ABSTRACT
In this study, hyaluronan (HA)-functionalized calcium phosphate nanoparticles (CaP-AHA/siRNA NPs) were developed for an injectable and targetable delivery of siRNA, which were prepared by coating the alendronate-hyaluronan graft polymer (AHA) around the surface of calcium phosphate-siRNA co-precipitates. The prepared CaP-AHA/siRNA NPs had a uniform spherical core-shell morphology with an approximate size of 170 nm and zeta potential of -12 mV. The coating of hydrophilic HA improved the physical stability of nanoparticles over one month due to the strong interactions between phosphonate and calcium. In vitro experiments demonstrated that the negatively charged CaP-AHA/siRNA NPs could effectively deliver EGFR-targeted siRNA into A549 cells through CD44-mediated endocytosis and significantly down-regulate the level of EGFR expression. Also, the internalized CaP-AHA/siRNA NPs exhibited a pH-responsive release of siRNA, indicating that the acidification of lysosomes probably facilitated the disassembling of nanoparticles and the resultant ions sharply increased the inner osmotic pressure and thus expedited the release of siRNA from late lysosomes into the cytoplasm. Furthermore, in vivo tumor therapy demonstrated that high accumulation of CaP-AHA/siEGFR NPs in tumor led to a significant tumor growth inhibition with a specific EGFR gene silencing effect after intravenous administration in nude mice xenografted with A549 tumor, along with a negligible body weight loss. These results suggested that the CaP-AHA/siRNA NPs could be an effective and safe systemic siRNA delivery system for a RNAi-based tumor targeted therapy strategy.
Subject(s)
Calcium Phosphates/chemistry , Hyaluronic Acid/chemistry , Nanoparticles , Neoplasms/therapy , RNA, Small Interfering/administration & dosage , A549 Cells , Animals , Genes, erbB-1 , Humans , Mice , Mice, Nude , Xenograft Model Antitumor AssaysABSTRACT
Radionuclide hypoxia imaging has become an indispensable core of tumor diagnosis. Nitroimidazole derivatives have been extensively used as the hypoxia imaging agents in preclinical and clinical research. It is the key to design the ideal structure for promising agents. The type and quantity of nitroimidazole, the linker structure and chiral may have an impact on the imaging results. The characteristics of the imaging agents including single electron reduction potential (SERP), oil-water partition coefficient (log P) and pharmacokinetics are also the key factors. In this review, we highlight the factors for hypoxia imaging, providing clues for the structure design of new agents.
