title: Targeted PDT agent eradicates TrkC expressing tumors via photodynamic therapy (PDT).
abstract: This contribution features a small molecule that binds TrkC (tropomyosin receptor kinase C) receptor that tends to be overexpressed in metastatic breast cancer cells but not in other breast cancer cells. A sensitizer for (1)O2 production conjugated to this structure gives 1-PDT for photodynamic therapy. Isomeric 2-PDT does not bind TrkC and was used as a control throughout; similarly, TrkC- cancer cells were used to calibrate enhanced killing of TrkC+ cells. Ex vivo, 1- and 2-PDT where only cytotoxic when illuminated, and 1-PDT, gave higher cell death for TrkC+ breast cancer cells. A 1 h administration-to-illumination delay gave optimal TrkC+/TrkC--photocytotoxicity, and distribution studies showed the same delay was appropriate in vivo. In Balb/c mice, a maximum tolerated dose of 20 mg/kg was determined for 1-PDT. 1- and 2-PDT (single, 2 or 10 mg/kg doses and one illumination, throughout) had similar effects on implanted TrkC- tumors, and like those of 2-PDT on TrkC+ tumors. In contrast, 1-PDT caused dramatic TrkC+ tumor volume reduction (96% from initial) relative to the TrkC- tumors or 2-PDT in TrkC+ models. Moreover, 71% of the mice treated with 10 mg/kg 1-PDT (n = 7) showed full tumor remission and survived until 90 days with no metastasis to key organs.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya , 50603 Kuala Lumpur, Malaysia.
authors.forename: Chin Siang
authors.initials: CS
authors.lastname: Kue
authors.forename: Anyanee
authors.initials: A
authors.lastname: Kamkaew
authors.forename: Hong Boon
authors.initials: HB
authors.lastname: Lee
authors.forename: Lip Yong
authors.initials: LY
authors.lastname: Chung
authors.forename: Lik Voon
authors.initials: LV
authors.lastname: Kiew
authors.forename: Kevin
authors.initials: K
authors.lastname: Burgess
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001896:Boron Compounds / Q000737:chemistry* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010539:Permeability; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000627:therapeutic use; D020812:Receptor, trkC / Q000378:metabolism*; D012074:Remission Induction
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000970:Antineoplastic Agents; D001896:Boron Compounds; D017319:Photosensitizing Agents; D020812:Receptor, trkC
keywords: histochemistry; imaging; metastatic breast cancer; photodynamic therapy (PDT); theranostic; tropomyosin receptor kinase C (TrkC)