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The in Vitro Study of Targeting Therapy on Laryngeal Carcinoma Cell Line with Folate Modified Magnetic Nanoparticles Loaded Cisplatin

Author: LiuJie
Tutor: XieMinQiang
School: Southern Medical University,
Course: Department of Otolaryngology Head and Neck Surgery
Keywords: Laryngeal Molecular targeted Folate receptor Cisplatin Magnetic nanoparticle drug
CLC: R739.65
Type: Master's thesis
Year: 2011
Downloads: 101
Quote: 1
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Abstract

Laryngeal cancer is more common malignant tumors of the head and neck, and the incidence of about 1.5-3/10 million people, accounting for about 1% of systemic cancer, nasopharyngeal and nasal sinus cancer, otorhinolaryngology after the northern ranks second, ranks third in the South. Laryngeal cancer early symptoms often delay to late stage 'is a clear diagnosis, especially supraglottic cancer and hypopharyngeal cancer. High rate of lymph node metastasis of advanced cancer, surgery full cut low, less than 30% of the 5-year survival rate, but also in patients with life-long loss of speech function. The laryngeal cancer local recurrence and cervical lymph node metastasis is the leading cause of death. Advanced cancer, whether surgery, radiotherapy or chemotherapy, the effects were not satisfied, how to improve the survival rates and quality of life in the treatment of advanced laryngeal problems plagued clinicians. Molecular targeted therapy is a new tumor treatment, it is capable of specifically acting on the tumor occurred play a key role in the development of the target molecule, or the use of tumors with high expression of the receptor by ligand coupling drug targeting transported into the tumor cells to achieve treatment of tumors, and the purpose of reducing the systemic toxicity. Folate receptor as a molecular target for cancer therapy has entered clinical application, the ligand is a small molecular weight of the vitamin folic acid, which is highly expressed in the tumor cell surface; almost no expression in most normal tissues. The use of high affinity receptors for folic acid and folic acid can be conjugated with folate drug targeting to tumors. Our group preliminary study found that the laryngeal high expression of the folate receptor, and has been successfully prepared folic acid targeting upload cisplatin and the gene's magnetic nanoparticle drug in the the laryngeal matrix metalloproteinase 2 gene silencing and the treatment of nasopharyngeal carcinoma study good results. But found that the drug stability and drug loading is still not satisfied, this study based on the drug preparation process optimization, and laryngeal carcinoma cells Hep-2 as a research object, through drug uptake and inhibition experiments in vitro evaluation of this optimization After the folic acid molecule targeting Cisplatin magnetic nanoparticle drug targeting and therapeutic effect. Is divided into three parts: the first part of the folic acid molecule targeting upload cis-platinum magnetic nanoparticle drug preparation process optimization and characterization of the preparation process optimization mainly at the end of the amino polyethylene glycol preparation process will tosyl chloride and polyethylene glycol the proportion increased from 4-5:1 to 6:1, the reaction significantly faster. Folate carboxyl activation process to optimize the ratio of each component, with the increase in the amount of coupling of the terminal amino group of the polyethylene glycol. Characterization results show: Cisplatin magnetic nanoparticle drug the improved folate molecules targeting carrier average hydrodynamic diameter of 110.9 ± 1.7nm, the zeta potential of -26.45 ± 1.26 mV, the cisplatin content to 1.3mg/ml iron content of about .1.39mg/ml, maximum saturation magnetization of 22.2emu / g, has a good stability and the magnetic response. The second part, folic acid molecular targeted carrier cisplatin magnetic nanoparticle drug targeting of laryngeal cancer cells to folate receptor-positive laryngeal carcinoma Hep-2 cells for study, folic acid receptor-positive nasopharyngeal carcinoma cells HNE-1 and folic acid receptor-negative nasopharyngeal carcinoma cell CNE-2 as a control to examine folic acid molecular targeted magnetic nanoparticle drug cisplatin (FA-CDDP-ASA-MNPs) the targeted cellular uptake of iron staining and transmission electron microscopy. The results showed: folic acid molecular targeted magnetic nanocarrier containing cis-platinum magnetic nano drug are susceptible to folate receptor expression positive laryngeal cancer cells Hpe-2 and nasopharyngeal carcinoma HNE-1 cells uptake, and not susceptible to folate receptor expression CHE-2 negative intake, nano drug taken up by cells present in the cytoplasm, and the results show that it has good molecular targeting. The third part, folic acid molecules targeting contained cis-platinum magnetic nanoparticle drug inhibitory effects on laryngeal cancer cells in vitro using MTT, flow cytometry and transmission electron microscopy was used to detect the FA-CDDP-ASA-MNPs, CDDP and FA-ASA-MNPs on laryngeal carcinoma cells Hep-2 in vitro inhibitory effect and cytotoxicity. MTT results showed significant dose-dependent and time-dependent manner: FA-CDDP-ASA-conjugate MNPs possessed superparamagnetism, and CDDP both Hep-2 inhibition rate to cisplatin content 8μg/ml for 48 h, FA-CDDP -ASA-MNPs inhibition rate reached 82.2%, up to 93.3% of CDDP was no significant difference between sex (P gt; 0.05), while no effect on the growth of Hep-2, FA-ASA-MNPs. Flow cytometry results consistent with MTT, FA-CDDP-ASA-MNPs, CDDP with Hep-2 cells after 48 hours of culture, the cells were obvious apoptosis, and increased apoptotic rate with the increase in drug concentration, but the difference between the two was not significant (P gt; 0.05). Low concentrations causes the cells in G0/G1 phase, the high concentration does not affect the cell cycle (P gt; 0.05), and the same concentration of FA-ASA-MNPs Hep-2 apoptosis does not affect, but it allows the cell cycle to S phase transfer. TEM results showed that the intake of the FA-CDDP-ASA-MNPs cells appear obvious apoptotic morphological change in cell morphology and uptake of FA-ASA-MNPs no change. These results suggest that folic acid the cisplatin and we prepared molecular targeted magnetic nanocarrier connection still has the effect of Hep-2 cells grown in vitro inhibition of cisplatin alone the same, while the carrier itself non-cytotoxic, and can be Hep -2 uptake, high concentrations may affect the cell cycle.

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