Disregarded Effect of Biological Fluids in siRNA Delivery: Human Ascites Fluid Severely Restricts Cellular Uptake of Nanoparticles

Abstract

Abstract:Small interfering RNA (siRNA) offers a great potential for the treatment of various diseases and disorders. Nevertheless, inefficient in vivo siRNA delivery hampers its translation into the Introduction:

High‐Pressure Nebulization as Application Route for the Peritoneal Administration of siRNA Complexes

“…All samples were prepared in a dust free laminar flow (LAF) and measurements were performed using a Zetasizer Nano‐ZS (Malvern instruments, Worcestershire, UK) at 25 °C. DLS measurements of complexes prepared in Opti‐MEM or biological fluids are not possible since proteins and other macromolecules can interfere with the measurements …”

“…Extracellularly, the nanoparticles have to ensure that the siRNA remains undamaged when circulating through the body. When developing nanocarriers for intraperitoneal delivery, stability in the extracellular fluids is an important requisite . Proteins in the blood and ascites fluid may, however, lead to a premature siRNA release and/or aggregation of the particles .…”

“…When developing nanocarriers for intraperitoneal delivery, stability in the extracellular fluids is an important requisite . Proteins in the blood and ascites fluid may, however, lead to a premature siRNA release and/or aggregation of the particles . When nanoparticles interact with the cell membrane they are mostly taken up by endocytosis.…”

Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis — Mission possible?

“…interact with different components including proteins and degrading enzymes that may lead to their aggregation, premature release of cargo, loss of targeting capabilities, decrease of cellular uptake, and eventually dramatic limitation of biological activity [51][52][53][54][55][56]. In this context, we have recently established an in vitro model to evaluate the performance of NPs in the presence of ascites fluid obtained from a patient diagnosed with peritoneal carcinomatosis.…”

“…Our data demonstrate that the ascites fluid does not only influence the colloidal stability of the NPs, but also drastically lowers cellular uptake of liposome-siRNA complexes. Thus, even NPs such as PEGylated liposomes that were colloidally stable in ascites fluid (in terms of aggregation and release), lost their ability to silence genes in SKOV-3 human ovarian cancer cells due to their incapability to carry the siRNA into the cells [51]. It should be noted that generally, only limited amount of ascites fluid has developed in the patients which are eligible for CRS and adjuvant IP therapy.…”