Construction Of Nanocomposites Based On Berberine Dimers For Breast Cancer Targeting And Their Anti-cancer Properties Through PTT/PDT In Synergy

Cancer,especially breast cancer,is one of the biggest threats to human health today.According to the latest cancer data,the morbidity rate of breast cancer ranks first among all cancer patients.Currently,chemotherapy is the main treatment for cancers.Chemotherapeutic agents such as cisplatin and paclitaxel have been used in clinical for many years,and their efficacy has been fully realized.However,single-line chemotherapy also has its limitations,such as high side effects and multidrug resistance.Therefore,it is urgent to explore multimodal therapy to achieve efficient treatment of cancer.Recently,photodynamic therapy(PDT)and photothermal therapy(PTT)have attracted broad attention because of their advantages of minimal invasion,high temporal and spatial accuracy,controllability,and local effective treatment.PDT is based on the photoactivation of photosensitizers(PS)after absorbing light of a specific wavelength to produce reactive substances that are highly toxic to cells and can be used to eradicate cancer cells.Meanwhile,PTT is based on the conversion of light energy into heat by absorbing light energy through photothermal conversion materials.The increase of temperature in the PTT process can promote the release of photosensitizers,in addition to the acceleration of the blood flow in tissues to increase the oxygen level,thus enhancing the effect of PDT.On the other hand,the reactive oxygen species produced by PDT can also kill the heat-resistant tumor cells produced by PTT.Therefore,it is very important to construct nanocomposites combining PDT and PTT to achieve the therapeutic effect of 1+1>2.Berberine is a kind of isoquinoline alkaloid extracted from the Chinese herb Huanglian.It has broad-spectrum anticancer activities.Berberine and its derivatives can be used to kill cancer through multiple targets.However,its chemotherapeutic activity alone is often not strong enough and has disadvantages such as poor lipophilicity and consequently low bioavailability.Based on the optical properties,some researchers have applied berberine and its derivatives to eradicate cancer cells by utilizing their phototoxicity.Based on the above background,in this thesis,we have synthesized two berberine dimers BD3 and berberine tetramer BD4 following the two berberine dimers BD1 and BD2 previously reported by our group.We studied their PDT abilities toward breast cancer in detail.Besides,nanocomposite AuNSs-BD2@HA was synthesized based on BD2,and the nanocomposite is found to exhibit the best PDT efficacy.The nanocomposite was further applied to PDT and PTT in synergy for breast cancer treatment.The main results obtained are briefly described as follows.(1)Following the synthetic method for BD1 and BD2,one new berberine dimer BD3 and one berberine tetramer BD4 have been synthesized with 2,6-dimethylpyridine and tetrakis(methyl phenyl)ethylene as linkers.BD1,BD2,and BD4 all possess aggregation-induced emission(AIE)effects and give rise to intense fluorescence in a mixed solution of DMSO and a certain proportion of water.The SOSG,DCFH-DA,and MTT experiments demonstrated that BD2 has superior PDT activity,and the apoptosis experiments verified that BD2-mediated PDT can induce apoptosis of cancer cells.(2)The AuNSs-BD2@HA nanocomposite has been synthesized based on BD2,which showed the best PDT activities among all compounds.The nanocomposite was characterized by UV,DLS,zeta potential,and SEM.The ability of AuNSs-BD2@HA to generate singlet oxygen and the PTT effect were tested in vitro,and the synergistic PTT and PDT therapeutic outcome has been further verified both in vitro and in vivo.The results showed that AuNSs-BD2@HA could target breast cancer cells and effectively kill cancer cells through PTT in synergy with PDT,and significantly inhibit tumor growth in vivo.