Study On Benzoporphyrin Derivative Monoacid Ring A In Photodynamic Therapy For Prevention Of Intimal Hyperplasia

Study on Benzoporphyrin Derivative Monoacid Ring A inPhotodynamic Therapy for Prevention of IntimalHyperplasiaAbstract:Background and Objective:Photdynamic therapy (PDT) is based on the use of light-sensitive molecules called photosentizers. When photosentizer molecules are activated by light at specific wavelengths, a variety of active forms of oxygen are created, which produces peroxidative reactions that can cause cell damage and death. Benzoporpyrin derivative monoacid ring A (BPD-MA), a chlorin-type compound, is a new photosensitizer currently in phase I-LI clinical trials for the treatment of cutaneous malignancies , psoriasis and pathologic neovascularization. and other hyperplastic disease. Restenosis(RS) is the results of the transportation and abnormal proliferation of vascular sooth muscle cells (VSMCs) following percutaneous transluminal coronary angioplasty (PTCA). It's a new research of prevention and treatment restenosis with BPD-MA-PDT. The purpose of this study is: (1) to study the absorption regularity of BPD-MA in VSMCs and ECs; (2) to find out the effects of alteration of VSMCs function status on their absorption ability of BPD-MA; (3) to investigate the absorption characteristic of BPD-MA in rabbit plasma and arterial tissue; (4) to observe the efficacy of intravascular BPD-MA-PDT on restenosis model, to provide a basis for a more proper and suitable PDT on restenosis after angioplasty.Methods and resultsFirstly, the enzyme-dispersed cultured ECs and substracte- attachedcultured VSMCs were identified respectively, grouped, BPD-MA was addedinio each grouP to the end conceniration of l, 2, 4, 6, 8, l0, l2, 14, l6, 20ug/ml,then the BPD-MA absorption characteristics in these two kind of cel1s wereanalyzed using fluorospectrophotometer at 0, 15, 30, 60, l20, l80, 240min ofcoincubation. The results showed that absorption of BPD-MA in SMCs andECs were time- and concentration dependent. When incubation concentrationwas l0ug/ml, the absorption in SMCs reached peak while the ECs absorptionpeak at l8ug/ml, and SMCs absorbed BPD-MA higher than ECs at anyconcentration. The absorption increased with incubation time in both SMCs andECs, but it was higher in SMCs than ECs at any incubation time exceptirrunediateness.Secondly, SMCs were added into 24-well cultUre plate, divided into 3groups: PDGF group, l0% fetal bovine serum (FBS) group and 2% FBS group.Cells were synchronized by incubated with 2% FBS for 48h, then thecorresponding growth factor were added into each grouP to incubate for l2h,and the absorpion characteristic was analysized with fluorospectrophotometer.It was showed that the uptake of drug increased in the following order: PDGFgrouP >l0%FBS grouP>2% FBS grouP (P<0.05).Thirdly, BPD-MA absorption characteristics in blood and arterial tissues ofrabbits were analyzed with fluorospectrophotometer. It was shOwed that BPD-MA uPtake and discharge in deial tissue are concentration- and time-dependent with the dosage in blood, but the uptake and discharge in tissue isslower than in b1ood. The concentraion of drug reached peak once BPD-MAwas completely administered intravenously to the anesthetized New ZealandWhite rabbits, and raPidly attained plateau of the curve 20min after injection,and there were no difference between normal and injured arteries at 40 and 80min after injection.Fourthly, rabbits were randomly assigned to the fOllowing groups: group l,injured only; group 2, only drug; grouP 3, only light at 30mW/cm2 fOr l5min;- 6 -group 4, drug plus light at 30mW/cm2 for 15mm; group 5, drug plus light at 90mW/cm2 for 15 mm. BPD-MA was administered in a dose of 2.5mg/kg. Light was provided by a fiberoptic probe with a 3 cm cylindric diffuser attached to a copper vapor laser providing 51 0.6nm laser light. Anesthetized New Zealand White rabbits underwent placement of balloon catheters introduced via femoral artery cutdowns. Catheters were passed retrograde 10cm into the lower abdominal...