Photosensitizer (PS)-cyanine dye (CD) conjugates: Impact of the linkers joining the PS and CD moieties and their orientation in tumor-uptake and photodynamic therapy (PDT)

Nadine S. James, Penny Joshi, Tymish Y. Ohulchanskyy, Yihui Chen, Walter Tabaczynski, Farukh Durrani, Masayuki Shibata, Ravindra K. Pandey

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

To investigate the impact of linker(s) joining the photosensitizer HPPH [3-(1’-hexyloxy) ethyl-3-devinylpyropheophorbide-a] and the cyanine dye (CD) in tumor-imaging and photodynamic therapy (dual-function agents), a series of HPPH-CD conjugates were synthesized. The modifications were done in an attempt to minimize Forster Resonance Energy Transfer (FRET) between the two chromophores and maximize singlet oxygen production. Among the conjugates containing variable length of linkers, the HPPH-CD conjugate, in which the photosensitizer (PS) and the CD was joined by four Carbon [(CH2)4] units showed higher tumor uptake, improved tumor contrast and limited skin uptake in mice bearing Colon-26 (BALB/c) or U87 tumors in Nude mice. The bi-functional agents in which the HPPH was linked at the meta-position of phenyl-substituted CD 5, 6 and 7 showed longer tumor response (cure) than the corresponding para-substituted analogs 2, 3, and 4, which suggests that the orientation of the PS and CD moieties within the conjugate also makes a substantial difference in tumor-specificity. Compared to HPPH, the singlet oxygen yields of all the HPPH-CD conjugates were significantly low, and required a higher therapeutic dose to achieve the same in vivo response obtained by HPPH-PDT alone. However, conjugate 6 produced a higher singlet oxygen yield with reduced FRET and exhibited enhanced long-term PDT efficacy in mice bearing Colon-26 (BALB/c) and U87 tumors (nude) than its counterparts, including our lead compound (HPPH-CD), making it the most efficacious of the series. Thus, these conjugates bearing cyanine dye moiety (CD) provide an opportunity of imaging deeply seated tumors for fluorescence-guided surgery with an option of PDT.

Original languageEnglish (US)
Pages (from-to)770-785
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume122
DOIs
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

Keywords

  • Dual function agent
  • Fluorescence imaging
  • Forster resonance energy transfer
  • Photodyanamic therapy
  • Photosensitizer

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