Study On The Hyaluronic Acid Shell-sheddable Carborane-TAT Nanomicelles Boron Agent

Boron neutron capture therapy(BNCT)has received widespread attention as a new type of dual-targeted radiotherapy technology.Compared with traditional radiotherapy,BNCT has the characteristics of good targeting,high safety,and strong lethality.However,the current application process of BNCT has encountered the problem that the boron agent was not highly specific to tumor cells and the tumor tissues have insufficient boron uptake.In this paper,a nanomicelle boron agent was designed with cell-penetrating TATmodified o-carborane as the assembly unit.Connect the o-carborane with the cellpenetrating peptide TAT,and then the Carborane-TAT micelles were self-assembled by thin film hydration.The surface of Carborane-TAT micelles is positively charged due to the large number of amino groups of TAT,which can adsorb with negatively charged hyaluronic acid(HA)to form a core-shell structure of Carborane-TAT@HA micelles.Carborane-TAT@HA micelles can achieve the EPR effect(high permeability and retention effect)and active membrane penetration.This article consists of the following parts:In chapter 1,the principle of boron neutron capture therapy and the research progress of boron agents were reviewed.In chapter 2,describe the synthesis process of cell-penetrating peptide modified ocarborane derivatives,as well as the preparation and characterization of Carborane-TAT micelles and Carborane-TAT@HA micelles.The results show that the amphiphilic compound obtained by modifying o-carborane with cell-penetrating peptides can selfassemble to form Carborane-TAT nanomicelles.Further by charge adsorption with HA layer-by-layer assembly to obtain Carborane-TAT@HA micelles.The Zeta potential of Carborane-TAT@HA micelles is negative,which can avoid non-specific adsorption of plasma proteins,to achieve long-term circulation.The presence of the hyaluronic acid shell makes Carborane-TAT@HA micelles have better stability and resistance to dilution than Carborane-TAT micelles.Carborane-TAT@HA micelles were unstable and disintegrate in an acidic environment.In chapter 3,preliminary biological evaluation of Carborane-TAT and CarboraneTAT@HA micelles.The results show that Carborane-TAT@HA micelles were enveloped by HA shell during systemic circulation,which can avoid non-specific uptake by normal tissues.After passively targeting the tumor tissue through the EPR effect of nanomicelles,the micelles were disintegrated in response to the tumor’s acidic environment(p H 6.5)to expose TAT,and the drug penetrates the cell membrane into the cell interior through TAT.Animal body distribution experiments show that the uptake of Carborane-TAT@HA micelles in tumor tissues is 4 times that of normal tissues.In summary,the boron agent has high selectivity to tumor tissues,displayed excellent drug delivery potential,and can meet the basic requirements of BNCT.