Hydroxyapatite Nanoparticles Stimulate Exosome Secretion from Monocytes for Target Delivery of Temozolomide in Glioma Treatment

The development of nano-particle carriers for drug delivery to central nervous system (CNS) is facing major hindrances in brain drug delivery and targeting. Only very few, if not none, nano-carriers have successfully proceeds to clinical trial. Most man-made carriers have a similar issue in common, which is they all consider foreign substances in our body. So after administration, the mononuclear phagocyte system (MPS) will rapidly clear these carriers away, making drug delivery and targeting very difficult to achieve. Other issues like carrier aggregation and toxicity while degradation, are also critical while delivery to important organs such as the brain. In order to make a breakthrough in CNS drug delivery and targeting, we believe a new concept of using nature carriers produced by our own body is needed to replace the traditional man-made materials. This study we focus on the development of nature carrier exosome for Temozolomide (TMZ) delivery and targeting to CNS for non-invasive glioblastoma multiform (GBM) treatment.Exosomes are attractive potential carriers for drug delivery because of their natural function of transferring biomolecules among cells without eliciting immune responses. It is a small bilipid layer-enclosed extracellular vesicle (EVs) that is produced by inward budding of cell endosome. Exosomes are recently demonstrated to have high blood brain barrier (BBB) penetration, and is suitable for mental drug delivery. Previously we have demonstrated cell treatment with hydroxyapatite (HAP) nano-particles could increase 3 folds of exosomes secretion from macrophage-like RAW264.7 cells and monocyte-like THP-1 cells. HAP particles can be easily uptake into cells and dissolved in acidic lysosomes, resulting in the rupture of their membranes followed by the release of Ca2+ into cytosol. This will increasing the intracellular Ca2+ concentration and stimulates exosome release, which can largely improve the production of exosomes from cell.In this study, we would like to administrate exosomes to GBM treatment. Using HAP to carry antibodies into cell, so high amount of exosomes with antibody embed on the surface can be collected for TMZ loading through freeze/thaw cycles; forming exosome-TMZ. Then we can re-administrate exosome-TMZ back to the patient for GBM targeting delivery. We hope this study can highlight the potential of using HAP nano-particles to stimulate the release of antibody labeled exosomes for TMZ loading in GMB treatment, pushing one step forward in the use of nature carriers in CNS drug delivery and targeting.