A Research On The Application Of MiR-27a-targeted Multifunctional Self-assembled Nanodrug And Berberine Self-assembled Nanodrug In Liver Cancer Therapy

Liver cancer is one of the most common malignancies and is always a real danger to our health.In recent years,new clinical practices including interventional treatment,radiation therapy,chemotherapy,and immunotherapy,for liver cancer therapy have been developed,but benefits that patients gained from these approaches are still limited.Because the early symptoms of liver cancer are quite inapparent,people are tend to pay little attention on them and then miss the optimal time for treating liver cancer.Furthermore,the recurrence,metastasis and drug resistance are the main reasons for the low survival rate of patients.Thus,there is an urge need for developing new liver cancer clinical practices which have higher efficiency and less side effects.Thanks to constant effort people made in nanomedicine,we are now provided with new options to make liver cancer therapy more effective.Nanocarrier is not only one of the key role in research,but also the main tool for the clinical application of nanomedicine.Because nanocarries are always designed to have great payloads and easily–functionalized surface,they can be used to deliver chemodrugs,organic dyes,nucleic acids,proteins and other funtioncal components,which rises up the possibility of using nanocarriers for liver cancer therapy.What's more,people developed carrier free drug delivery system under the nano-carrier design theory,which lower the risk of potential side effect caused by redundant carriers,and it has pointed out a new direction for developing new kind of effeciet chemodris for liver cancer.Based on all of these,we have conducted the following researches.(1)To realize miRNA based gene therapy for liver cancer,we have developed a multi-functionalnano-sizedself-assemblyanti-miR-27a/QD-HA-PEI.The self-assembly is a regular sphere.It has two fluorescence emission peaks at the wavelength of 450nm and 820nm.Its endocytosis process is completed through the interaction between HA and CD44 receptor,indicating this self-assembly is CD44targeted.We further proved that the drug release behavior of anti-miR-27a/QD-HA-PEI is pH-dependent,which means the acidic tumor cell micro environment is beneficial to its durg release.Futhermore,anti-miR-27a/QD-HA-PEI has been proved to be effective against liver cancer and safe to normal cells or tissues in vitro and in vivo.The therapy effect is then visualized as NIR QDs were connected on the self-assembly.We found that the self-assembly mainly distributed in tumor,liver and spleen,and the distribution is mainly determined by CD44 receptor levels.The NIR fluorescent signal is stable and can be detected one day after injection.At last,we discovered the mechanism of the anti-tumor effect is that anti-mIR-27a reduced the expression level of miR-27a,removed the inhibition of FOXO1 and PPAR?and finally inhibited the proliferation and promoted the apoptosis of heptocarcinoma cells.Our research indicates that anti-miR-27a/QD-HA-PEI is a promising nano-tool for gene therapeutics.(2)To make full use of the pharmacological activities of berberine,we prepared berberine micro rods(Ber-MRs)in gram scale.Ber-MRs was 500nm in width and was quite regular distributed under TEM.The FTIR and ~1H-NMR spectrum indicated that Ber-MRs had preserved all the active groups of berberine,while the degree of crystallization decreased compared to raw Ber,indicating a potential higher water solubility of Ber-MRs.Then we evaluated the pharmacological activity and bio-safety of Ber-MRs.The results showed that Ber-MRs had similar pattern to raw Bers in vitro,and it was more effective to liver cancer in vivo owing to its higher oral bioavailability.Our research has proved that Ber-MRs was an efficient and safe chemodrug against liver caner.Due to the fluorescent feature and the same structure to berberine hydrochloride,Ber-MRs can be further applied for bio-imaging and impreoving the prognosis of liver caner.Moreover,Ber-MRs can be fast obtained in gram-scale,and its purify procedure is rather simple.We concluded that it has great potential for further convention of clinical use and mass production.In conclusion,we have developed a novel gene therapy platform for liver cancer which targets towards miRNA and a safe therapeutic agent for liver cancer chemotherapy which is promising for further convention of clinical use and mass production on the basis of self-assemble technique.Our research has provided new ideas and methods for effecient therapy of liver cancer.