Platinum(Ⅳ)prodrug-grafted Phosphorothioate DNA And Its Selfassembled Nanodrug For Delivery

Platinum-based anticancer drugs have occupied a crucial role in the treatment of various malignant tumors.However,their efficacy and applicability to cure the cancer are heavily restricted by severe side effect and systemic toxicities.Therefore,it is of great research significance to develope an biocompatible and efficient targeted drug deliver strategy.As an emerging delivery system,DNA nanostructures display good biocompatibility,the ability of targeted transport and multi-functional modification.The DNA materials also qualified many biological functions,including DNA aptamers with active targeting functions and antisense oligonucleotides for gene therapy and so on.Herein,in this paper,we designed a diblock DNA nanodrug delivery system: one of the block was phosphorothioate DNA for cisplatin prodrug grafted modification,and the other block was designed as the functional nucleotide sequence.After grafted of cisplatin prodrug,the two blocks showed different hydrophilicity and hydrophobicity,and then self-assembled into spherical nucleic acid(SNA)-like nanodrugs.Based on this,we have evaluated the targeting ability and antitumor effect of the nanodrug in cells and in mouse models.The specific research contents include the following two aspects:1.To solve the low selectivity,large systemic toxicity and side effects problems of cisplatin,we develop a biocompatible diblock DNA targeted nanodrug delivery strategy.The diblock DNA materials included the actively targeted MUC-1 aptamor block and the phosphorothioate DNA block grafed cisplatin prodrug and then self-assembled into MUC-1/Pt-SNA nanodrugs(MUC-1/Pt-SNAs).The MUC-1/Pt-SNAs showed high drug loading rate(up to 39.6%),good dispersibility,and the ability of efficient selective invasion into tumor cells that overexpress the MUC 1 protein.The nanodrug showed effectively inhibited tumor growth effects both in vitro and in vivo.2.In order to enhance the anti-tumor effect of chemotherapy cisplatin,a synergistic diblock DNA nanodrug delivery strategy of chemotherapy cisplatin combined with gene therapy was designed.The diblock DNA materials included the Bcl-2 antisense oligonucleotide sequence block and the phosphorothioate DNA block grafed cisplatin prodrug and then coassembling with the aforementioned MUC-1-Pt sequence into Bcl-2/MUC-1/Pt-SNA nanodrugs(Bcl-2/MUC-1/Pt-SNAs).The Bcl-2/MUC-1/Pt-SNAs effectively improved the drug loading rate of cisplatin,increased the effective dose of chemotherapeutic drugs in synergy with genetherapeutic drugs,reflected the excellent targeting ability to the cancer cells,and exhibited the synergistic antitumor effects by cisplatin prodrug and Bcl-2antisense nucleotide in vitro.In summary,a multi-founctional diblock DNA nanodrug delivery system was developed,which included modified phosphorothioate DNA block for grafting cisplatin prodrugs and fountional DNA block,achieving efficient targeted delivery and the successful synergy of gene therapy and chemotherapy.It provides new ideas for building a drug delivery system and achieving better tumor treatment.