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Updated: Sep 3, 2025
Preparation of Neutrally-charged, pH-responsive Polymeric Nanoparticles for Cytosolic siRNA Delivery
Published on: May 2, 2019
Co-Delivery of siRNA and Chemotherapeutic Drug Using 2C5 Antibody-Targeted Dendrimer-Based Mixed Micelles for
Satya Siva Kishan Yalamarty1, Nina Filipczak1, Xiang Li2
1Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
Abstract:
Multidrug resistance (MDR) observed in tumors significantly hinders the efficacy of chemotherapy. Downregulation of efflux proteins, such as P-glycoprotein (P-gp), using small interfering RNA (siRNA) can be an effective way to minimize the resistance in tumors. In this study, monoclonal antibody 2C5 (mAb 2C5)-PEG7k-DOPE conjugates were post-inserted into the mixed dendrimer micelles containing generation 4 (G4) polyamidoamine (PAMAM)-PEG2k-DOPE and PEG5k-DOPE. The inherent amphiphilic nature of DOPE conjugates causes the copolymers to self-assemble to form a micelle, which can encapsulate hydrophobic chemotherapeutic drugs in its core. The siRNA electrostatically binds to the cationic charges on the G4 PAMAM dendrimer. The tumor-specific mAb 2C5 on the surface of these nano-preparations resulted in improved tumor targeting. This active targeting to tumors can cause increase in the drug and siRNA accumulation at the tumor site, and thereby minimizing the off-target effects. The micelles were shown to have higher cellular association and effectiveness in vitro. The immunomicelle preparation was also tested for cytotoxicity in breast (MDA-MB-231) and ovarian (SKOV-3TR) MDR cancer cell lines.
Insights
This study developed novel immunomicelles to combat multidrug resistance (MDR) in cancer. These targeted nanoparticles deliver small interfering RNA (siRNA) and drugs directly to tumors, enhancing chemotherapy efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Multidrug resistance (MDR) in tumors significantly reduces chemotherapy effectiveness.
- P-glycoprotein (P-gp) is a key efflux protein contributing to MDR.
- Small interfering RNA (siRNA) offers a strategy to downregulate P-gp and overcome resistance.
Purpose of the Study:
- To develop targeted nanomicelles for co-delivery of siRNA and chemotherapeutic drugs.
- To enhance tumor targeting and minimize off-target effects of cancer therapy.
- To evaluate the efficacy of these immunomicelles in MDR cancer cell lines.
Main Methods:
- Fabrication of mixed dendrimer micelles incorporating PEGylated DOPE conjugates.
- Post-insertion of monoclonal antibody 2C5 (mAb 2C5)-PEG7k-DOPE for active tumor targeting.
- Encapsulation of hydrophobic drugs in micelle cores and electrostatic binding of siRNA to PAMAM dendrimers.
- In vitro evaluation of cellular association, effectiveness, and cytotoxicity in MDR cancer cell lines (MDA-MB-231 and SKOV-3TR).
Main Results:
- Self-assembled micelles effectively encapsulated hydrophobic drugs and bound siRNA.
- mAb 2C5 conjugation facilitated improved tumor targeting and accumulation of payload at the tumor site.
- The immunomicelles demonstrated enhanced cellular association and in vitro effectiveness.
- Cytotoxicity was observed in both breast and ovarian MDR cancer cell lines.
Conclusions:
- The developed immunomicelles show promise for overcoming MDR in cancer by enabling targeted co-delivery of siRNA and drugs.
- This approach offers a strategy to enhance chemotherapy efficacy and reduce systemic toxicity.
- Further investigation is warranted to explore their therapeutic potential in vivo.
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