| Cancer, the uncontrolled growth of cells, has been one of the main cause of death throughout the world for centuries. Tremendous efforts effort has been made in the therapy of cancer, and have significantly increased our knowledge of cancer. Currently, Surgery, chemotherapy, and radiotherapy are the major cancer therapies, but there are several factors- risk of recurrence and side effects- largely limiting their efficiency. So intense work have been done to searching for more effective therapeutic strategies. For instance, photothermal therapy(PTT), photodynamic therapy(PDT), magnetothermal therapy and control-released chemotherapy and so on.Compared to other therapies, as the magnetothermal therapy is powerful, non-invasive, harmless and without the problem of tissue penetration, it has been a promising tumor treatment approach and has gained increased interest recently. MNPs-induced hyperthermia can generate efficient heat when subjected to an alternating magnetic field(AMF), which has been demonstrated in numerous cancerous therapy. Currently, the magnetothermal materials as biomedicine mainly include Iron nanoparticles, such as b-Fe2O3, Fe3O4 and MFe2O4(M = Mn, Zn, Co etc.) nanomaterials. And Lots of works have been done to figure out the relationship between the heating rates, which general defined as specific loss power(SLP) or specific absorption rate(SAR), and the nanomaterials. As known, the mechanism of heat generation is through Brownian and Néel relaxations of nanoparticle magnetic moments. What’s more, the chemical component, size, morphology, and crystal form of nanomaterials have a crucial impart on Brownian and Néel relaxations. According to the work of Jinwoo Cheon and coworkers, exchange-coupled magnetic nanoparticles shown enhancement of magnetic heat induction, so we prepared the cubic core-shell nanoparticles(Zn0.4Co0.6)Fe2O4 @(Zn0.4Mn0.6)Fe2O4(denoted as MNPs). Furthermore, the cubic MNPs have large heating rates. As expected, this novel nanomaterial owned excellent magnetothermal effect.In addition, as the inherent feature of magnetic nanoparticles, the MNPs possessed longitudinal MR imaging effect. MR imaging has attracted an increasing attention in medical diagnosis because of non-invasive property, high spatial resolution, and barely damage to human. The darker MR imaging of the MNPs enable us to distinguish the tumor cells. As a result, the local heating of tumor cells can be realized by the combination of MR imaging and magnetothermal effect.In order to improve the local concentration and the permeability and retention(EPR) effect of MNPs at the target sites of tumor, the MNPs were further modified with methoxypoly(ethylene glycol) carboxyl acid(PEG-COOH) and hyaluronic acid(HA). In our work, the 3-(3,4-dihydroxyphenyl)propanehydrazide was firstly utilized to exchange with the surfactants of the MNPs, subsequently conjugated with PEG-COOH and HA. The poly(ethylene glycol) was widely used in the modification of nanomaterials because of its excellent performance in vivo. Meanwhile, the hyaluronic acid modified MNPs were prepared for targeted delivery of the MNPs to cancer. As known, the HA was a targeting moiety to various cancer cells due to the specific interaction with overexpressed CD44. Finally, the doxorubicin hydrochloride(DOX·HCl) were conjugated to the modified MNPs by the reaction with 3-(3,4-dihydroxyphenyl)propanehydrazide and formed an acid-labile hydrazine bond. The DOX is a classical anticancer drug and was applied in patient treatment early. Recently, various novel drug delivery strategies have been reported, and achieved good therapeutic effect. In our study, the hydrazine bond is unstable in acidic organelles, in which the DOX were released. Interestingly, the heat produced by magnetothermal effect further enhanced the DOX release rate.In this work, an integrated nanoplatform were developed by modifying PEG-COOH, HA and DOX onto the surface of MNPs via 3-(3,4-dihydroxyphenyl)propanehydrazide, which can significantly improve cancer therapy efficiency by taking advantage of a combined benefits from the functional ligands. It is reported that the MNPs has a large SLP value(about 4000 W/g), so the MNPs owned an excellent heat generation. Meanwhile, the magnetic nanoparticles have been proved to be a good T2- weight MR imaging agent. Besides, the modified PEG and HA improved the ERP(enhanced permeability and retention effect) and specific targeting, result in effective accumulation of the MNPs-PEG/HA-DOX in tumor cells. Subsequently, the acidic internal environment of tumor cells lead to the release of DOX in them. Finally, the MNPs produced huge amount of heat under alternating magnetic field(AMF), and enhanced both the release of DOX and the sensibility of tumor cells to DOX. Under the targeted of magnetic hyperthermia and chemotherapy, the tumor will soon be resolved. We had demonstrated the therapy effect of such a novel integrated nanoplatform in vitro and in vivo. |
PDF Full Text Request