion by downregulating EZH2 expression.
- Co-delivery of EZH2 siRNA and ETP via NPs induced a synergistic anti-cancer effect.
- Targeted NPs showed preferential accumulation in lung tumors with minimal distribution in normal organs.
- The targeted NPs significantly inhibited tumor growth and metastasis with reduced systemic toxicity.
Conclusions:
- Multifunctional NPs serve as an effective co-delivery system for NSCLC treatment.
- The combination of EZH2 siRNA and ETP delivered by NPs offers a promising synergistic therapeutic strategy.
- Targeted delivery enhances therapeutic efficacy and minimizes off-target effects for NSCLC treatment.
