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dc.contributor.authorJames, Nadine Stephanie
dc.date.accessioned2016-04-05T19:14:27Z
dc.date.available2016-04-05T19:14:27Z
dc.date.issued2013
dc.identifier.isbn9781267946119
dc.identifier.other1316931200
dc.identifier.urihttp://hdl.handle.net/10477/50720
dc.description.abstractNear-infrared (NIR) organic dyes have become important for many biomedical applications, including in vivo optical imaging. Conjugation of NIR fluorescent dyes to photosensitizing molecules (photosensitizers) holds strong potential for NIR fluorescence-imaging guided photodynamic therapy (PDT) of cancer. Therefore, we were interested in investigating the photophysical properties, in vivo tumor-affinity and fluorescence imaging potential of a series of heterocyclic polymethine dyes, which could then be conjugated to certain PDT agents. A series of symmetrical polymethine dyes containing a variety of bis-N-substituted indole or benzoindole moieties, where the N-alkyl side chain at the C-terminal position was functionalized with sulfonic, carboxylic acid, methyl ester or hydroxyl groups, were selected. Cyanine dye (IR783) (3) (bis-indole-N-butylsulfonate)-polymethine dye with a cyclic chloro-cyclohexene moiety showed best fluorescence-imaging ability, based on its spectral properties (λ Abs =782 nm, λ Fl =810 nm, ε = 261,000 M -1 cm -1
dc.description.abstractΦ Fl ≈0.08) and tumor uptake. Previously, studies showed that the bifunctional agent HPPH-CD (11) can be used for fluorescence imaging guided treatment of tumor by photodynamic therapy (PDT). However, the conjugate showed a significant difference between the tumor-imaging and therapeutic doses. It was demonstrated that the production of singlet oxygen ( 1 O 2 *, a key cytotoxic agent in PDT) by the conjugate upon excitation of the HPPH moiety was partially quenched by the CD-moiety; this phenomenon, caused by Forster Resonance Energy Transfer (FRET), resulted in a reduced PDT response when compared to treatment with HPPH alone. To improve the therapeutic potential of the conjugate, we synthesized a series of dual functional agents in which one or two HPPH moieties were separately conjugated to three different dyes (Cypate, modified IR820 or modified IR783). Structural modification of the conjugate by the introduction of one more HPPH moiety would enhance singlet oxygen production enabling the minimization of FRET and enhance long-term tumor response by the reduction of the PDT drug dose. These conjugates were compared with our lead compound HPPH-CD in terms of photophysical properties, in vitro and in vivo PDT efficacy, tumor uptake and imaging potential. The analogs in which the two HPPH moieties were linked to the modified IR820 (12) produced enhanced tumor uptake and tumor contrast in both cell lines. The long-term PDT efficacy (cure) of this conjugate in BALB/c mice was also enhanced; however, its efficacy in Nude mice bearing U87 tumors was intermediate. HPPH conjugated in the mono- and di- forms to Cypate, enhanced the imaging capability but not PDT efficacy in both analogs. Similarly, conjugation of HPPH to modified IR-783 in the mono- and di-forms showed enhanced imaging and a similar PDT efficacy to the conjugates containing the substituents HPPH and IR-820. Another series of conjugates were synthesized by varying the length that links the two moieties, from two to six carbon units and the intra-molecular orientation of the photosensitizer with respect to the fluorophore in the para- or meta-position. The conjugates were tested in vitro and in vivo using the tumor models U87, a human glioblastoma and Colon-26, a murine colon carcinoma for intracellular localization, cell phototoxicity, tumor uptake, PDT efficacy, and fluorescence imaging. The least and most efficacious within the series of conjugates were assessed for their cell death pathway in U87. Overall, the compounds that were linked in the meta-position seemed more efficacious in vitro and in vivo than the other compounds. The conjugate linked with four carbon units (medium linked) in the meta-position (6) was the most efficacious of the series.
dc.languageEnglish
dc.sourceDissertations & Theses @ SUNY Buffalo,ProQuest Dissertations & Theses Global
dc.subjectPure sciences
dc.subjectBiological sciences
dc.subjectHealth and environmental sciences
dc.subjectColon 26
dc.subjectFret
dc.subjectGlioblastoma
dc.subjectNear infrared
dc.subjectPhotodynamic therapy
dc.subjectTumor imaging
dc.subjectU87
dc.titleTumor imaging and photodynamic therapy (PDT) using versatile chlorin near infrared fluorophore (NIRF) conjugates
dc.typeDissertation/Thesis


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