FRET Imaging of Enzyme‐Responsive HPMA Copolymer Conjugate

Zhang, Rui; Yang, Jiyuan; Radford, D. Christopher; Fang, Yixin; Kopeček, Jindřich

doi:10.1002/mabi.201600125

Cited by 18 publications

(14 citation statements)

References 33 publications

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“…Alternative fluorescently activatable imaging probes for image-guided surgery or for tumor imaging that are based on FRET have been recently published. The FRET pair composed of two NIR dyes, whose fluorescence signal changes upon activation, thus the activation is detected in a second step by ratiometric image analysis 71 , 72 . While these reports demand further image analysis, which is time-consuming and also currently unavailable for real-time procedures, our system showed a Turn-ON capacity of about 3-fold change, using a simpler system bearing one kind of dye, which is paramount for clinical translation.…”

Section: Discussionmentioning

confidence: 99%

Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins

Blau¹,

Epshtein²,

Pisarevsky³

et al. 2018

Theranostics

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Complete tumor removal during surgery has a great impact on patient survival. To that end, the surgeon should detect the tumor, remove it and validate that there are no residual cancer cells left behind. Residual cells at the incision margin of the tissue removed during surgery are associated with tumor recurrence and poor prognosis for the patient. In order to remove the tumor tissue completely with minimal collateral damage to healthy tissue, there is a need for diagnostic tools that will differentiate between the tumor and its normal surroundings.Methods: We designed, synthesized and characterized three novel polymeric Turn-ON probes that will be activated at the tumor site by cysteine cathepsins that are highly expressed in multiple tumor types. Utilizing orthotopic breast cancer and melanoma models, which spontaneously metastasize to the brain, we studied the kinetics of our polymeric Turn-ON nano-probes.Results: To date, numerous low molecular weight cathepsin-sensitive substrates have been reported, however, most of them suffer from rapid clearance and reduced signal shortly after administration. Here, we show an improved tumor-to-background ratio upon activation of our Turn-ON probes by cathepsins. The signal obtained from the tumor was stable and delineated the tumor boundaries during the whole surgical procedure, enabling accurate resection.Conclusions: Our findings show that the control groups of tumor-bearing mice, which underwent either standard surgery under white light only or under the fluorescence guidance of the commercially-available imaging agents ProSense® 680 or 5-aminolevulinic acid (5-ALA), survived for less time and suffered from tumor recurrence earlier than the group that underwent image-guided surgery (IGS) using our Turn-ON probes. Our "smart" polymeric probes can potentially assist surgeons' decision in real-time during surgery regarding the tumor margins needed to be removed, leading to improved patient outcome.

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Section: Discussionmentioning

confidence: 99%

Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins

Blau¹,

Epshtein²,

Pisarevsky³

et al. 2018

Theranostics

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“…Among the numerous studies on proteases for such a purpose, hollow mesoporous silica nanoparticles loaded with Dox and conferred with a dual-enzyme sensitivity were conceived for the in situ imaging of Cathepsin B and the release of Dox mediated by proteases ( Figure 19) [169]. An enzymatically dependent FRET process was also used to monitor the payload release from PHPMA prodrug nanocarriers [171]. PHPMA was functionalized with donor Cy5 and acceptor Cy7, thus inducing FRET.…”

Section: Cathepsins As Probes For Imaging and Theranostic 26mentioning

confidence: 99%

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

Dheer

Nicolas

Shankar

2019

Advanced Drug Delivery Reviews

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Cathepsins are an important category of enzymes that have attracted great attention for the delivery of drugs to improve the therapeutic outcome of a broad range of nanoscale drug delivery systems. These proteases can be utilized for instance through actuation of polymer-drug conjugates (e.g., triggering the drug release) to bypass limitations of many drug candidates. A substantial amount of work has been witnessed in the design and the evaluation of Cathepsinsensitive drug delivery systems, especially based on the tetra-peptide sequence (Gly-Phe-Leu-Gly, GFLG) which has been extensively used as a spacer that can be cleaved in the presence of Cathepsin B. This Review Article will give an in-depth overview of the design and the biological evaluation of Cathepsin-sensitive drug delivery systems and their application in different pathologies including cancer before discussing Cathepsin B-cleavable prodrugs under clinical trials.

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“…Quenching of fluorescent intensity can be used for observation of DDS behavior in cells. The rate of enzymatic cleavage of spacer between drug and carrier [78,79] or multiblock polymer carriers [80] can be determined using Förster resonance energy transfer (FRET) in vitro. The loss of the FRET signal indicates that the donor fluorophore is not close enough to the acceptor fluorophore, e.g., because of the drug or dye release from the carrier [79].…”

Section: Imaging At the Cellular Levelmentioning

confidence: 99%

Fluorescence Imaging as a Tool in Preclinical Evaluation of Polymer-Based Nano-DDS Systems Intended for Cancer Treatment

2019

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Targeted drug delivery using nano-sized carrier systems with targeting functions to malignant and inflammatory tissue and tailored controlled drug release inside targeted tissues or cells has been and is still intensively studied. A detailed understanding of the correlation between the pharmacokinetic properties and structure of the nano-sized carrier is crucial for the successful transition of targeted drug delivery nanomedicines into clinical practice. In preclinical research in particular, fluorescence imaging has become one of the most commonly used powerful imaging tools. Increasing numbers of suitable fluorescent dyes that are excitable in the visible to near-infrared (NIR) wavelengths of the spectrum and the non-invasive nature of the method have significantly expanded the applicability of fluorescence imaging. This chapter summarizes non-invasive fluorescence-based imaging methods and discusses their potential advantages and limitations in the field of drug delivery, especially in anticancer therapy. This chapter focuses on fluorescent imaging from the cellular level up to the highly sophisticated three-dimensional imaging modality at a systemic level. Moreover, we describe the possibility for simultaneous treatment and imaging using fluorescence theranostics and the combination of different imaging techniques, e.g., fluorescence imaging with computed tomography.

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FRET Imaging of Enzyme‐Responsive HPMA Copolymer Conjugate

Cited by 18 publications

References 33 publications

Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins

Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

Fluorescence Imaging as a Tool in Preclinical Evaluation of Polymer-Based Nano-DDS Systems Intended for Cancer Treatment

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