| Summary: | 博士 === 長庚大學 === 化工與材料工程學系 === 99 === Abstract
In this research, we had three main projects. Firstly, we controlled the reaction conditions such as temperature or reaction time or concentration ratio to obtain four kinds of iron oxide (Fe3O4) magnetic nanoparticles (MNPs) with different magnetizations and crystallinities (i.e., low magnetization nanoparticles (LMNPs), medium magnetization nanoparticles (MMNPs), high magnetization nanoparticles (HMNPs) and superhigh magnetization nanoparticles (SHMNPs)). Secondly, we used a green and rapid technology (supercritical reaction system) to synthesize biocompatible conducted polymer poly[aniline-co-N-(1-one-butyric acid) aniline] (SPAnH) containing carboxylic acid group coating on the surface of MNPs as a shell to form magnetic nanocarriers (MNCs). Finally, for the potential of magnetically targeted therapy, some drugs were further bioconjugated on the surface of prepared MNCs as therapeutic agents, such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), Paclitaxel (PTX), Doxorubicin (DOX) and Epirubicin (EPI).
Four types of magnetic nanocarriers (MNCs) (i.e. LMNCs, MMNCs, HMNCs, SHMNCs) with a core of MNPs and a shell of SPAnH were prepared. Their magnetizations measured by superconducting quantum interference device (SQUID) and all had superparamagnetic properties. Meanwhile, they presented positive zeta potentials to avoid aggregation. The results obtained by TEM and XRD showed that the morphology of MNPs was spherical and the diameter was between 8-12 nm. Moreover, the MNCs could be swallowed into cells by the pathway of endocytosis in the cellular uptake study.
In the prostate cancer study, the PTX was immobilized on LMNC to enhance its thermal stability and improve its solubility in aqueous solution. Moreover, the inhibitory effect of LMNC/PTX on PC3 and/or CWR22R cells growth was greater than free PTX, the IC50 value was significantly reduced ~50 % and 76 % for PC3 and CWR22R when applying magnetic targeting to the LMNC/PTX.
In the bladder cancer study, we conjugated the EPI and DOX on HMNC and SHMNC, respectively. The SHMNC/DOX could not only have a super-high magnetization but also reverse of p-glycoprotein (P-gp) pump drug resistance of MGH-U1 bladder cancer cell and nuclear drug resistance (NDR) of MGH-U1R bladder cancer cell. The advantaged properties enhanced the cellular concentration ~23 % relative to free DOX, and it could be guide to the specific area by lower strength of extra magnetic field. On the other hand, the HMNC/EPI could be used to reverse the NDR of MGH-U1R, resulting in the EPI could across the nuclear pores and stay in the nuclei to cause DNA damage. Moreover, malignant NDR bladder cancer can be effectively inhibited after 14 days in mice by just two injections and magnetic targeting (MT).
In the brain cancer studies, the anticancer drug BCNU was conjugated on LMNC. Although the tumor size could be inhibited by low dose of LMNC/BCNU (5 mg/kg) with MT, the inhibition still limited. Therefore, the dose decreased to 1.68 mg/kg to inhibit effectively the tumor growth with the combination of MT and focused ultrasound (FUS). Further study, the o-(2-aminoethyl)polyethylene glycol (EPEG) was also immobilized on the surface of HMNC to form a self-protecting magnetic nanomedicine (i.e., SPMNM) that could simultaneously provide low reticuloendothelial system uptake, high active-targeting, and in vivo magnetic resonance imaging (MRI) traceability. The synergetic drug delivery approach provided approximately a 3.4-fold improvement of the drug’s half-life (from 18 h to 62 h) and significantly prolonged the median survival rate in animals that received a low dose of BCNU, compared with those that received a high dose of free BCNU (63 days for those that received 4.5 mg BCNU/kg carried by the nanocarrier versus 50 days for those that received 13.5 mg of free-BCNU).
The aforementioned results indicated that the prepared MNCs could conjugate various drugs to enhance the thermal stabilities of drugs and be a potential drug delivery system for magnetically targeted therapy to brain cancer, prostate cancer and bladder cancer and so on.
Keywords: magnetic nanoparticles, drug delivery, cancer therapy, conducted polymer
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