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Is tumor cell specificity distinct from tumor selectivity in vivo?A quantitative NIR molecular imaging analysis of nanoliposome targeting

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Nano Research 2021年第5期14卷 1344-1354页

作者： Girgis Obaid Kimberley Samkoe Kenneth Tichauer Shazia Bano Yeonjae Park Zachary Silber Sassan Hodge Susan Callaghan Mina Guirguis Srivalleesha Mallidi Brian Pogue Tayyaba Hasan Wellman Center for Photomedicine Massachusetts General Hospital and Harvard Medical SchoolBostonMA02114USA Department of Bioengineering University of Texas at DallasRichardsonTX75080USA Thayer School of Engineering Dartmouth CollegeHanoverNH037551USA Armour College of Engineering Illinois Institute of TechnologyChicagoIL60616USA Division of Health Sciences and Technology Harvard University and Massachusetts Institute of TechnologyCambridgeMA02139USA

The significance and ability for receptor targeted nanoliposomes(tNLs)to bind to their molecular targets in solid tumors in vivo has been questioned,particularly as the efficiency of their tumor accumulation and selectivity is not always predictive of their efficacy or molecular specificity.This study presents,for the first time,in situ near-infrared(NIR)molecular imaging-based quantitation of the in vivo specificity of tNLs for their target receptors,as opposed to tumor selectivity,which includes influences of enhanced tumor permeability and retention.Results show that neither tumor delivery nor selectivity(tumor-to-normal ratio)of cetuximab and IRDye conjugated tNLs correlate with epidermal growth factor receptor(EGFR)expression in U251,U87,and 9L tumors,and in fact underrepresent their imaging-derived molecular specificity by up to 94.2%.Conversely,their in vivo specificity,which we quantify as the concentration of tNL-reported tumor EGFR provided by NIR molecular imaging,correlates positively with EGFR expression levels in vitro and ex vivo(Pearson’s r=0.92 and 0.96,respectively).This study provides a unique opportunity to address the problematic disconnect between tNL synthesis and in vivo specificity.The findings encourage their continued adoption as platforms for precision medicine,and facilitates intelligent synthesis and patient customization in order to improve safety profiles and therapeutic outcomes.

关键词： molecular recognition receptors nanoparticles specificity cancer

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A mechanistic consideration of oxygen enhancement ratio, oxygen transport and their relevancies for normal tissue sparing under FLASH irradiation

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Holistic Integrative Oncology 2022年第1期1卷 170-180页

作者： Mengyu Jia Xu Cao brian W.pogue Hao Peng School of Precision Instrument and Opto-Electronics Engineering Tianjin UniversityTianjin 300072China Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education&School of Life Science and Technology Xidian UniversityXi’an 710126ShanxiChina Thayer School of Engineering Dartmouth CollegeHanoverNHUSA Department of Medical Physics Wuhan UniversityWuhan 430072China NewRT Medical Systems Inc. Wuxi 214144China

Our study investigated the role of oxygen in mediating the FLASH efect.This efect,which was frst reported in vitro in the 1950s and in vivo in the 1970s,recently gained prominence with a number of publications showing diferential sparing between normal tissues and tumors.Oxygen depletion(and subsequent induction of transient hypoxia)is the oldest and most prominent hypothesis to explain this efect.To better understand how the oxygen depletion hypothesis and oxygen enhancement ratio(OER)are relevant for interpreting FLASH benefts,an analytical model was proposed to estimate the sparing factor.The model incorporated factors such as OER,oxygen partial pressure(pO_(2)),loco-regional oxygen difusion/metabolism,total dose and dose rate.The sparing factor,was used to quantify the sparing of normal tissue(initially physoxic).The radiosensitivity parameters of two cell types(V79 Chinese hamster cells and T1 human kidney cells)were selected.Furthermore,the transient behavior of OER during fnite time intervals was modeled,for both without and with the presence of oxygen transport using a difusion model.For tissues with an oxygen consumption rate of 20mmHg/s and a distance of 60μm away from blood vessels,the sparing factor demonstrates an increase from 1.03/1.06(V79/T1)at 2.5Gy/s up to 1.28/1.72(V79/T1)at 100Gy/s(total dose:10Gy).For normal tissues of initial pO_(2) between 1.5 and 8mmHg,the beneft from pushing the dose rate above 100Gy/s is found to be marginal.Preliminary animal experiments have been conducted for validation.Overall,our study predicts that the dose rate associated with maximum normal tissue protection is between 50Gy/s and 100Gy/s.Other than the postulation of the hypoxic stem cell niches in normal tissues,we believe that a framework based upon the oxygen depletion hypothesis and OER is not able to efciently interpret diferential responses between normal and tumor tissue under FLASH irradiation.

关键词： FLASH radiotherapy OER Oxygen depletion

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Color Cherenkov imaging of clinical radiation therapy

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Light(Science & Applications) 2021年第12期10卷 2380-2386页

作者： Daniel A.Alexander Anthony Nomezine Lesley A.Jarvis David J.Gladstone brian W.pogue Petr Bruza Thayer School of Engineering Dartmouth CollegeHanoverNHUSA DoseOptics LLC LebanonNHUSA Geisel School of Medicine Dartmouth CollegeHanoverNHUSA Norris Cotton Cancer Center DartmouthHitchcock Medical CenterLebanonNHUSA

Color vision is used throughout medicine to interpret the health and status of tissue.Ionizing radiation used in radiation therapy produces broadband white light inside tissue through the Cherenkov effect,and this light is attenuated by tissue features as it leaves the body.In this study,a novel time-gated three-channel camera was developed for the first time and was used to image color Cherenkov emission coming from patients during treatment.The spectral content was interpreted by comparison with imaging calibrated tissue phantoms.Color shades of Cherenkov emission in radiotherapy can be used to interpret tissue blood volume,oxygen saturation and major vessels within the body.

关键词： therapy clinical Color

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基于纳米粒子的切伦科夫成像与治疗

基于纳米粒子的切伦科夫成像与治疗

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中国稀土学会2021学术年会

作者：姚翠萍曹旭李炯张镇西 brian W pogue 西安交通大学西安电子科技大学生命学院 Dartmouth College Thayer School of Engineering

带电粒子在介质中的运动速度大于光速时,就会产生切伦科夫辐射。医用直线加速器用高能X射线或电子辐射生物组织时,在体内原位所产生的切伦科夫辐射可以用于治疗和成像。本研究采用医用直线加速器在放疗过程中产生的切伦科夫辐射,一方面... 详细信息

带电粒子在介质中的运动速度大于光速时,就会产生切伦科夫辐射。医用直线加速器用高能X射线或电子辐射生物组织时,在体内原位所产生的切伦科夫辐射可以用于治疗和成像。本研究采用医用直线加速器在放疗过程中产生的切伦科夫辐射,一方面进行成像,以监测放疗过程中的某些分子事件,比如放疗过程中肿瘤内部氧的分布与变化;另一方面利用这种辐射实现放疗和其他疗法,比如化疗的协同治疗,以提高肿瘤的预后。研究中,采用新型树枝状磷光氧传感器PtG4,通过尾部静脉注射对肿瘤进行靶向标记,测量一个放疗周期内PtG4的磷光寿命,获得整个放疗周期内肿瘤内部的氧分压变化,以评估放疗过程中肿瘤的乏氧状态。另一方面,可靶向肿瘤的,能被X射线激发的释药体系—装载阿霉素的纳米胶束,通过静脉注射,24小时候可在肿瘤部位富集。对肿瘤部位进行X射线辐射,以达到放化疗的协同作用。实验结果表明,不同肿瘤内部的乏氧状态有所不同,并且乏氧严重的肿瘤放疗效果比普通肿瘤的效果更差。通过这种方法,可获得肿瘤内部的氧分压的不均匀性分布。协同治疗结果表明,释药体系的加入可有效延长小鼠的寿命。这种方法也具有临床转化的优势。

关键词：靶向 X-射线切伦科夫辐射,肿瘤

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MR-GUIDED PULSE OXIMETRY IMAGING OF BREAST IN VIVO

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Journal of Innovative Optical Health Sciences 2011年第2期4卷 199-208页

作者： ZHIQIU LI SHUDONG JIANG VENKATARAMANAN KRISHNASWAMY SCOTT CDAVIS SUBHADRA SRINIVASAN KEITH D.PAULSEN brian W.pogue Thayer School of Engineering Dartmouth College Hanover NH 03755USA

A near-infrared(NIR)tomography system with spectrally-encoded sources in two wavelength bands was built to quantify the temporal oxyhemoglobin and deoxyhemoglobin contrast in breast tissue at a 20 Hz bandwidth.The system was integrated into a 3T magnetic resonance(MR)imaging system through a customized breast coil interface for simultaneous optical and MRI acquisition.In this configuration,the MR images provide breast tissue structural information for NIR spectroscopy of adipose andfibro-glandular tissue in breast.Spectral characterization performance of the NIR system was verified through dynamic phantom experiments.Normal human subjects were imaged withfinger pulse oximeter(PO)plethysmogram synchronized to the NIR system to provide a frequency-locked reference.Both the raw data from the NIR system and the recovered absorption coefficients of the breast at two wavelengths showed the same frequency of about 1.3 Hz as the PO output.The frequency lock-in approach provided a practical platform for MR-localized recovery of small pulsatile variations of oxyhemoglobin and deoxyhemoglobin in the breast,which are related to the heartbeat and vascular resistance of the tissue.

关键词： High frame-rate fast imaging MR-guided near-infrared tomography breast hemodynamics

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