Preparation Of Sialic Acid-coupled ICG/CPT Molecules And Evaluation Of Their Antitumor Activity

Cancer is one of the significant causes of health problems worldwide.Current cancer treatments include surgical resection,radiotherapy,chemotherapy,immunotherapy,phototherapy,etc.However,a common obstacle faced by many treatments,including immunotherapy,chemotherapy and phototherapy,is the lack of targeting to tumor tissues,which causes systemic side effects in patients.Researchers mostly deliver drugs through nanocarriers to solve the problem of poor tumor targeting.However,the biosafety of nanocarriers is still controversial,and their effectiveness is usually affected by the physicochemical properties of the carriers,including size,charge and surface coating.In addition,the development of cancer nanocarriers has been further hindered by the characterization,safety issues,regulatory and manufacturing defects.In contrast,tumor-targeted small-molecule agents are more accessible to characterize and mass-produce due to their well-defined structure,thus facilitating clinical translation.Studies have shown that sialic acid(Sia)functionalization can effectively target tumor tissues.Notably,Sia conjugation can also improve the water solubility of drugs.It is expected to play an essential role in developing small-molecule agents for targeting tumors.Based on this,this thesis mainly used Sia as a small-molecule ligand to develop novel tumor-targeted sialic acid molecules.Sia has been used as a targeted ligand for tumor fluorescence imaging,and satisfactory results have been obtained.However,systematic studies on direct-coupled antitumor agents still need to be included.Therefore,this study took phototherapy,which is an emerging hot spot treatment and traditional chemotherapy,and selected the near-infrared photosensitizer indocyanine green(ICG)and the chemotherapy drug 20-(+S)-camptothecin(CPT)to be coupled with Sia to enhance tumor targeting and reduce side effects.The main content can be divided into the following two parts:In the first part.ICG was conjugated to the C2 and C9 positions of Sia to construct tumor-targeted photothermal agents Sia-C2-ICG and Sia-C9-ICG,and the effects of different positions on tumor targeted therapy were explored.Compared with free ICG,Sia-ICGs not only enhanced the photothermal conversion efficiency and photothermal stability,but also improved its safety,like significantly reducing the toxicity of free ICG.while enhancing its effectiveness,including promoting cell uptake,prolonging the half-life in vivo,and producing tumor suppression effect better in mice.Compared conjugated products at two sites of Sia,Sia-C9-ICG was superior to Sia-C2-ICG in both tumor targeting and tumor suppression.This study provided experimental data support for the tumor targeting and safety of Sia-C9-conjugated small-molecule preparations.In the second part,Sia was coupled with chemotherapy drug CPT by C9 position to prepare a tumor-targeted prodrug.In order to release the drug at the tumor tissue better,disulfide bonds were introduced to generate Sia-ss-CPT.The experimental results showed that Sia-ss-CPT significantly increased the water solubility and lactone stability of CPT,reduced its side effects,increased its compatibility in vivo,and significantly inhibitd the growth of subcutaneous tumors in mice.Therefore,sialic acid has excellent development prospects in coupling hydrophobic chemotherapy drugs to target tumor tissues and improve tumor suppression rate.In summary,novel small molecules formed by coupling Sia as a tumor-targeted ligand with chemotherapy drugs or other antitumor compounds has the advantages of good tumor targeting,a high drug utilization rate,and no obvious toxic side effects.Therefore,developing effective antitumor small molecules with Sia as a tumor-targeted ligand is expected to be further advanced to the clinic and play an increasingly important role in tumor treatments.