Quantification Of Receptor And Tumor State Of Gastric Cancer With Dynamic Optical Imaging

Compared with the traditional static optical imaging,the dynamic optical imagingcombining with kinetic model analysis can obtain more quantitative information in vivo,such as the metabolism curve,clearance rate and binding potential,which can providemore comprehensive depiction for the physiological and pathological characteristics of thetumor.Therefore,this technique plays an irreplaceable role in quantitative study of tumorreceptor and drug efficacy evaluation.Polypeptide GX1 has a good specificity for targetingthe blood vessels of gastric cancer.Conjugated with the fluorescent dye,near infraredfluoresent probe Cy5.5-GX1 has been synthetized successfully and used in the specificdiagnosis and targeted therapy of gastric cancer.However,the specific diagnosis andgrowth evaluation of gastric cancer based on the static optical imaging can only determinethe size of the tumor,but can not reflect the microenvironment of tumor in real time andpredict its growth state sensitively.This paper focused on the specific diagnosis and growth evaluation of gastric cancer.Using dynamic optical imaging,we carried out the quantitative study on the evaluation of vascular targeting peptide GX1 and tumor growth in gastric cancer.First,we investigated the influences of common factors on quantitative results of dynamic fluorescence imaging,including probe injection dose,CCD integration time,and dynamic data acquisition scheme,to optimize the dynamic data acquisition conditions.Secondly,based on the optimized dynamic data acquisition conditions,we quantitated the targeted receptor of Cy5.5-GX1 with dynamic fluorescence imaging.Finally,Based on the two ways of intravenous and intraperitoneal injection,the corresponding kinetic models suitable for dynamic bioluminescence imaging were established,and the quantitative evaluation of tumor growth was carried out.The main contents of this thesis can be detailed as follows:1.We investigated the influence of a probe injection dose and camera integration time on quantifying pharmacokinetics of Cy5.5-GX1 in gastric cancer.First,Gurfinkel exponential model(GEXPM)and Lammertsma simplified reference tissue model(SRTM)combined with a singular value decomposition analysis were used to quantitatively analyze the acquired dynamic fluorescent images,which provides three dynamic parameters,including the binding potential(BP),the sum of kinetic rate constants(SKRC),and the tumor-to-muscle region fluorescence signal ratio(TMR).Second,we designed a series of gradients for the probe injection doses and the camera integration time,and calculated the corresponding dynamic parameters listed above.We then established the dynamic parameters as a function of probe injection dose and camera integration time.Last,based on the above-established relationships,we determined the optimized probe injection dose and camera integration time for static and dynamic optical imaging,respectively.Results of this chapter can provide a reference for quantifying the dynamic characteristics of GX1-based fluoresent probe using dynamic fluorecence imaging.2.We discussed the influence of dynamic data acquisition scheme on quantitative results of dynamic fluorescence imaging.In order to ensure the integrity of dynamic data,the caudal vein catheterization technique was necessary for dynamic data acquisition.The technique required complex operations by professionals,increasing the complexity of data acquisition in dynamic optical imaging.First,a series of dynamic data acquisition schemes were designed according to three factors,including sampling starting point,sampling sparsity,and sampling uniformity.Second,by using the GARTM model,the influence of three factors on quantitating BP value of Cy5.5-GX1 was tested on both the simulated and measured data set.Last,we statistically analysed the above quantification results and selected the best dynamic data acquisition scheme suitable for dynamic optical imaging.Results here showed that the caudal vein catheterization technique can be avoided when only quantitating BP value of the targeted probe Cy5.5-GX1 was of interest.3.Based on the optimal imaging parameters and dynamic data acquisition scheme,we performed a quantitative study of pharmacokinetics characteristics of Cy5.5-GX1.Using dynamic optical imaging,we quantitated several kinetic parameters of Cy5.5-GX1 in vivo with a combination of several kinetic models and SVD method.First,we calculated the SKRC value of the targeted probe Cy5.5-GX1 using the GEXPM model;Second,based on the GARTM and SRTM models,we quantitated the BP value and receptor turnover time(RTT)which was linearly related to the available receptor density of GX1.Quantitative results showed that there was a linear correlation between the BP value and SKRC value.These results is effective in promoting the study of the pharmacokinetics of vascular targeting peptide GX1 in gastric cancer.4.By injecting the fluorescent substrate with the intravenous and intraperitoneal injection,the quantitative evaluation of gastric tumor growth based on dynamic bioluminescence imaging was carried out.First,we analyzed the metabolic characteristics of fluorescein substrates injected via both of these ways,and constructed the corresponding compartmental model suitable for dynamic bioluminescence imaging.Second,we collected the dynamic bioluminescent images data,and fitted them with the three-exponential-model to accurately estimate the time point of light intensity peak(TLP).Third,after obtaining the metabolic curve of fluorescein substrate,we obtained the SKRC value of the fluorescein substrate by fitting the curve with the corresponding constructed compartmental model.Last,we statistically analyzed the quantitative parameters,including the TLP and SKRC values,to determine whether they can reflect the growth of tumor.These results showed that the changes of tumor microenvironment could be reflected earlier and more sensitively by using dynamic bioluminescence imaging,which could be used in the growth monitoring and drug therapeutic response of tumor.