Polymers successfully deliver siRNAs to treat breast cancers in a preclinical model
Small interfering RNAs, or siRNAs, promise to treat tumors, thanks to their ability to specifically knock down oncogenes that promote tumor growth, without the toxicity that accompanies chemotherapy. However, siRNAs need a delivery vehicle to protect them from degradation and clearance on their journey through the bloodstream to the cancerous tumor.
Eugenia Kharlampieva, Ph.D., and Eddy Yang, MD, Ph.D., of the University of Alabama at Birmingham demonstrated a 100-nanometer polymersome that efficiently and safely transports PARP1 siRNA to cancerous tumors triple-negative breast in mice. There, siRNA knocked down the expression of the DNA repair enzyme PARP1 and, remarkably, increased the survival of mice with breast cancer fourfold.
PARP inhibitors have successfully targeted tumors with DNA repair defects and can modulate the tumor immune microenvironment. However, due to bone marrow suppression, it has been difficult to combine many PARP inhibitors with chemotherapy. Specifically targeting PARP1 in the tumor may enable new combination treatments.
“To the best of our knowledge, our work represents the first example of biodegradable, non-ionic polymeric nanovesicles capable of efficiently encapsulating and delivering PARP1 siRNAs to knock down PARP1 in vivo,” they report in the review. Applied Biological Materials ACS. “Our study provides an advanced platform for the development of precisely targeted therapeutic vectors, which could help develop efficient drug delivery nanovectors for breast cancer gene therapy.”
Their rapid and safe approach for the encapsulation and delivery of PARP1 siRNAs to breast cancer cells uses polymeric nanovesicles assembled from three biodegradable block copolymers linked together in a straight chain. The first block, a chain of 14 molecules of N-vinylpyrrolidone, is linked to the second block, a chain of 47 molecules of dimethylsiloxane, and which is linked to a third block of another chain of 14 molecules of N-vinylpyrrolidone.
UAB researchers used simple methods that allow these block polymers to assemble into hollow-sphere polymers 100 nanometers in diameter that have a robust shell thickness of about 13 nanometers. The assembly method is capable of large-scale production and consistent quality control.
The polymers assembled in the presence of a micromolar PARP1 siRNA were able to load the RNA inside the nanocarriers. When these were opened by ultrasound in vitro, the siRNA was released unchanged. The polymersomes could also be loaded with a Cy5.5 fluorescent dye; 18 hours after injection of the dye-loaded nanocarriers into tumor-bearing mice, the dye had accumulated in the tumors by passive targeting.
SiRNA-loaded polymersomes were tested with HER2-positive and trastuzumab-resistant breast cancer cells in culture. They reduced PARP1 protein levels in the cells, which inhibited their proliferation and suppressed the NF-κB transcription factor pathway, similar to what researchers have previously reported using PARP inhibitors.
The researchers were also able to attach a fluorescent dye covalently to the outside of these versatile nanocapsules, and they suggest that targeting molecules can be added in the same way to make the polymer lodge in a tumor.
“These non-ionic and biodegradable PVPON14-PDMS47-PVPON14 nanovesicles capable of efficiently encapsulating and delivering PARP1 siRNAs to successfully eliminate PARP1 in vivo have strong potential to become an advanced platform for the development of precisely targeted therapeutic carriers “, Yang mentioned. “They could contribute to the development of highly effective drug nanocarriers for breast cancer gene therapy.”
PVPON is poly(N-vinylpyrrolidone) and PDMS is poly(dimethylsiloxane). The siRNAs that polymersomes can carry are very small, about 21-25 nucleotides long, but they can specifically inhibit oncogene expression by degrading its messenger RNA.
Reference: Yang Y, Kozlovskaya V, Zhang Z, et al. Poly(N-vinylpyrrolidone)-block-Poly(dimethylsiloxane)-block-Poly(N-vinylpyrrolidone) Triblock copolymer polymers for PARP1 siRNA delivery to breast cancers. ACS Appl Bio Mater. 2022;5(4):1670-1682. doi: 10.1021/acsabm.2c00063
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