Journal
BIOCONJUGATE CHEMISTRY
Volume 29, Issue 11, Pages 3746-3756Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.8b00636
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Funding
- Terry Fox Research Institute [1075]
- Canadian Institute of Health Research (Foundation) [154326]
- Canadian Cancer Society Research Institute [704718]
- Vanier Canada Graduate Scholarship
- Canada Foundation for Innovation
- Prostate Cancer Canada
- Natural Sciences, and Engineering Research Council of Canada
- Princess Margaret Cancer Foundation
- NIH [CA134675, CA184228, CA202199, EB024495]
- Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research
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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.
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