Ultrasound-assisted siRNA delivery via arginine-grafted bioreducible polymer and microbubbles targeting VEGF for ovarian cancer treatment

Abstract

The major drawback hampering siRNA therapies from being more widely accepted in clinical practice is its insufficient accumulation at the target site mainly due to poor cellular uptake and rapid degradation in serum. Therefore, we designed a novel polymeric siRNA carrier system, which would withstand serum-containing environments and tested its performance in vitro as well as in vivo. Delivering siRNA with a system combining an arginine-grafted bioreducible polymer (ABP), microbubbles (MB), and ultrasound technology (US) we were able to synergize the advantages each delivery system owns individually, and created our innovative siRNA-ABP-MB (SAM) complexes. SAM complexes show significantly higher siRNA uptake and VEGF protein knockdown in vitro with serum-containing media when compared to naked siRNA, and 25k-branched-polyethylenimine (bPEI) representing the current standard in nonviral gene therapy. SAM complexes activated by US are also able to improve siRNA uptake in tumor tissue resulting in decelerating tumor growth in vivo.

Highly effective antiangiogenesis via magnetic mesoporous silica-based siRNA vehicle targeting the VEGF gene for orthotopic ovarian cancer therapy

“…RNA interference (RNAi) technology has been intensively evaluated in the treatment of ovarian cancer by knockdown of genes responsible for progression of cancer, which is achieved by delivery vectors. [12][13][14][15][16][17] Two research groups have reported highly effective suppression of ovarian tumor growth by construction of available vectors. One research group synthesized vasohibin-2 (associated with proangiogenic activity) siRNA and mixed it with atelocollagen to inhibit ovarian tumor growth.…”

“…15 Another group developed a bioreducible polymer for delivery of VEGF-siRNA using ultrasound, which had a similar ability to inhibit tumor growth. 17 Although these two siRNA delivery systems are useful for treating ovarian cancer via intratumoral injection, there remains a need for smarter vectors to enable systemic delivery of therapeutic siRNAs to improve their efficacy in the treatment of ovarian cancer and with the biocompatibility and safety needed for clinical application.…”

Localized, non-viral delivery of nucleic acids: Opportunities, challenges and current strategies

“…Similarly, improved cytoplasmatic uptake of lipoplexes through cell membrane pores was observed [117]. Ultrasound facilitated delivery was also successfully used for siRNA transfection with naked siRNA [118], siRNA-liposome complexes [119] and siRNA-polycation complexes [120]. These studies point towards potential improvements of NA delivery efficiency in vivo using ultrasound.…”

Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats

“…20 They were also developed as a carrier of drugs and genes that can be released in a targeted manner for therapy using ultrasound irradiation. [21][22][23] UTMD also reportedly increases renal interstitial permeability, 24,25 which increases the intercellular gap and changes the microenvironment. In addition, the beneficial involvement of endocrine cytokines after UTMD improves the implantation of MSCs.…”