title: A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy.
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.
authors: Department for Tissue & Energy, Division of Surgery & Interventional Science, University College London, Cruciform Building, Gower Street, London, WC1E 6AE, UK. l.lovat@ucl.ac.uk.
authors: H
authors: H
authors: Pye
authors: M A
authors: MA
authors: Butt
authors: H W
authors: HW
authors: Reinert
authors: A
authors: A
authors: Maruani
authors: J P M
authors: JP
authors: Nunes
authors: J S
authors: JS
authors: Marklew
authors: M
authors: M
authors: Qurashi
authors: L
authors: L
authors: Funnell
authors: A
authors: A
authors: May
authors: I
authors: I
authors: Stamati
authors: R
authors: R
authors: Hamoudi
authors: J R
authors: JR
authors: Baker
authors: M E B
authors: ME
authors: Smith
authors: S
authors: S
authors: Caddick
authors: M P
authors: MP
authors: Deonarain
authors: G
authors: G
authors: Yahioglu
authors: V
authors: V
authors: Chudasama
authors: L B
authors: LB
authors: Lovat
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000068936:Theranostic Nanomedicine; D000068878:Trastuzumab / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000074322:Antineoplastic Agents, Immunological; D017319:Photosensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human