Comparative Tumor Imaging and PDT Efficacy of HPPH Conjugated in the Mono- and Di-Forms to Various Polymethine Cyanine Dyes: Part - 2

Abstract

Previous reports from our laboratory have shown that a bifunctional agent obtained by conjugating a photosensitizer (HPPH) to a cyanine dye (CD) can be used for fluorescence image-guided treatment of tumor by photodynamic therapy (PDT). However, the resulting HPPH-CD conjugate showed a significant difference between the tumor-imaging and therapeutic doses. It was demonstrated that the singlet oxygen (1O2*, a key cytotoxic agent in PDT) produced by the conjugate upon excitation of the HPPH moiety was partially quenched by the CD-moiety; this resulted in a reduced PDT response when compared to HPPH-PDT under similar treatment parameters. 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). The newly synthesized 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. Among the analogs investigated, the conjugate, in which two HPPH moieties were linked to the modified IR820 produced enhanced tumor uptake and tumor contrast in both Colon 26 (a murine Colon carcinoma) and U87 (a human glioblastoma) cell lines. The long-term PDT efficacy (cure) of this conjugate in BALB/c mice, bearing Colon 26 tumors was also enhanced; however, its efficacy in Nude mice bearing U87 tumors was slightly reduced. It was also found that in all the conjugates the singlet oxygen generation and, consequently, PDT efficacy were compromised by a competing pathway, whereby an electronic excitation of HPPH, the energy donor, is deactivated through an electronic excitation energy transfer (Forster Resonance Energy Transfer, FRET) to the CD fluorophore, the energy acceptor, resulting in overall reduction of the singlet oxygen production. Conjugates with increased FRET showed reduced singlet oxygen production and PDT efficacy. Among the conjugates investigated, the bifunctional agent in which two HPPH moieties were linked to the benzoindole-based cyanine dye 11 showed superiority over the lead candidate 9 (mono HPPH-cyanine dye).

Sinoporphyrin sodium, a novel sensitizer, triggers mitochondrial-dependent apoptosis in ECA-109 cells via production of reactive oxygen species

“…Selective accumulation of DVDMS in tumor cells was found in this study, and may be due to the acidic environment around tumors, more low-density lipoprotein on tumor surfaces, poor lymphatic drainage, or leaky vasculature. 27 The preferential accumulation of DVDMS in tumor cells paves the way for targeted therapy. Moreover, compared with hematoporphyrin, protoporphyrin IX, and Photofrin II, DVDMS shows higher red fluorescence, which may have advantages in further clinical applications, eg, accurate tracing of tumors and imaging.…”

“…27 A 35 mm diameter planar transducer (Institution of Applied Acoustics, Shaanxi Normal University, Shaanxi Province, People's Republic of China) was submerged in an acrylic tank filled with distilled, degassed water. Continuous-wave ultrasound was provided by a generator (T&C Power Conversion, Rochester, NY, USA).…”

Bacteriochlorin-containing triad: Structure and photophysical properties

“…Combining porphyrin-based photosensitizers with fluorophores is the original pathway to achieve wide series of theranostic conjugates [3,15,16]. In this study, we report the preparation and physicochemical characterization of the triad, in which two bacteriochlorin moieties are linked to dicarbocyanine dye as a model theranostic for fluorescence imaging and phototherapy of tumors.…”

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy

“…38 A modified IR-783 after linking with two moieties of the photosensitizer HPPH showed perfect tumor-imaging capability and produced long-term PDT efficacy for mice bearing colon tumors. 36 Encapsulating NIRF dyes with polymers or inorganic materials to form a variety of nonmetallic nanoparticles also enhanced the photostability, biocompatibility, and fluorescence intensity of dyes with reduced self-aggregation to improve PDT efficacy. 42,[80][81][82] As a conventional NIR dye, ICG has limited applications as a specific imaging agent for cancer detection because of poor stability and rapid decomposition in polar solution.…”