| Tumors show a rising trend in incidence rate for the past few years, which brings patients and their family great suffering and economic pressure. At present, a series of improved treatments was researched and used for curing tumors. The study shows that there are a lot of differences in micro-environment between tumors and normal tissues, such as angiogenesis, permeability and retention effect(EPR), and the extracellular pH differences, which can be used for drugs to recognize tumors specifically. Therefore, the tumor treatments are turning towards targeted therapy from traditional radiotherapy and chemotherapy. Targeted drug delivery system(TDDS) is employed to delivery drugs to the target tissues specifically, resulting that the drug can be concentrated in the target tissue to better exert its biological activity and lower toxicity. Carriers play a crucial role in TDDS, which controll the drug release and determine effectiveness of targeting.The metallic ruthenium(Ru) and its complexes have been reported that they own low toxicity to normal cells and can be easily absorbed by tumor tissues, which makes it as the most promising non-platinum metal for tumor treatment. In addition, there have been a few ruthenium complexes as anti-tumor drugs entering clinical trials. In this study, a well-defined pH-sensitive block copolymer, i.e., succinic anhydride(SA)-modified poly(2-diisopropylaminoethyl methacrylate)-block-poly(2-aminoethyl methacrylate hydrochloride)(PDPA-b-PAMA/SA, PbPs), was selected as the drug carrier for a insoluble metal drug [(Phenanthroline)3Ru]2+(PF6)2(3P-Ru), resulting in a drug loaded polymer micelles(PbPS-PM-Ru). Subsequently, the targeted-effect of PbPS-PM-Ru to tumor acidic environment and the inhibition on tumor cell growth in vivo and vitro was investigated. The main content of this study is as follows:(1) Base on the amphipathicity and self-assembly stability of PbPs, film hydration method was used for preparing drug loaded polymer micelle. Then the physicochemical properties and morphology of this micelle were characterized. The results showed that diameter of this micelle was about 110 nm, and its surface was uniformed distribution with negative charge and revealed as a regular spherical or spheroidal. Meanwhile, the micelle PbPS-PM-Ru inherited the pH-sensitivity from PbPS, leading that PbPS-PM-Ru could be polymerizated into larger formulation under the weak acidic condition(pH 6.5), which could release larger amount of drug more quickly compared to under the normal physiological conditions(pH 7.4). Moreover, this micelle displayed excellent stability, showing that no significant drug leak was found after 60 d later while stored at 4°C.(2) MTT assay was used to investigate the cytotoxicity of PbPS and the anti-tumor activity of 3P-Ru in vitro. Additionally, a preliminary study of durg 3P-Ru’s anti-tumor mechanism was probed with Hoechst 33342/PI double staining and flow cytometry. The results indicated that PbPS displayed no significant cell growth inhibitory effect within concentration of 100 μg/mL and could be used as a potential drug carrier. Meanwhile, durg 3P-Ru showed excellent growth inhibition on tumor cells, and the inhibition was diaplayed with concentration-dependent and time-dependent. Analysis the anti-tumor mechanism of 3P-Ru indicated that it may exert anti-tumor effect by inducing apoptosis.(3) In vivo distribution in normal mice and tumor targeting in tumor-bearing mice of PbPS-PM-Ru were determined by using tissue homogenate, section and non-invasive in vivo imaging, respectively. The results displayed that PbPS-PM-Ru was distributed in each internal organ of normal mice, and presented the distribution peak after dosing 4 h. While in the tumor-bearing mice, PbPS-PM-Ru gathered in the tumor cells with a high concentration, achieving tumor targeting. Furthermore, it was found slow-growing solid tumors occuring at inoculation site when PbPS-PM-Ru was injected intravenously to the tumor-bearing mice for a week, and the volume were much smaller than the control group, which further confirmed the growth inhibition on tumor cells of 3P-Ru.In summary, PbPS is a promising carrier for insoluble drugs. PbPS-PM-Ru was formed by self-assembly of PbPS with a hydrophobic core, and could pack the insoluble drugs to achieve solubilization. In addition, the pH sensitivity of PbPS facilitates durgs targeting to the weak acidic environment of tumors, making PbPS as a promising tumor targeting vector. Furthermore, 3P-Ru showed good anti-tumor activity in vivo and vitro, which could be selected for further research to develop the anti-tumor durgs. |
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