Nearly 20% of HER2-positive breast cancers develop resistance to HER2-targeted therapies requiring the use of advanced therapies. Silencing RNA therapy may be a powerful modality for treating resistant HER2 cancers due to its high specificity and low toxicity. However, the systemic administration of siRNAs requires a safe and efficient delivery platform because of siRNA's low stability in physiological fluids, inefficient cellular uptake, immunoreactivity, and rapid clearance. We have developed theranostic polymeric vesicles to overcome these hurdles for encapsulation and delivery of small functional molecules and PARP1 siRNA for in vivo delivery to breast cancer tumors. The 100 nm polymer vesicles were assembled from biodegradable and non-ionic poly(N-vinylpyrrolidone)14-block-poly(dimethylsiloxane)47-block-poly(N-vinylpyrrolidone)14 triblock copolymer PVPON14-PDMS47-PVPON14 using nanoprecipitation and thin-film hydration. We demonstrated that the vesicles assembled from the copolymer covalently tagged with the Cy5.5 fluorescent dye for in vivo imaging could also encapsulate the model drug with high loading efficiency (40%). The dye-loaded vesicles were accumulated in tumors after 18 h circulation in 4TR breast tumor-bearing mice via passive targeting. We found that PARP1 siRNA encapsulated into the vesicles was released intact (13%) into solution by the therapeutic ultrasound treatment as quantified by gel electrophoresis. The PARP1 siRNA-loaded polymersomes inhibited the proliferation of MDA-MB-361TR cells by 34% after 6 days of treatment by suppressing the NF-kB signaling pathway, unlike their scrambled siRNA-loaded counterparts. Finally, the treatment by PARP1 siRNA-loaded vesicles prolonged the survival of the mice bearing 4T1 breast cancer xenografts, with the 4-fold survival increase, unlike the untreated mice after 3 weeks following the treatment. These biodegradable, non-ionic PVPON14-PDMS47-PVPON14 polymeric nanovesicles capable of the efficient encapsulation and delivery of PARP1 siRNA to successfully knock down PARP1 in vivo can provide an advanced platform for the development of precision-targeted therapeutic carriers, which could help develop highly effective drug delivery nanovehicles for breast cancer gene therapy.
|Number of pages||13|
|Journal||ACS Applied Bio Materials|
|State||Published - Apr 18 2022|
Bibliographical noteFunding Information:
This work was supported by NSF DMR Award No. 1608728 (E.K.). E.S.Y. is a ROAR Southeast Cancer Foundation Endowed Chair and acknowledges support by grants from Autotec LLC, Breast Cancer Research Foundation of Alabama, and American Association for Cancer Research/Triple Negative Breast Cancer Foundation (15-20-43-YANG). The MDA-MB-361TR cell line was kindly provided by Drs. Rachel Schiff and C. Kent Osborne (Department of Medicine, Baylor College of Medicine, Houston, TX, USA). UAB High-Resolution Imaging Facility is acknowledged for the use of TEM. Small-animal imaging studies were supported through the UAB Comprehensive Cancer Center and by UAB Preclinical Imaging Shared Facility Grant P30CA013148 (J.M.W.). Bio-SANS is funded by the Office of Biological and Environmental Research of the U.S. Department of Energy; HFIR at ORNL is supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. S.Q. was supported by resources of the Spallation Neutron Source Second Target Station at ORNL.
© 2022 American Chemical Society.
- anticancer drug delivery
- in vivo imaging
- triblock copolymer
ASJC Scopus subject areas
- Chemistry (all)
- Biomedical Engineering
- Biochemistry, medical