Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent

Bioconjug Chem. 2018 Nov 21;29(11):3746-3756. doi: 10.1021/acs.bioconjchem.8b00636. Epub 2018 Oct 29.

Abstract

We describe a simple and effective bioconjugation strategy to extend the plasma circulation of a low molecular weight targeted phototheranostic agent, which achieves high tumor accumulation (9.74 ± 2.26%ID/g) and high tumor-to-background ratio (10:1). Long-circulating pyropheophorbide (LC-Pyro) was synthesized with three functional building blocks: (1) a porphyrin photosensitizer for positron-emission tomography (PET)/fluorescence imaging and photodynamic therapy (PDT), (2) a urea-based prostate-specific membrane antigen (PSMA) targeting ligand, and (3) a peptide linker to prolong the plasma circulation time. With porphyrin's copper-64 chelating and optical properties, LC-Pyro demonstrated its dual-modality (fluorescence/PET) imaging potential for selective and quantitative tumor detection in subcutaneous, orthotopic, and metastatic murine models. The peptide linker in LC-Pyro prolonged its plasma circulation time about 8.5 times compared to its truncated analog. High tumor accumulation of LC-Pyro enabled potent PDT, which resulted in significantly delayed tumor growth in a subcutaneous xenograft model. This approach can be applied to improve the pharmacokinetics of existing and future targeted PDT agents for enhanced tumor accumulation and treatment efficacy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorophyll / analogs & derivatives*
  • Chlorophyll / chemistry
  • Chlorophyll / pharmacokinetics
  • Chlorophyll / therapeutic use
  • Copper Radioisotopes / chemistry
  • Copper Radioisotopes / pharmacokinetics
  • Copper Radioisotopes / therapeutic use*
  • Male
  • Mice
  • Mice, Nude
  • Optical Imaging / methods
  • Peptides / chemistry
  • Peptides / pharmacokinetics
  • Peptides / therapeutic use
  • Photochemotherapy / methods
  • Photosensitizing Agents / chemistry
  • Photosensitizing Agents / pharmacokinetics
  • Photosensitizing Agents / therapeutic use*
  • Porphyrins / chemistry
  • Porphyrins / pharmacokinetics
  • Porphyrins / therapeutic use*
  • Positron-Emission Tomography / methods
  • Prostate-Specific Antigen / analysis*
  • Prostatic Neoplasms / diagnostic imaging*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Theranostic Nanomedicine / methods

Substances

  • Copper Radioisotopes
  • Copper-64
  • Peptides
  • Photosensitizing Agents
  • Porphyrins
  • Chlorophyll
  • pyropheophorbide a
  • Prostate-Specific Antigen