Preparation And Anticancer Study Of Bola-type Nucleoside Based Drug Self-delivery System

Bolaamphiphiles have unique chemical structures,which can self-assemble to form nanoparticles with diverse morphologies.The self-assemblies made of bolaamphiphiles have been actively employed as drug delivery system,especially for anticancer drug delivery.The anticancer nucleoside analogues are structurally similar to natural nucleosides,which can interfere in DNA/RNA synthesis or inhibit the activity of nucleic acid polymerases,leading to the inhibition of cancer cells proliferation,consequently exerting potent anticancer activity.Drug self-delivery refers that the active drugs bearing nanoscale characteristics can realize the intracellular delivery by themselves without the aid of additional carriers.This kind of drug delivery system hence exhibits the advantages of higher drug loading,excellent targeting ability and lower toxicity.Therefore,a series of novel bola-type nucleosides have been developed in this thesis and used to construct the drug self-delivery system for anticancer study.We first designed and synthesized the bola-type bitriazolyl acyclonucleoside analogues.Both bola-type and non-bola bitriazolyl acyclonucleoside analogues have been obtained via Cu?I?catalyzed Huisgen 1,3-dipolar cycloaddition,in which the1,2,4-triazole acyclonucleosides as the polar heads and the alkyl chains with different length as hydrophobic backbones.Then,the antiproliferation activity of the synthesized bola-type nucleoside analogues have been assessed in various cancer cells.These compounds not only displayed potent antiproliferation activity via inducing apoptosis,but also were able to downregulate HSP90,a well-known tumor biomarker.Based on the unique structure of bola-type nucleoside analogues,we continued to study their ability of self-assembly.Further,the drug loading and release of the nanoparticles formed by these compounds were conducted.The morphologies and nanoscale properties of bola-type nucleoside based nanoparticles were evaluated by CAC determination as well as DLS and TEM analysis.Moreover,the response of the fluorine-containing compounds to ROS was monitored by ¹⁹FNMR as well.At last,we studied the release of DOX from the bola-type nucleoside based drug delivery system in simulated tumor microenvironment.The above results suggested that these compounds can not only form nanosize self-assemblies to realize self-delivery but also release the loaded drugs effectively in response to the stimulus in tumor microenvironment.In summary,we developed a series of bola-type nucleoside analogues with anticancer activity capable of building up novel drug self-delivery system to treat cancer and other life-threating disease,with ultimate goal to advance life and medicinal science.