Pegylation of a chlorine6 polymer conjugate increases tumor targeting of photosensitizer

M. R. Hamblin, J. L. Miller, I. Rizvi, B. Ortel, E. V. Maytin, T. Hasan

Research output: Contribution to journalArticlepeer-review

146 Citations (Scopus)

Abstract

Photodynamic therapy is emerging as a viable modality for the treatment of many cancers. A limiting factor in its use against intracavity tumors such as disseminated ovarian cancer is insufficient selectivity of the photosensitizer for tumor compared with normal tissue. We report on an approach to improve tumor targeting by exploiting differences between cell types and by chemical modification of a photosensitizer conjugate. Attachment of polyethylene glycol (pegylation) to a polyacetylated conjugate between poly-l-lysine and chlorine6 increased the relative phototoxicity in vitro toward an ovarian cancer cell line (OVCAR-5) while reducing it toward a macrophage cell line (J774), compared with the nonpegylated conjugate. Surprisingly, the increased phototoxicity of the pegylated conjugate correlated with reduced oxygen consumption. Pegylation also reduced the tendency of the conjugate to aggregate and reduced the consumption of oxygen when the conjugates were illuminated in solution in serum containing medium, suggesting a switch in photochemical mechanism from type II (singlet oxygen) to type I (radicals or electron transfer). Pegylation led to more mitochondrial localization as shown by confocal fluorescence microscopy in OVCAR-5 cells, and, on illumination, produced a switch in cell death mechanism toward apoptosis not seen with J774 cells. Conjugates were injected i.p. into nude mice bearing i.p. OVCAR-5 tumors, and the pegylated conjugate gave higher amounts of photosensitizer in tumor and higher tumor:normal tissue ratios and increased the depth to which the chlorine6 penetrated into the peritoneal wall. Taken together, these results suggest that pegylation of a polymerphotosensitizer conjugate improves tumor-targeting and may increase the efficacy of photodynamic therapy for ovarian cancer.

Original languageEnglish
Pages (from-to)7155-7162
Number of pages8
JournalCancer Research
Volume61
Issue number19
Publication statusPublished - 1 Oct 2001
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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