pH-responsive high-density lipoprotein-like nanoparticles to release paclitaxel at acidic pH in cancer chemotherapy

Jae-Yoon Shin,1,* Yoosoo Yang,1,* Paul Heo,1 Ji-Chun Lee,1 ByoungJae Kong,1 Jae Youl Cho,1 Keejung Yoon,1 Cheol-Su Shin,2 Jin-Ho Seo,3 Sung-Gun Kim,4 Dae-Hyuk Kweon11Department of Genetic Engineering, College of Biotechnology and Bioengineering, and Center for Human Interface Nano Technology, Sungkyunkwan University, 2APTech Research Center, Suwon, 3Department of Agricultural Biotechnology, Seoul National University, Seoul, 4Department of Biomedical Science, Youngdong University, Chungbuk, South Korea*These authors contributed equally to this workBackground: Nanoparticles undergoing physicochemical changes to release enclosed drugs at acidic pH conditions are promising vehicles for antitumor drug delivery. Among the various drug carriers, high-density lipoprotein (HDL)-like nanoparticles have been shown to be beneficial for cancer chemotherapy, but have not yet been designed to be pH-responsive.Methods and results: In this study, we developed a pH-responsive HDL-like nanoparticle that selectively releases paclitaxel, a model antitumor drug, at acidic pH. While the well known HDL-like nanoparticle containing phospholipids, phosphatidylcholine, and apolipoprotein A-I, as well as paclitaxel (PTX-PL-NP) was structurally robust at a wide range of pH values (3.8–10.0), the paclitaxel nanoparticle that only contained paclitaxel and apoA-I selectively released paclitaxel into the medium at low pH. The paclitaxel nanoparticle was stable at physiological and basic pH values, and over a wide range of temperatures, which is a required feature for efficient cancer chemotherapy. The homogeneous assembly enabled high paclitaxel loading per nanoparticle, which was 62.2% (w/w). The molar ratio of apolipoprotein A-I and paclitaxel was 1:55, suggesting that a single nanoparticle contained approximately 110 paclitaxel particles in a spherical structure with a 9.2 nm diameter. Among the several reconstitution methods applied, simple dilution following sonication enhanced the reconstitution yield of soluble paclitaxel nanoparticles, which was 0.66. As a result of the pH responsiveness, the anticancer effect of paclitaxel nanoparticles was much more potent than free paclitaxel or PTX-PL-NP.Conclusion: The anticancer efficacy of both paclitaxel nanoparticles and PTX-PL-NP was dependent on the expression of scavenger receptor class B type I, while the killing efficacy of free paclitaxel was independent of this receptor. We speculate that the pH responsiveness of paclitaxel nanoparticles enabled efficient endosomal escape of paclitaxel before lysosomal break down. This is the first report on pH-responsive nanoparticles that do not contain any synthetic polymer.Keywords: pH responsiveness, nanoparticle, apolipoprotein A-I, paclitaxe

Experimental and numerical investigation on cross flow in the PMR200 core

Papers presented to the 11th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, South Africa, 20-23 July 2015.The Prismatic Modular Reactor (PMR) is one of the major Very High Temperature Reactor (VHTR) concepts, which consists of hexagonal prismatic fuel blocks and reflector blocks made of nuclear grade graphite. However, the shape of graphite blocks could be easily changed by neutron damage during the reactor operation and the shape change can make the gaps between the blocks inducing bypass flow. Two types of gap shape should be considered. The vertical gap and horizontal gap are called bypass gap and cross gap, respectively. The cross gap complicates flow field in reactor core by connecting coolant channel and bypass gap and it could lead to loss of effective coolant flow in fuel blocks. In this paper, cross flow experimental facility was constructed to investigate the cross flow phenomena in the core of the VHTR and the experiment was carried out under varying flow rates and gap sizes. The results of the experiments were compared with CFD (Computational Fluid Dynamics) analysis results. In order to apply the CFD code to the cross flow phenomena, the prediction capability of the CFD code was verified. Good agreement between experimental results and CFD predictions was observed and the characteristics of the cross flow was discussed in detail.This work was supported by a Basic Atomic Energy Research Institute (BAERI) grant funded by the Korean government Ministry of Education and Science Technology (MEST) (NRF-2010-0018759)am201

Simulation study of dose enhancement in a cell due to nearby carbon and oxygen in particle radiotherapy

The aim of this study is to investigate the dose-deposition enhancement by alpha-particle irradiation in a cellular model using carbon and oxygen chemical compositions.A simulation study was performed to study dose enhancement due to carbon and oxygen for a human cell where Geant4 code used for the alpha-particle irradiation to the cellular phantom. The characteristic of dose enhancement in the nucleus and cytoplasm by the alpha-particle radiation was investigated based on concentrations of the carbon and oxygen compositions and was compared with those by gold and gadolinium.The results show that both the carbon and oxygen-induced dose enhancement was found to be more effective than those of gold and gadolinium. We found that the dose-enhancement effect was more dominant in the nucleus than in the cytoplasm if carbon or oxygen is uniformly distributed in a whole cell. In the condition that the added chemical composition was inserted only into the cytoplasm, the effect of the dose enhancement in nucleus becomes weak.We showed that high-stopping-power materials offer a more effective dose-enhancement efficacy and suggest that the carbon nanotubes and oxygenation are promising candidates for dose utilization as dose enhancement tools in particle therapy.Comment: 19 pages, 6 figures, 4 tables. presented to 7th KOREA-JAPAN Joint Meeting on Medical Physics (2014.09.25) accepted to Journal of the Korean Physical Society (2015.03.10