Preparation Of Nano - Drug RGD-MS2-D0X And Its Application In Cancer Treatment

Doxorubicin (DOX) is one of the most used chemotherapy in cancer therapy. However, due to its low solubility and poor specificity, patients will suffer from severe adverse effects. Besides, patients will develop drug-resistance after a long time of treatment. These factors together limit the application of DOX in tumor therapy.Nanoparticle-based drugs are merging as a new strategy in tumor therapy during the recent years. Nanoparticle-based drugs target to cancerous tissues via the enhanced permeation and retention effect (EPR). Compared to small molecules, nanoparticle-based drugs have several advantages:nano-scaled drugs have a longer circulating time in vivo due to their large molecule; besides, nanoparticle can package a lot of drugs and enrich drugs with higher concentration in tumor tissues; what is more, nanoparticle-based drugs have a higher selectivity to tumors and a reduced side effects profile.MS2 viral like particles (VLPs) are noninfectious nanoscale particles featured by high stability, and they are easy to produce at a large scale in vitro within a short time. Therefore, MS2 VLPs are used for drug delivery. However, MS2 VLPs lack targeting specificity. Therefore, additional specific ligand is needed to improve the targeting specificity.Our research used MS2 as vector by conjugating RGD and DOX to MS2 with the heterobifunctional cross-linker SM(PEG)24 to produce a novel nanoparticle-based drug RGD-MS2-DOX which has high specific targeting.The transmission electron microscopy and dynamic light scattering showed that the nanodrugs were all fusiform shape and they were finely dispersed. RGD-MS2-DOX diameter size of about 30nm determined by the transmission electron microscopy and dynamic light scattering spectrophotometer. We studied its tumor-killing capacity both in vivo and in vitro. We used Hela, HUVECs and HepG3 cell lines which are high-expressing α vβ3 receptors to do our research. We found that RGD-MS2-DOX entered cells via receptor-mediated endocytosis. More importantly, the uptake and accumulation of DOX was significantly increased in avβ3 expressed cells treated with RGD-MS2-DOX than RAD-MS2-DOX and DOX due to ligand-receptor specific binding. Not only, RGD-MS2-DOX entered cells through time-dependent mechanism, and more drugs entered cells when prolonging the cultured time. Confocal microscope observed that RGD-MS2-DOX entered cells and released free DOX within cells. The released DOX can then enter nucleus and exert cell-killing capacity. Our in vitro studies showed that RGD-MS2-DOX exhibited excellent antitumor activities. To assess its anti-tumor effect in vivo, we used balb/c nude mice bearing HepG2 cells. We found that RGD-MS2-DOX had a reduced side effects and showed improved inhibition of tumor growth.We successfully designed and produced a novel nanoparticle RGD-MS2-DOX. Our active targeting nanoparticle-based drug may be a promising new drug for tumor therapy, and more future studies are needed.