title: Improved micro-distribution of antibody-photon absorber conjugates after initial near infrared photoimmunotherapy (NIR-PIT).
abstract: Near infrared photoimmunotherapy (NIR-PIT), a targeted cancer therapy which uses an antibody-photo absorber conjugate (APC) and near infrared light exposure, dramatically improves nano-drug delivery into treated tumor beds due to enhanced vascular permeability. We investigated the micro-distribution of APCs in a variety of NIR-PIT treated tumors. Either cetuximab (cet) or trastuzumab (tra) conjugated with IR700 (cet-tra-IR700) was administered, as appropriate, to each mouse model of tumor. Tumor-bearing mice implanted with A431-GFP, MDAMB468-GFP, 3T3Her2-GFP or N87-GFP were separated into 5 groups: group 1=no treatment; group 2=cet-tra-IR700 i.v., no light exposure; group 3=cet-tra-IR700 i.v., NIR light exposure; group 4=cet-tra-IR700 i.v. and additional cet-tra-IR700 i.v. at 24h but no light exposure; group 5=cet-tra-IR700 i.v., NIR light exposure and additional cet-tra-IR700 i.v. immediately after NIR but no additional NIR light exposure. In vivo, ex vivo and microscopic fluorescence imaging was performed. Fluorescence from the surface of the tumor (s-tumor) was compared to fluorescence from deeper areas of the tumor (d-tumor). In general, there was no significant difference in the fluorescence intensity of GFP in the tumors among all groups, however the highest IR700 fluorescence intensity was consistently shown in group 5 tumors due to added APC after NIR-PIT. Fluorescence microscopy in all tumor types demonstrated that GFP relative fluorescence intensity (RFI) in s-tumor was significantly lower in group 3 and 5 (NIR-PIT groups) than in group 1, 2, and 4 (no NIR-PIT) yet there was no significant difference in d-tumor RFI among all groups. IR700 fluorescent RFI in the d-tumor was highest in group 5 (NIR-PIT+additional APC) compared to the other groups. Cell killing after NIR-PIT was primarily on the surface, however, APCs administered immediately after NIR-PIT penetrated deeper into tissue resulting in improved cell killing after a 2nd NIR-PIT session. This phenomenon is explained by increased vascular permeability immediately after NIR-PIT.
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892 United States.
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Nagaya
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892 United States.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892 United States.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Sato
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892 United States.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Harada
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892 United States.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892 United States. Electronic address: kobayash@mail.nih.gov.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D002232:Carbocyanines / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008027:Light; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000628:therapy*; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002232:Carbocyanines; C525731:IRD 700; D009943:Organophosphorus Compounds; D017319:Photosensitizing Agents; D000068878:Trastuzumab; D000068818:Cetuximab
keywords: Drug delivery; Enhanced permeability and retention effect; Micro distribution; Near infrared light; Photoimmunotherapy