Poly(N-vinylpyrrolidone)- block-Poly(dimethylsiloxane)- block-Poly(N-vinylpyrrolidone) Triblock Copolymer Polymersomes for Delivery of PARP1 siRNA to Breast Cancers

Yiming Yang, Veronika Kozlovskaya, Zhuo Zhang, Chuan Xing, Steve Zaharias, Maksim Dolmat, Shuo Qian, Jun Zhang, Jason M. Warram, Eddy S. Yang, Eugenia Kharlampieva

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1670-1682
Number of pages13
JournalACS Applied Bio Materials
Volume5
Issue number4
DOIs
StatePublished - Apr 18 2022

Bibliographical note

Publisher Copyright:
© 2022 American Chemical Society.

Keywords

  • PARP1
  • RNA
  • anticancer drug delivery
  • in vivo imaging
  • poly(N-vinylpyrrolidone)
  • polymersomes
  • triblock copolymer

ASJC Scopus subject areas

  • Biomaterials
  • General Chemistry
  • Biomedical Engineering
  • Biochemistry, medical

Fingerprint

Dive into the research topics of 'Poly(N-vinylpyrrolidone)- block-Poly(dimethylsiloxane)- block-Poly(N-vinylpyrrolidone) Triblock Copolymer Polymersomes for Delivery of PARP1 siRNA to Breast Cancers'. Together they form a unique fingerprint.

Cite this