Biodegradable, nonionic polymeric nanovesicles efficiently encapsulate and deliver siRNA

Small interfering RNAs, or siRNAs, hold promise for the treatment of tumors, due to their ability to specifically knock out oncogenes that promote tumor growth, without the toxicity associated with chemotherapy. However, the siRNAs require a delivery vehicle to protect them from degradation and clearance on their journey through the bloodstream to the cancer tumor.

Eugenia Kharlampieva, Ph.D., and Eddy Yang, MD, Ph.D., of the University of Alabama at Birmingham have demonstrated a 100 nanometer polymer that safely and efficiently transports PARP1 siRNA to triple-negative breast cancer tumors in mice. There, the siRNA precipitated expression of the DNA repair enzyme PARP1, and, remarkably, gave breast cancer-bearing mice a four-fold increase in survival.

PARP inhibitors have been successful in targeting tumors with defects in DNA repair and can modulate the tumor immune microenvironment. However, due to bone marrow suppression, combining many of the PARP inhibitors with chemotherapy has been challenging. Targeting PARP1 in the tumor specifically may allow for new combination treatments.

“To our knowledge, our work represents the first example of biodegradable, non-ionic polymeric nanovesicles that are able to efficiently encapsulate and deliver PARP1 siRNA to knock down PARP1 in vivo,” they report. in the magazine ACS applied biomaterials† “Our study provides an advanced platform for developing precision-targeted therapeutic carriers, which could help develop effective nanocarriers for drug delivery for breast cancer gene therapy.”

Their rapid and safe approach to encapsulation of PARP1 siRNA and delivery to breast cancer cells uses polymeric nanovesicles composed of 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 14-molecule chain of N-vinylpyrrolidone.

The UAB researchers used straightforward methods that allowed these block polymers to assemble into 100 nanometer-diameter, hollow-sphere polymersomes with a robust shell thickness of about 13 nanometers. The assembly method is capable of large-scale production and consistent quality control.

Polymersomes assembled in the presence of one micromolar PARP1 siRNA were able to load the RNA into the nanocarriers. When these were disrupted by ultrasound in vitro, the siRNA was released unchanged. The polymersomes can also be loaded with Cy5.5 fluorescent dye; 18 hours after injection of the dye-loaded nanocarriers into tumor-bearing mice, dye had accumulated in the tumors by passive targeting.

siRNA-loaded polymersomes were tested with HER2-positive, trastuzumab-resistant breast cancer cells in culture. They decreased the protein levels of PARP1 in the cells, which inhibited their proliferation and suppressed the NF-KB transcription factor pathway, similar to what the researchers reported previously with PARP inhibitors.

Researchers were also able to covalently attach fluorescent dye to the outside of these versatile nanocapsules, and they suggest targeting molecules could be added in the same way to bring the polymersome home into a tumor.

This non-ionic, biodegradable PVPON14PDMS47PVPON14 nanovesicles capable of the efficient encapsulation and delivery of PARP1 siRNA to successfully knock down PARP1 in vivo have strong potential to become an advanced platform for the development of precision-targeted therapeutic carriers. They could help develop highly effective drug delivery nanocarriers for breast cancer gene therapy.”


Eddy Yang, University of Alabama at Birmingham

PVPON is poly(N-vinylpyrrolidone) and PDMS is poly(dimethylsiloxane). The siRNAs that the polymersomes can carry are very small, about 21 to 25 nucleotides in length, but they can specifically inhibit oncogene expression by degradation of its messenger RNA.

Kharlampieva is a distinguished professor in the Department of Chemistry at the UAB College of Arts and Sciences. Yang is a professor in the Department of Radiation Oncology, Marnix E. Heersink School of Medicine at UAB, and he holds the ROAR Southeast Cancer Foundation Endowed Chair in Radiation Oncology. Both are senior scientists at the O’Neal Comprehensive Cancer Center.

Co-authors with Kharlampieva and Yang in the study, “Poly(N-vinylpyrrolidone)-block-poly(dimethylsiloxane)-block-poly(N-vinylpyrrolidone) triblock copolymer polymersomes for the delivery of PARP1 siRNA to breast cancer,” are Yiming Yang , Veronika Kozlovskaya, Steve Zaharias, Maksim Dolmat and Jun Zhang, UAB Chemistry Department; Zhuo Zhang, Chuan Xing, UAB Department of Radiation Oncology; Shuo Qian, Oak Ridge National Laboratory, Oak Ridge, Tennessee; and Jason M. Warram, UAB ENT Department.

Support came from the National Science Foundation Division of Materials Research award 1608728, the American Association for Cancer Research/Triple Negative Breast Cancer Foundation grant 15-20-43-YANG, and grants from Autotec LLC and the Breast Cancer Research Foundation of Alabama .

Source:

Reference magazine:

Yang, Y., et al† (2022) Poly(N-vinylpyrrolidone) Block-Poly(dimethylsiloxane)-block-Poly(N-vinylpyrrolidone) Triblock Copolymer Polymers for Delivery of PARP1 siRNA to Breast Cancer. ACS applied biomaterialsdoi.org/10.1021/acsabm.2c00063

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