Investigation Of Protein Based Delivery And Targets Of Anti-Cancer Drugs

Cancer,also known as malignant tumor,is one of the major public health problems that seriously endanger human health.At present,the treatment methods for cancer mainly include surgery,chemotherapy,radiotherapy,immunotherapy and so on.Innovative researches have greatly promoted the development of new cancer medicines and treatment technologies.Chemotherapy is the most widely used cancer treatment option among many cancer treatment strategies,whether is used alone or combinated with surgery or radiotherapy.Due to the poor pharmacokinetic characteristics,conventional chemotherapeutics usually only have a relatively low treatment window.In addition,conventional chemotherapeutics do not kill cancer cells specifically,but they can also affect the normal cells with fast proliferation.And this will lead to life-threatening side-effects for cancer patients.Solving these problems and improving the pharmacological properties were important things for chemotherapy.In addition,the studying on the interactions between some metal-drugs and proteins could further develop the therapeutic potential of existing drugs,and make it possible to replace the drugs which have high toxicity or poor efficacy.It would provide more anti-cancer drug options in the treatment of cancer.In this thesis,we mainly introduced the relevant researches about anti-cancer drug delivery systems and the metal-drug targets based on the proteins in the first chapter.It mainly involved nanomedcine delivery systems using protein as drug carrier firstly.And then,we introduced the functional proteins such as antibodies and nanobodies witch were used as active targeting drug carriers.Finally,we also introduced the interaction of some metal-drugs with some functional proteins and the potential applications of metal-drugs in the treatment of APL.In charpter 2,we designed a co-delivery system using human serum albumin(HSA)to deliver paclitaxel(PTX)and all-traps-retinoic acid(ATRA)in order to enhance anti-metastasis while killing cancer cells.The co-delivery nanoparticles were generated by self-assembling of HSA together with PTX and ATRA.The preparation of co-delivery nanoparticles was achieved without using any toxic chemicals;therefore,the delivery vector is highly biocompatible.This co-delivery system inhibited the proliferation of cancer cells more efficiently than the mixture of two drugs;more importantly,it significantly reduced the metastatic cancer in lung in comparison to the single delivery PTX-HSA nanoparticles.Further investigations showed that the co-delivery nanoparticles significantly inhibit the activity of MMPs and suppressed the sternness of cancer cells,which are associated with the metastasis of cancer cells.Interestingly,the co-delivery nanoparticles demonstrated more pronounced anti-metastasis effects than the combination therapy using two free drugs or two HSA loaded single drugs.This work suggests that the co-delivery of a cell differentiation agent could significantly enhance the anti-metastasis effect of anti-cancer drugs,and strengthen the anticancer efficacy as well.In charpter 3,we developed a multifunctional nanobody-drug conjugate(NDC)for targeted delivery of platinum(Ⅳ)prodrug and MRI contrast agent.NDC can be specifically internalized into EGFR positive cancer cells.Therefore,the drug accumulation is increased in EGFR positive tumor and decreased in major orangs,resulting in higher therapeutic effect and lower side-effects in comparison to the treatment of cisplatin.The fusion of anti-albumin nanobody improves the pharmacokinetic properties of NDC,which further enhances the drug efficacy.In addition,the Gd-binding domain enables in situ detection of the drug distribution in vivo.This work shows the prospective application of nanobody in modular design of multiple functional drug conjugates.In charpter 4,we hypothesized Ru(Ⅱ)complexes could also react with the ring-finger of PML in the way similar to ATO based on coordination chemistry.In this work,we investigated four ruthenium arene complexes in the reaction of PML protein and the effect on APL cells.Results indicate that[(η6-p-bip)Ru(en)Cl][PF6](Ru-1)can selectively react with PML,leading to the zinc-release and protein unfolding.Consequently,the degradation of the fusion protein PML-RARa occurs,which causes the differentiation of APL cells.In addition,this Ru-1 can also bind to DNA and the DNA damage triggers the apoptosis of APL cells.Therefore,Ru-1 acts as a dual functional agent that inhibits the growth of APL cells and induces the cell differentiation.The non-selective Ru(Ⅱ)compound,though also highly reactive to PML,does not exhibit anti-APL activity.The selectivity of Ru-1 to PML suggests new strategy for the development of anti-APL drugs.