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Aptamer-functionalized hybrid nanoparticle for the treatment of breast cancer
David Powell1, Sruti Chandra2, Kyra Dodson2
1Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, United States.
Purpose:
Resistance to chemotherapeutic agents such as doxorubicin is a major reason for cancer treatment failure. At present the treatment option for metastatic breast cancer is very poor. Therefore, development of an effective therapeutic strategy to circumvent MDR of metastatic breast cancer is highly anticipated. The MDR of metastatic breast cancer cells was accompanied with the overexpression of P-gp transporter. Even though the overexpression of P-gp could be minimized by silencing with siRNA, the question is how they can be selectively targeted to the cancer cells. We propose that aptamer surface labeling of the nanoparticles could enhance the selectively delivery of p-gp siRNA into the metastatic breast cancer cells. Our hypothesis is that conjugating nanoparticles with a cancer cell specific aptamer should allow selective delivery of therapeutic drugs to tumor cells leading to enhanced cellular toxicity and antitumor effect as compared to unconjugated nanoparticles. The primary objective of this study is to develop a targeted nanocarrier delivery system for siRNA into breast cancer cells.
Design Methods:
For targeted delivery, Aptamer A6 has been used which can bind to Her-2 receptors on breast cancer cells. For aptamer binding to particle surface, maleimide-terminated PEG-DSPE (Mal-PEG) was incorporated into the nanoparticles. Initially, three blank hybrid nanoparticles (i.e. F21, F31, and F40) out of nine different formulations prepared by high pressure homogenization (HPH) using different amount of DOTAP, cholesterol, PLGA or PLGA-PEG and Mal-PEG were chosen. Then protamine sulfate-condensed GAPDH siRNA (TRITC conjugated; red) or P-gp siRNA was encapsulated into those nanoparticles. Finally, the particles were incubated with aptamer A6 (FITC conjugated; green) for surface labeling.
Results:
Aptamer labeled-nanoparticles having PLGA are smaller in size than those having PLGA-PEG. Surface charge was reduced when the particles were labeled with aptamer. Cell transfection was increased significantly in Her-2 (+) SKBR-3 and 4T1-R cells but not in Her-2 poorly expressed MDA MB-231 and MCF-7 cells. The knockdown of P-gp was increased significantly when the particles were labeled with aptamer. No significant cellular toxicity was observed for any of these formulations.
Conclusion:
This preliminary study concludes that aptamer-functionalized hybrid nanoparticles could be used to deliver P-gp targeted siRNA into the breast cancer cells to overcome chemoresistance.
Insights
Aptamer-functionalized nanoparticles effectively deliver P-gp siRNA to breast cancer cells, enhancing treatment efficacy. This targeted approach overcomes multidrug resistance (MDR) and shows potential for improved cancer therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Multidrug resistance (MDR) in metastatic breast cancer, often due to P-glycoprotein (P-gp) overexpression, significantly limits chemotherapy effectiveness.
- Current treatment options for metastatic breast cancer are limited, highlighting the need for novel therapeutic strategies to overcome MDR.
- Targeted delivery of therapeutic agents, such as small interfering RNA (siRNA) against P-gp, to cancer cells is crucial for enhancing treatment outcomes.
Purpose of the Study:
- To develop and evaluate aptamer-functionalized hybrid nanoparticles for the targeted delivery of P-gp siRNA into metastatic breast cancer cells.
- To investigate the potential of aptamer conjugation to enhance the selective uptake of nanoparticles by Her-2 receptor-positive breast cancer cells.
- To assess the efficacy of aptamer-targeted nanoparticles in delivering P-gp siRNA and overcoming chemoresistance in breast cancer models.
Main Methods:
- Nine hybrid nanoparticle formulations were prepared using high-pressure homogenization, incorporating varying amounts of DOTAP, cholesterol, PLGA, PLGA-PEG, and maleimide-terminated PEG-DSPE (Mal-PEG).
- Blank nanoparticles (F21, F31, F40) were selected, and protamine sulfate-condensed P-gp siRNA (or GAPDH siRNA) was encapsulated.
- Nanoparticles were surface-labeled with Aptamer A6, which targets Her-2 receptors, for selective delivery to cancer cells.
Main Results:
- Aptamer-labeled nanoparticles exhibited smaller sizes compared to non-aptamer-labeled counterparts, with reduced surface charge.
- Significant increases in cell transfection were observed in Her-2-positive SKBR-3 and 4T1-R cells, but not in Her-2-poorly expressed MDA MB-231 and MCF-7 cells.
- Aptamer labeling significantly enhanced the knockdown of P-gp, indicating improved delivery and therapeutic effect, with no observed cellular toxicity.
Conclusions:
- Aptamer-functionalized hybrid nanoparticles represent a promising strategy for targeted delivery of P-gp siRNA to breast cancer cells.
- This targeted delivery system has the potential to overcome chemoresistance mediated by P-gp overexpression.
- The study provides a foundation for developing advanced nanocarrier systems for enhanced breast cancer therapy.
