| Lung cancer is the leading cause of cancer-related deaths worldwide Chemotherapy is still an important method of lung cancer treatment However,chemotherapy can cause adverse reactions such as nausea and vomiting.In recent years,due to the limitations of monotherapy,combination therapy has become a new trend in cancer treatment.This article adopts combination therapy on the basis of studying new preparations of chemotherapy drugs,aiming to reduce the side effects of chemotherapy drugs and improve the treatment effectPhotothermotherapy is a method that utilizes the characteristics of tumor cells that are less heat-resistant than normal tissue cells.Under near-infrared light,it can induce tumor cell apoptosis by increasing tissue temperature,or increase the sensitivity of tumor cells to radiation or chemotherapy.Photothermal therapy is more and more widely used in combined therapy of tumors due to its less invasiveness,strong targeting,and small side effects.Tumor starvation therapy inhibits tumor cell growth and survival by restricting blood flow or depriving it of basic nutrients/oxygen supply,and can be combined with chemotherapy to improve antitumor effects.Paclitaxel is a commonly used BCS ? chemotherapeutic drug for the treatment of small cell lung cancer.However,its extremely low water solubility limits the further application of PCL.Based on this,PCL-Soluplus and TPGS were used as the excipients to encapsulate PCL.PCL-Soluplus-TPGS micelles(PM)with a particle size of 62.55±0.54 nm were prepared by solvent evaporation method,which greatly improved the solubility of PCL.Considering the advantages of abundant sources of red blood cell membrane(RBM),long circulation half-life,good biocompatibility,and the stability of nano preparations,the prepared RBM was coated on the PM surface to prepare an RPM preparation with a particle size of 80.12±0.02 nm and a potential of-9.53±0.13mV,and the encapsulation rate reached 101.90±0.01%.The results of infrared measurement of RPM can also indicate that PCL has been completely contained in the RPM preparation.In order to combine photothermal therapy and improve the application of RPM in tumors,indocyanine green(ICG)was encapsulated in RPM to prepare RPIM formulation.Under the irradiation of near-infrared light,the temperature of the RPIM preparation was significantly increased,and exhibited a good light-heat conversion effect.Arginine deiminase(ADI)can be used as an anticancer enzyme for tumor starvation therapy.However,ADI has a short half-life and strong antigenicity,which limits its further application.Therefore,in this paper,cyclodextrin,Soluplus,and TPGS were used as excipients to construct the ADI enzyme supramolecular complex AP,which was then loaded with RCM to prepare the RAP preparation.The experimental results showed that the particle size was 485.1 ± 13.5 nm,the potential was-9.96 ± 0.13 mV,and the transmission electron microscope showed a round shape.The optimal temperature of RAP was 37?,the optimal pH was 6.5,and the stability of 55? was higher than that of free ADI.The Mie equation of RAP was Y=0.04943X+0.03086,r=0.9991(n=3),the Km of the RAP was 1.60±0.04 mmol·L-1,and the Vmax was 32.40±0.26 ?mol·min·L-1;The Mie equation was Y=0.09417X+0.0431,r=0.9995(n=3),Km of ADI was 2.18 ± 0.46 mmol·L-1,and Vmax was 23.2 ± 1.94 ?mol·min·L-1.Compared with ADI,RAP had a smaller Km,so RAP had a stronger affinity for the substrate arginine.Albumin combining with drugs affect the distribution,bioavailability,and adjust the toxicity of drugs in vivo.Finally,the fluorescence experiment was carried out after RAP and human serum albumin were co-incubated.The results showed that there was an interaction between RAP and human serum albuminThe inhibitory effects of ADI and RAP,PCL and RPM on the proliferation of H446 cells in vitro were investigated.ADI and RAP,PCL,and RPM all inhibit proliferation of H446 cells.The half-inhibitory concentration(IC50)of PCL on H446 cells within 24 h and 48 h were 21.345 and 2.722 ?g·mL-1,respectively,while RPIM on H446 cells during 24 h,The IC50 within 48h were 1.357 and 0.038 ?g·mL-1,respectively.The half-inhibitory concentrations(IC50)of ADI for H446 cells within 24 h and 48 h were 0.560 and 0.197 ?g·mL-1,respectively,while the half-inhibitory concentrations(IC50)of RAP for H446 cells within 24 h and 48 h were 0.132 and 0.069 ?g·mL-1,respectively.Compared with free drugs(ADI,PCL),the inhibitory effects of preparations(RAP,RPIM)were better.The MTT experiment of combined use of PCL and ADI and sequential administration exhibited that sequential administration of ADI was more benifitial to PCL playing an antitumor effectIn addition,the pharmacokinetics of RPM combined with RAP were investigated.The pharmacokinetic results of the ADI+PCL,ADI+ADI/PCL,RAP+RPM,and RAP+RAP/RPM groups after intravenous injection showed that in the ADI pharmacokinetic behavior investigation,the AUC(0-168)of the RAP+RPM group was 185%of the ADI+PCL group,and the AUC(0-168)of the RAP+RAP/RPM group was 172%of the ADI+ADI/PCL group.RAP preparation prolonged the circulation time of ADI and improved the bioavailability of ADI.In the investigation of PCL pharmacokinetic behavior,the AUC(0-8)of the RAP+RPM group was 67.91 times as that of the ADI+PCL group,and the A UC(0-8)of the RAP+RAP/RPM group was 52.2 times as that of the ADI+ADI/PCL group RAP formulation improved the bioavailability of PCLIn conclusion,the new biomimetic formulations RPM and RAP constructed in this paper greatly improved the bioavailability of PCL and ADI,and enhanced the anti-small cell lung cancer activity of API.The purpose of this study is to integrate chemotherapy,photothermotherapy and starvation therapy into one unit,and all kinds of therapies work together to improve the effect of anti-small cell lung cancer,and provide new strategies for the clinical treatment of small-cell lung cancer. |
PDF Full Text Request