Mesoporous Hydroxyapatite as Drug Carrier for Long-acting Antidepression Treatment and Stimulation of Exosome

• Main Authors: Yan-Jye Shyong, 熊彥傑
• Other Authors: Feng-Huei Lin
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/h8ns54

博士 === 國立臺灣大學 === 醫學工程學研究所 === 105 === An antidepressant carrier was designed to maintain over two weeks of constant medication release. The carrier was injected into muscle where cellular activity was involved to achieve the goal of constant release. Meso-porous hydroxyapatite (mesoHAP) was synthesized into an adequate size by co-precipitation method; and then gone through a series of hydrophobic surface modification for olanzapine (OLZ) loading by physical absorption to produce mesoHAP-OLZ. Owing to its hydrophobic nature, OLZ is not effectively released from mesoHAP-OLZ in aqueous environment. However, once engulfed by macrophage, lysosome/endosome hybrid was ruptured due to osmotic pressure alteration, resulting in the release of OLZ into cytoplasma. OLZ was then exocytosed to the extracellular space due to high calcium ion (Ca2+) concentration, and finally circulated in the blood. In the in vivo study, the efficiency of the treatment was evaluated from 3 perspectives; locomotor activities, biomarkers, and learning and memory ability. MesoHAP-OLZ can increase the locomotor activity in rats with induced depression determined by open field test (OFT) and forced swim test (FST). Serotonin (5-HT), one of the most important biomarker in depression can also be increased by mesoHAP-OLZ, leading to increased hippocampus activity as measured by functional magnetic resonance imaging (fMRI). MesoHAP-OLZ can also improve learning and memory ability in rats with induced depression using Morris water maze (MWM) test. Our findings provide a useful treatment strategy to achieve long-term drug release with a single intramuscular (IM) injection and solve the non-compliant medication intake that often occurred in antidepressant therapy. In the second part of study, we further used Ca2+-containing material to stimulate the release of exosome, a possible next generation drug carrier, exosome. Exosomes are attractive as potential carriers for drug delivery because of their natural function of transferring biomolecules among cells without eliciting immune responses. However, an obstacle to the application of exosomes for drug delivery is the difficulty in collecting sufficient numbers of these vesicles. We found that treatment with calcium phosphate (CaP) particles increased the number of exosomes secreted from macrophage-like RAW264.7 cells and monocyte-like THP-1 cells. CaP particles were easily internalized into cells and dissolved in acidic late-endosomes or lysosomes, resulting in the rupture of their membranes followed by the release of Ca2+ into cytosol. However, the Ca2+ concentrations in exosomes secreted from CaP particle-treated cells were similar to that in exosomes from untreated control cells, implying that exosomes secreted from cells treated with CaP particles are not contaminated by the Ca2+ released from CaP particles. This study highlights the potential of a new technique for the efficient production of exosomes using CaP particles.