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Optical drug monitoring: photoacoustic imaging of nanosensors to monitor therapeutic lithium in vivo.

ABSTRACT: Personalized medicine could revolutionize how primary care physicians treat chronic disease and how researchers study fundamental biological questions. To realize this goal, we need to develop more robust, modular tools and imaging approaches for in vivo monitoring of analytes. In this report, we demonstrate that synthetic nanosensors can measure physiologic parameters with photoacoustic contrast, and we apply that platform to continuously track lithium levels in vivo. Photoacoustic imaging achieves imaging depths that are unattainable with fluorescence or multiphoton microscopy. We validated the photoacoustic results that illustrate the superior imaging depth and quality of photoacoustic imaging with optical measurements. This powerful combination of techniques will unlock the ability to measure analyte changes in deep tissue and will open up photoacoustic imaging as a diagnostic tool for continuous physiological tracking of a wide range of analytes.

SUBMITTER: Cash KJ

PROVIDER: S-EPMC4364417 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Optical drug monitoring: photoacoustic imaging of nanosensors to monitor therapeutic lithium in vivo.

Cash Kevin J KJ Li Chiye C Xia Jun J Wang Lihong V LV Clark Heather A HA

ACS nano 20150121 2

Personalized medicine could revolutionize how primary care physicians treat chronic disease and how researchers study fundamental biological questions. To realize this goal, we need to develop more robust, modular tools and imaging approaches for in vivo monitoring of analytes. In this report, we demonstrate that synthetic nanosensors can measure physiologic parameters with photoacoustic contrast, and we apply that platform to continuously track lithium levels in vivo. Photoacoustic imaging achi ...[more]

PMID: 25588028

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Project description:Molecular photoacoustic imaging (PA) is a promising technology to understand tumor pathology and guide precision therapeutics. Despite the capability of activatable PA probes to image tumor-specific biomarkers, limitations in their molecular structure hamper them from effective drug delivery and the drug release monitoring. Herein, we developed a perylene diimide (PDI) based theranostic platform that provides noninvasive PA imaging signals to monitor tumor-specific pH-responsive drug release. Methods: we first designed and synthesized an acid-responsive amine-substituted PDI derivative. The pH sensitive properties of the PDI was demonstrated by density functional theory (DFT) calculations, UV-vis experiments and PA studies. The theranostic platform (THPDINs) was fabricated by self-assembly of the acid-responsive PDI, a pH irrelevant IR825 dye, and anti-cancer drug doxorubicin (DOX). The PA properties in various pH environment, drug delivery, cytotoxicity, cell uptake, ratiometric PA imaging and anti-tumor efficacy of the THPDINs were investigated in vitro and in vivo by using U87MG glioma cell line and U87MG tumor model. Results: We found that our designed PDI was sensitive to the tumor specific pH environment, reflected by absorbance shift, PA intensity and aggregation morphology changes in aqueous solution. The as-synthesized pH sensitive PDI acted as a molecular switch in the THPDINs, in which the switch can be triggered in the mild acidic tumor microenvironment to accelerate DOX release. Meanwhile, the DOX release could be monitored by ratiometric PA imaging. Conclusions: We developed a multifunctional PDI based theranostic platform for noninvasive real-time ratiometric PA imaging of tumor acidic pH and monitoring of drug release in living mice simultaneously. This strategy will shed light on the development of smart activatable theranostic nanoplatforms and will significantly advance the application of PA theranostics in biology and medicine.

Project description:Background & aimsCurrently, staging of fibrosis in preclinical rodent liver fibrosis models is achieved histologically. Many animals are used at multiple time-points to assess disease progression or therapeutic responses. Hepatic myofibroblasts promote liver fibrosis therefore quantifying these cells in vivo could assess disease or predict therapeutic responses in mice. We fluorescently labelled a single chain antibody (C1-3) that binds hepatic myofibroblasts to monitor fibrogenesis in vivo.MethodsCCl4 was used to induce acute liver injury in WT and cRel(-/-) mice. Bile duct ligation was used to model chronic fibrosis. Hepatic myofibroblasts were depleted using a liposome-drug delivery system or chemically with sulfasalazine. An IVIS® spectrum visualised fluorophore-conjugated C1-3 in vivo.ResultsIVIS detection of fluorescently labelled-C1-3 but not a control antibody discriminates between fibrotic and non-fibrotic liver in acute and chronic liver fibrosis models. cRel(-/-) mice have a fibro-protective phenotype and IVIS signal is reduced in CCl4 injured cRel(-/-) mice compared to wild-type. In vivo imaging of fluorescently labelled-C1-3 successfully predicts reductions in hepatic myofibroblast numbers in fibrotic liver disease in response to therapy.ConclusionsWe report a novel fluorescence imaging method to assess murine hepatic myofibroblast numbers in vivo during liver fibrosis and after therapy. We also describe a novel liposomal antibody targeting system to selectively deliver drugs to hepatic myofibroblasts in vivo. C1-3 binds human hepatic myofibroblast therefore imaging labelled-C1-3 could be used for clinical studies in man to help stage fibrosis, demonstrate efficacy of drugs that promote hepatic myofibroblast clearance or predict early therapeutic responses.Lay summaryIn response to damage and injury scars develop in the liver and the main cell that makes the scar tissue is the hepatic myofibroblast (HM). C1-3 is an antibody fragment that binds to the scar forming HM. We have fluorescently labelled C1-3 and given it to mice that have either normal or scarred livers (which contain HM) and then used a machine called an in vivo imaging system (IVIS) that takes pictures of different wavelengths of light, to visualise the antibody binding to HM inside the living mouse. Using fluorescently labelled C1-3 we can assess HM numbers in the injured liver and monitor response to therapy. We have also used C1-3 to target drugs encapsulated in lipid carriers (liposomes) to the HM to kill the HM and reduce the liver disease.

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Optical drug monitoring: photoacoustic imaging of nanosensors to monitor therapeutic lithium in vivo.

Publications

Optical drug monitoring: photoacoustic imaging of nanosensors to monitor therapeutic lithium in vivo.

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