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Published on: September 19, 2014
A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy
1Department for Tissue & Energy, Division of Surgery & Interventional Science, University College London, Cruciform Building, Gower Street, London, WC1E 6AE, UK. l.lovat@ucl.ac.uk.
Abstract:
In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments' lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities.
Insights
This study developed a dual-action HER2-targeting antibody fragment for cancer theranostics. It enables near-infrared fluorescent imaging for precise tumor resection and photodynamic therapy for residual cancer cells.
Area of Science:
- Oncology
- Bioconjugation Chemistry
- Medical Imaging
Background:
- Surgical resection of localized tumors is crucial but challenging due to recurrence risks from inadequate resection or organ damage from overzealous treatment.
- Accurate tumor margin delineation and eradication of microscopic disease are critical for improving patient outcomes in cancer surgery.
Purpose of the Study:
- To develop a novel theranostic agent combining near-infrared (NIR) fluorescent imaging and photodynamic therapy (PDT) for HER2-positive cancers.
- To create a dual-conjugated antibody fragment capable of guiding surgical resection and eliminating residual cancer cells.
Main Methods:
- Production of a HER2-targeting antibody Fab fragment conjugated with a NIR-dye and a photosensitizer (chlorin e6).
- Utilized functional disulfide re-bridging and click chemistry for site-specific conjugation.
- Evaluated in vitro binding specificity, NIR fluorescence, and photodynamic activity on HER2-positive and HER2-negative cell lines.
Main Results:
- The theranostic agent demonstrated specific binding to HER2-positive cells in vitro.
- Successful cellular NIR fluorescence imaging and selective photodynamic therapy activation upon laser exposure were observed.
- The dual-conjugated agent showed minimal interference between imaging and therapeutic functions.
Conclusions:
- The developed HER2-targeting theranostic agent successfully integrates fluorescence imaging and photodynamic therapy.
- This approach offers potential for improved surgical guidance and targeted cancer treatment, reducing recurrence and organ damage.
