Design And Tumor Delivery Of Hydroxycamptothecin Liposomes With Different Stiffness

Pancreatic cancer(PC),a major histological type of cancer in sporadic sporadic and familial cancers,has a very low survival rate of only 6%.Literature studies have found that extracellular matrix(ECM)in pancreatic cancer is massively fibrotic,up to 90% of the total volume,so nanoparticles rarely reach tumor cells.As one of the most commonly used preparations for nanotherapy,liposomes have a lot of advantages,for example,sustained release,targeting,cell and tissue compatibility,which are often used in tumor therapy.At present,there are more than 10 kinds of products such as doxorubicin hydrochloride long-circulating liposome and paclitaxel liposome.Although liposomes have been successfully applied in the field of drug therapy,their drug delivery efficiency still needs to be further improved.How to rationally design and prepare liposome drug carriers,which can effectively overcome multiple physiological barriers and accurately deliver drug molecules to targeted tissue and cells,remains to be studied.In this subject,based on the physicochemical characteristics of the composition of the phospholipids with different carbon chain lengths and unsaturation,we have rationally prepared a series of hydroxycamptothecin liposomes with different rigidity which has the particle size of about 85 nm,a carbon chain length from 12 to 22,and an unsaturation of 0 and 1.Through in vitro AFM characterization experiments,we found that the carbon chain length,unsaturation,and composition of phospholipids determine the rigidity of the liposomes.As the length of the carbon chain increases,the rigidity of the liposome increases;as the degree of unsaturation increases,the rigidity of the liposome decreases.Among them,Lip3 as the moderately rigid hydroxycamptothecin liposome,that the prescription of phospholipid is DPPC: DSPE-PEG2000=95%: 5% can rapidly diffuse in tumor interstitial ECM in vitro,and the diffusion rate is about 4.1~ 11.8-folds higher than other groups;in vitro cell uptake showed that the six groups of liposomes were endocytosed into cells through the clathrin-mediated pathway,and the stiff liposomes Lip4 had the best cell uptake capacity,which was about 3.0~8.2-folds higher than other groups.The anti-tumor activity in vitro was about 1.5 to 2.9-folds higher than other groups.The osmotic mechanism study found that the Lip3 produced a suitable deformation in the 3D Bx PC-3 & HPSC tumor sphere,transformed into a "bar-like",rapid movement and showed the best penetration depth and ability,about 4.0 to 6.1-folds higher than other groups;In the 3D Bx PC-3 tumor sphere,Lip4 showed the best penetration ability due to the strongest cellular uptake.Further studies have found that Lip3 can quickly reach the tumor site in the mice,maintain a high retention times,and the penetration depth is about 2.5 to 7.5-folds higher than other groups.In conclusion,liposomes with intermediate rigidity can effectively overcome multiple physiological barriers during tumor delivery(enzyme,tumor stroma and cell barrier,etc.),have more efficient drug delivery efficiency,and finally reach target tissues and significantly inhibit pancreatic cancer.This topic reveals the mechanism of rigid-regulated liposomes to overcome multiple physiological barriers,and provides new ideas for the rational design of high-efficiency liposome delivery systems.