title: Photodynamic tumor eradication with a novel targetable photosensitizer: strong vascular effects and dependence on treatment repetition versus potentiation.
abstract: A novel pyropheophorbide-a (PPa) derivative, Ac-sPPp, was developed in our lab for targeted photodynamic therapy (PDT) and combination therapies. Its versatile peptide moiety, high water-solubility, amphiphilicity, and micellar aggregation allow efficient coupling to targeting moieties and convenient mixing with other therapeutics. Photosensitizer immunoconjugate (PIC) targeted PDT, using Ac-sPPp conjugated to therapeutic anti-epidermal growth factor receptor (EGFR) antibody cetuximab, and PDT + chemotherapy combination treatment, using Ac-sPPp mixed with stealth liposomal doxorubicin (Doxil), were investigated as promising strategies for potentiating PDT and improving target specificity. Passively targeted PDT with Ac-sPPp only or surfactant-solubilized PPa was also investigated for comparison. The A-431 human vulvar squamous cell carcinoma, xenografted in nude mice, was chosen as a tumor model because of its high EGFR expression and sensitivity to liposomal doxorubicin in vitro. Fluorescence imaging and PDT experiments showed that Ac-sPPp formulations circulated far longer and provided superior tumor contrast and superior tumor control compared to PPa. Strong PDT vascular effects were observed by laser Doppler imaging regardless of whether Ac-sPPp was passively or actively targeted. Passively targeted Ac-sPPp PDT gave equivalent or better tumor control than PIC-targeted PDT or PDT + Doxil combination therapy, and when treatments were repeated, it also yielded the highest cure rate.
authors.affiliation: Geisel School of Medicine at Dartmouth, Surgical Research Laboratories, Lebanon, NH, USA. Mark.Savellano@dartmouth.edu
authors.forename: Mark D
authors.initials: MD
authors.lastname: Savellano
authors.forename: Nicci
authors.initials: N
authors.lastname: Owusu-Brackett
authors.forename: Ji
authors.initials: J
authors.lastname: Son
authors.forename: Tanay
authors.initials: T
authors.lastname: Ganga
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Leung
authors.forename: Dagmar H
authors.initials: DH
authors.lastname: Savellano
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D008027:Light; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D061848:Optical Imaging; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011166:Porphyrins / Q000138:chemical synthesis / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D014846:Vulvar Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology
chemical_list: C584551:Ac-sPPp compound; D061067:Antibodies, Monoclonal, Humanized; D004151:Dipeptides; D005456:Fluorescent Dyes; D018796:Immunoconjugates; D017319:Photosensitizing Agents; D011166:Porphyrins; D004317:Doxorubicin; D000068818:Cetuximab