| Platinum drugs have excellent anti-tumor activity against a variety of cancers.Since the discovery of cisplatin,platinum drugs have always occupied a pivotal position in the field of cancer chemotherapy.However,serious side effects caused by off-target,especially nephrotoxicity and neurotoxicity,restrict the clinical application of platinum drugs.In order to solve this problem,scientists have developed a tetravalent platinum prodrug strategy.The tetravalent platinum prodrug has certain stability because of its unique octahedral structure,and it is not toxic.It can only show cell killing effect after being reduced to divalent platinum.The combination of tetravalent platinum prodrugs and nano-drug delivery systems amplifies this advantage.Icodextrin(ICO)is a starch-derived polysaccharide,which has been used clinically as a peritoneal dialysis fluid for decades.It has good water solubility and safety,and has many hydroxyl groups on the surface that can be chemically modified.It is an ideal nano carrier material.In this paper,the covalent combination of icodextrin and polycaprolactone(PCL)was used to construct a nano-drug delivery platform,and then folic acid(FA)and cisplatin prodrugs were further modified to prepare folic acid target NPs.Fluorescence imaging and photothermal-chemotherapy combined treatment of tumor sites are realized by loading Di R.The main results of this paper are as follows:(1)First,cisplatin prodrugs were prepared by the reaction of cisplatin oxide and succinic anhydride,and then a suitable nanocarrier ICO-PCL was screened out by the reaction of icodextrin with PCL or PLA with different molecular weights.The grafting rate of PCL was 98.2%.Then,folic acid and cisplatin prodrugs were coupled to ICO-PCL by esterification reaction to obtain Pt-ICO-PCL and FA-ICO-PCL.The drug loading efficiency of Pt was 2.5%,and the degree of substitution of folic acid was 800 %.(2)By optimizing the ratio of Pt-ICO-PCL and FA-ICO-PCL involved in NPs and preparation method,it is determined that the ratio of the two componrnts is 8:2 and the NPs prepared by the dialysis method are smaller and easier to 4T1 cell uptake.The average size of Pt FIP,Pt IP,DPt FIP,DPt IP nanoparticles with this ratio is between 60-95 nm.They are stable in PBS,and their particle size does not change much after placed at 4 ℃for 14 days.The release of platinum in Pt IP and Pt FIP has reduction responsiveness.It can be released quickly in 10 m M DTT,and the cumulative release rate can reach 89.7% and81.0%,respectively.(3)The uptake behavior of DPt IP and DPt FIP nanoparticles was studied by flow cytometry and laser confocal microscope,and the killing effect of Pt IP,DPt IP,Pt FIP and DPt FIP nanoparticles on 4T1 breast cancer cells was studied by MTT experiment.The results indicate that compared with DPt IP,DPt FIP is more easily taken up by 4T1 cells,and the results of cell killing experiments also show that Pt FIP has higher anti-tumor activity than Pt IP.For both DPt IP and DPt FIP nanoparticles,laser irradiation can significantly enhance the anti-tumor efficacy.(4)The 4T1 subcutaneous tumor model was used to investigate the fluorescent imaging ability of DPt FIP nanoparticles on the tumor site,the photothermal effect in vivo and the anti-tumor efficacy.Compared with free Di R and DPt IP,DPt FIP has higher sensitivity for tumor imaging.At 48 h after administration,the intratumor fluorescence intensity of DPt FIP group was 25.3 times and 1.9 times that of Di R and DPt IP,respectively.The results of pharmacodynamic experiments show that the inhibitory effect of single photothermal or chemotherapy on 4T1 tumors is relatively limited,and the combination of photothermal andchemotherapy can significantly enhance the anti-tumor efficacy,and the tumor inhibition rate of the DPt FIP group can reach 80.7%.The safety evaluation results show that the design of cisplatin nanoprodrugs can significantly reduce the toxic and side effects of cisplatin. |
PDF Full Text Request