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.