The Mechanism Of Polyethylene Glycol Doxorubicin Hydrochloride Liposome Induced Hand-foot Syndrome

Objective: Pegylated liposomal doxorubicin(PLD)is a chemotherapeutic drug with a polyethylene glycolated double lipid layer and Doxorubicin(DOX)molecular aqueous core in the center.Compared with traditional anthracycline DOX,PLD can significantly reduce cardiac toxicity,alopecia,bone marrow suppression and other adverse reactions and improve patient compliance.However,the incidence of Hand-Foot Syndrome(HFS)caused by HFS increases significantly with the increase of dose.The current arguments mainly focus on local drug accumulationm,skin inflammatory reaction and other aspects,and there is no relevant systematic experimention to support it.Therefore,we explored the mechanism of HFS induced by PLD through the rats model of HFS,and laid a foundation for the clinical prevention and treatment of HFS.Methods: The healthy female SD rats(Sprague Dawley,SD)were provided by Animal Experimental Center of Hebei Medical University.Twenty rats were randomly divided into two groups: PLD group(PLD)and Vehicle control group(5% glucose injection).Venous blood was collected from all rats and photos of the hind PAWS and palms were collected.Establishing the HFS model(PLD or 5% glucose injection was injected through tail vein,7mg/kg,once every 3 days,for 10 days,with a cumulative dose of 28mg/kg for each rat).Blood samples and photos were collected again 10 days later,HFS grading was evaluated.The blood samples were quantitatively tested for 4-hydroxybenzenesulfonic acid.Optical Microscope and immunohistochemical staining(CD31,CD34,F8)were used to observe the changes of the skin of rats’ hind paws.Scanning electron microscope(SEM)was used to observe the changes of capillary and pore diameter of endothelial cells in rats’ hind paws,and the changes of organelle structure were observed by transmission electron microscope.Evans Blue method was used to quantitatively measure the damage of microvascular permeability there.Detecting topical drugs in skin tissue quantitatively.Results:1.The incidence of grade 3/non-grade 3 HFS in PLD group was 50%respectively,no HFS occurred in the Vehical control group.2.Targeted metabonomics detection: after intravenous administration of PLD,the content of 4-hydroxy-benzenesulfonic acid in peripheral circulation was compared between the two groups of rats with 3-degree/non-3-degree HFS before administration,P=0.907>0.1,showing no statistical difference;But the comparison between the two groups was significant After administrating PLD,P =0.008 < 0.01;There was no statistical difference in the content of 4-hydroxy-benzene sulfonic acid before and after treatment in same group.3.Compared with the Vehicle control group,the rats’ hind paws’ skin of the PLD group showed corneous separation,epidermal thinning and basal layer cell swelling.The dermis was loose and edema、the blood vessels in the dermis were dilated,the inflammatory cells were infiltrated around.The capillary wall became thin and the number of endothelial cells decreased.CD31,CD34 and F8 were less distributed.4.Scanning electron microscopy showed that SD rats’ hind paws’ skin in PLD groups may be like this : The tight junction of capillary endothelium and micropores of the basement membrane were opened、surrounding edema were observed also.Slight nuclear pyknosis of endothelial cells;Transmission electron microscopy showed that the capillary basement membrane mic-rop-ores were opened in the hind paw skin after PLD.5.EVB test: Compared with the Vehicle control group,the microvascular leakage in the hind paw skin of the PLD group was more serious,and the difference of drug leakage in two groups was statistically significant(P <0.01).6.Local drug detection: Dorubicin accumulated in the hind paw skin of rats in PLD group,while no drug was detected in Vehicle control group.Conclusions:1.We were able to establish a PLD-induced HFS SD rats model successfully.2.The possible mechanism of PLD-induced HFS is that PLD can cause damage to the capillary wall of the skin tissue on the palmar side of the hind paw of SD rats,increase the permeability,exudate PLD,accumulation of doxorubicin in the skin tissue,damage the epidermis,and thus cause the occurrence of HFS.3.The occurrence of HFS may be related to the lacking in 4-hydroxybenzene sulfonic acid from metabolomics.