| The morbidity of renal cancer is second only to bladder cancer in urological tumors.The 2017 CSCO renal cancer diagnosis and treatment guidelines showed that the morbidity of renal cancer had been increasing rapidly in recent years with the rapid aging of China's population(annual increase of 6.5 percent on average).Renal imaging remains was an important tool to differentiate and manage benign from malignant neoplasms of kidney.The correct diagnosis rate of typical lesions was more than 95%,but misdiagnosis was occurred occasionally in the minor incidentaloma and atypical lesions.It was reported that around 30% of renal masses less than 2 cm in size and 20% greater than 4 cm in diameter were benign by postoperative pathologic report.About 16% to 33% of nephrectomies were performed for benign lesions.It is very important for clinical and imaging workers to improve the preoperative diagnosis of renal tumors.This also becomes the difficulty and hotspot of imaging studies.Vascular permeability enhancement and retention effect(EPR effect)was discovered and proposed by Japanese scholar Hiroshi Maeda in 1986.EPR effect is the theoretical basis of high specificity and selectivity of nanomedicine.Micellar and other nanoparticle drug delivery systems cross the blood tumor tissue barrier to passive or active target accumulation in tumor tissues by the EPR effect,to improve the diagnosis or therapeutic effect of the tumors.There were significant differences in heterogeneity of blood tumor tissue barrier between tumors of different organs.The kidney filtration barrier is consistent with its urinary function,the renal blood flow is very rich,but its distribution is very uneven in the kidney.The renal vascular bed consists of two sets of interconnected capillaries,which are connected in series by the efferent arterioles.When the normal renal tissues were destroied by renal tumors,the blood tumor tissue barrier of renal tumor is different from blood tumor tissue barrier in other organ tumors,and has its unique pathophysiological characteristics.Angiotensin ? can selectively enhanced tumor vascular permeability and blood flow in other organ tumors,to improve EPR effect of macromolecular drugs in the tumor tissues,to be used in the diagnosis and treatment of tumor.Angiotensins II constricts the efferent glomerular artery rather than the afferent glomerular artery.It can influence normal renal tissues,and the renal tumor BF distribution may be different from tumors in other organs,which has its unique imaging findings.Understanding the mechanism can help to understand the EPR effect of renal tumors.Many basic researches with landmark significance were unable to replicate in the clinical,many drugs had good curative effect in animal experiment,but it had a poor curative effect in clinical trials.Some drugs had to be halted,even in the third phase of clinical trials.These had led to a heated debate among scholars,even suspected whether the EPR effect of tumor is real or not.First,to investigate the effects of angiotensin ?on normal renal tissue and renal tumor blood flow distribution in the rabbit renal VX2 tumors using perfusion CT combined with computed tomographic angiography(CTA),clarify the mechanism of angiotensin ?effect on intrarenal tumor hemodynamics,to improve preoperative correct diagnosis of renal indeterminate small lesions.Second,we measured the iodine content of micelles marked with prolonium iodide by gemstone spectral imaging,to assess the accuracy of the measurement of micelle was measured by gemstone spectral imaging.And,observe the biological distribution of micelles in vivo,this is the basis for quantitative evaluation of tumor EPR effect.Third,we measured the iodine content of micelles marked with prolonium iodide by gemstone spectral imaging,to observe the accumulation process of micelles in rabbit renal VX2 tumor,to quantificationally study the EPR effect of tumor.Finally,using vitro human kidney tumor specimens as the experimental object,which are very similar to vivo human tumors.To study the relationship between size of polymer micelle carrier and the EPR effect of human kidney tumors,to answer this hot issue whether the EPR effect of tumor is real or not.This study was approved by the institutional animal care and use committee.The main contents of this article are as follows:Part ? Perfusion CT Assessment of the Effect of Angiotensin II on Blood Flow Distribution in Rabbit VX2 Intrarenal TumorObjective: To investigate the effects of angiotensin ?on normal renal tissue and renal tumor blood flow distribution in the rabbit renal VX2 tumors using perfusion CT combined with computed tomographic angiography(CTA),clarify the mechanism of angiotensin ?effect on intrarenal tumor hemodynamics.Methods:Twenty-four male New Zealand white rabbits were random divided into A,B,C three groups.Solitary autologous perirenal adipose tissue were implanted into left kidney of group A(blank control group),solitary fresh VX2 tumor tissue masses were implanted into left kidney of group B(negative control group)and C(angiotensin II group).In rabbits of A and B group,perfusion CT of the renal was performed.In rabbits of C group,angiotensin II perfusion CT was performed at the same scanning parameters.BF,BV,MTT,and PS were calculated for the tumor,CAT,CDT,RRC and PVM,calculate the RPS.Measure the start developing time,time to peak and maximum inner diameter of the aorta abdominalis,left renal artery and left renal vein.The foregoing perfusion CT thin layer image of each pass as the CTA images data import ADW 4.5 workstation for volume rendering(VR)and maximum density projection(MIP)to show the dynamic changes of the renal blood vessels.Results:Compared with the groups A and B,angiotensin II significantly prolonged SDT of the LRV;prolonged TTP of RRA,LRA,and LRV;increased the MID of AA,RRA,and LRA.Compared with normal renal cortex tissues of group A,the tumor BF,BV,and PS values of group B were significantly lower(P<0.001,P=0.001,and P=0.041 respectively,LSD-t),MTT was prolonged(P=0.079,LSD-t),and RPS increased(P<0.001,LSD-t).Compared with group B,tumor BF,BV,MTT,and PS values in group C were unaffected,only the tumor RPS was increased from 83.23±29.17 % to 120.94±31.84 % by angiotensin II infusion(P=0.007,LSD-t).Compared with group B,angiotensin II significantly increased the RPS value of the renal cortex distant from the tumor(CDT)(P=0.019,LSD-t)and right renal cortex(RRC)(P=0.003,LSD-t),the BF values of renal cortex immediately adjacent to the tumor(CAT),CDT and RRC were significantly lower(P<0.001,P=0.010,and P<0.001,respectively,LSD-t),while the BV,PS and MTT values of CAT,CDT and RRC have no obvious change.Summary: Perfusion CT can accurately observe that angiotensin ?influence on normal renal tissue and renal tumor blood flow distribution,Clarify the mechanism of angiotensin ? effect on intrarenal tumors hemodynamics.Angiotensin II induced high blood pressure,efferent arteriole was contracted,the blood flow could have been entered into tumor tissue,more entered into the glomeruli,it lead to the blood flow of renal tumors decreased instead of increased.Angiotensin II selective increases RPS in intrarenal tumors and renal cortex adjacent to the tumor versus that in renal cortex distant from the tumor and right renal cortex,RPS can be as one more effective perfusion parameters,it can help to improve preoperative correct diagnosis of renal indeterminate small lesions.There is the blood-tumor barrier around the renal tumor,it not only manifests in the abnormality of ultrastructure,but also the difference in function.Angiotensin II significantly reduced BF of the CAT,significantly increased the RPS of CAT.Part II Preliminary application of gemstone spectral imaging in biological distribution of micelles of the rabbit in vivo.Objective: To measured the iodine content of micelles marked with prolonium iodide by gemstone spectral imaging,to assess the accuracy of the measurement of micelle was measured by gemstone spectral imaging.And,observe the biological distribution of micelles in vivo,this is the basis for quantitative evaluation of tumor EPR effect.Methods:Professor Shi-linqi's research group of Polymer Chemistry Institute of Nankai University was responsible for the preparation of micelles marked with prolonium iodide.The 100 nm micelle was prepared into different concentrations,the IC value of micellar was determined by GSI technology,and the linear equation between IC value and micelle concentration was obtained.Micellar metabolism:Six male New Zealand white rabbits were random divided into two groups: iodide group and 100 nm micelles group.First,baseline GSI scan was performed,the scan range was from liver to bladder.Then,the IC values of ioversol and 100 nm micelle were all configured with a solution of 7 mg/ml.The GSI scan were performed at 5min,10 min,30min,1h,2h,3h,4h,5h,and 6h after intravenous injection of 25 ml of drugs.At the same time,3ml blood was collected,IC was measured and injected back into the rabbit.The IC values of the liver,gallbladder,renal papillary region or renal calyx were measured,and the dynamic evolution curve were plotted to calculate AUC,TTP and IC peak value.Results: The IC value and micelle concentration are linearly positive,and the linear equation of IC value is:Y = 1.403*X + 0.8123,R=0.9909,P<0.0001.The iodine in the blood is basically cleared by the kidney for only 30 min.On the contrary,the blood IC of the 100 nm micelle was very slow,until 6h the blood IC was still as high as 9.69±0.93(100?g/cm3).Micelles have a long blood circulation time,it are mainly metabolized by kidney,can meet the needs of EPR effect by GSI.Summary: The IC value and micelle concentration are linearly positive.Micelles have a long blood circulation time,safe and non-toxic.It is mainly metabolized by kidney,can meet the needs of EPR effect by GSI.Part III Gemstone spectral imaging study of EPR effect in rabbit VX2 renal tumorObjective: To measured the iodine content of micelles marked with prolonium iodide by gemstone spectral imaging,to observe the accumulation process of micelles in rabbit renal VX2 tumor,to quantificationally study the EPR effect of tumor,to answer this hot issue whether the EPR effect of tumor is real or not.Methods: Effects of micellar dose on EPR effect of vivo tumor: Six male VX2 tumor model rabbits were random divided into two groups: 2ml group and 10 ml group.GSI scan were performed before and after injection drugs,the scan time is same as before.Finally,the perfusion CT scan was performed.The IC values of tumor tissues were measured,and AUC,TTP and IC peak were calculated.Effects of micellar particle size on EPR effect of vivo tumor: Twenty-four male VX2 tumor model rabbits were random divided into four groups: 80 nm,100nm,150 nm and 170 nm.The scanning scheme and data processing are the same as before.The EPR effect of vitro tumor: Eighteen male VX2 tumor model rabbits were random divided into three groups: 45 nm,70nm and 130 nm.The left kidney with tumor was removed from rabbit.The renal artery,renal vein and ureter were connected with the drug peristaltic pump,venous effluent collector and urine collector respectively.Take 1 ml of micelle and 50 ml of HTK mixture,the vitro tumor was infused with peristaltic pump.The scanning scheme and data processing are the same as before.Results: With the increase of micellar dose,the concentration of micelles in the blood also increased,the AUC and IC peaks of tumor tissues were increased and TTP was extended.Under the same doses,with the increase of particle size of the micelle,TTP of vivo VX-2 renal tumor from 2.5 h(80 nm)to extend 3.5 h(170 nm).There were no significant difference in AUC and IC peak of tumor between 80 nm,100nm,150 nm and 170nm(P > 0.05 and P > 0.05 respectively).Under the same doses,there were significant differences between the 45 nm,70nm and 130 nm micelles of the EPR effect of vitro renal tumors(P < 0.05).The AUC and IC peaks of both 70 nm group and 130 nm group were significantly higher than that of the 45 nm group(P < 0.05).With the increase of particle size of the micelles,TTP extended from 2h(45nm)to 3h(130nm).Summary: Increasing the dose of micelle can increase the AUC and IC peak value of the micellar EPR effect,and prolong TTP.The ability of micelles pass through blood tumor barrier are inversely proportional to the micellar particle size,the larger the particle size,the greater the resistance,and the longer the time of tumor EPR effect reaches saturation state.The micellar enrichment curve of the vitro tumors were increase-platform type curve.Due to the influence of the blood barrier and the RES(liver,spleen),the micellar enrichment curve of the vivo tumors were increase-decrease type curve.The experimental results show that the EPR effect exists objectively.Part ? Gemstone spectral imaging preliminary study of EPR effect in human kidney tumor specimensObjective: Using vitro human kidney tumor specimens as the experimental object,which are very similar to vivo human tumors.To study the relationship between size of polymer micelle carrier and the EPR effect of human kidney tumors,to answer this hot issue of nanomedicine whether the EPR effect of tumor is real or not.Methods: 33 human kidney tumor specimens were collected from the urological surgery of the affiliated hospital of hebei university,Using queue design,and were divided into three groups: 45 nm,70 nm and 130 nm micellar groups.The renal artery,renal vein and ureter were connected with the drug peristaltic pump,venous effluent collector and urine collector respectively.Take 3 ml of micelle and 300 ml of HTK mixture,the vitro human kidney tumor specimens were infused with peristaltic pump.First,baseline GSI scan was performed,and the GSI scan were performed at 1h,2h,3h,4h,5h,and 6h after micellar perfusion.The IC values of tumor tissues were measured,and AUC,TTP and IC peak were calculated.The data of before and after infusion 1h,2h,3h,4h,5h and 6h in the third part,which were used as the control,the AUC,TTP,and IC peak of human kidney tumor specimens were compared with vitro rabbit kidney tumor.Results: Under the same doses,it was basically the same that the shape and trend of the enrichment curve of three kinds of particle size micelle(45nm,70 nm and 130nm)in human kidney tumor specimens.The enrichment curve of 130 nm micelle was slightly higher than that of the 45 nm and 70 nm micelles.The AUC of 130 nm group was significantly higher than 45 nm and 70 nm group(P < 0.01,LSD-t test).There was no difference between 45 nm and 70 nm micelle(P>0.05,LSD-t test).The IC peak of 130 nm micelles was higher than that in the 45 nm group(P < 0.05,LSD-t test).TTP was between 3 and 4h.The AUC of 70 nm and 130 nm micelle in vitro rabbit renal tumor were much higher than AUC in human kidney tumor specimens(P < 0.01,student-t test).The AUC of 45 nm micelle in human kidney tumor specimens was much higher than AUC in vitro rabbit renal tumor(P < 0.05,student-t test).The TTP of three kinds of particle size micelle in human kidney tumor specimens were generally longer than that in vitro rabbit renal tumor.There were no significant differences in the IC peaks of the three types of micellebetween human kidney tumor specimens and vitro rabbit renal tumor.Summary: Both human and animal kidney tumor experiments demonstrated that the EPR effect of tumor exists objectively.The ability of micelles pass through blood tumor barrier of human kidney are inversely proportional to the micellar particle size,the larger the particle size,the greater the resistance,and the longer the time of tumor EPR effect reaches saturation state.Compared with experimental animals,the EPR effect of human kidney tumor was more complex,with low AUC,same IC peak value,and longer TTP.Conclusion:1.Perfusion CT can accurately observe that angiotensin ?influence on normal renal tissue and renal tumor blood flow distribution,Clarify the mechanism of angiotensin ? effect on intrarenal tumors hemodynamics.2.Angiotensin II selective increases RPS in intrarenal tumors and renal cortex adjacent to the tumor,RPS can be as one more effective perfusion parameters,it can help to improve preoperative correct diagnosis of renal indeterminate small lesions.3.Both human and animal kidney tumor experiments demonstrated that EPR effect of tumor exists objectively.Compared with experimental animals,the EPR effect of human kidney tumor was more complex.4.The tumor EPR effect was positively correlated with the dose of micelle,and was inversely proportional to the size of micelle,the larger the particle size,the greater the resistance.The micellar enrichment curve of the vitro tumors were increase-platform type curve,the micellar enrichment curve of the vivo tumors were increase-decrease type curve. |
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