TY - JOUR
T1 - Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent
AU - Harmatys, Kara M.
AU - Overchuk, Marta
AU - Chen, Juan
AU - Ding, Lili
AU - Chen, Ying
AU - Pomper, Martin G.
AU - Zheng, Gang
N1 - Funding Information:
The authors would like to acknowledge Lili Ding for performing western blots and assisting with flow cytometry measurements; Dr. Il Minn for PSMA binding affinity Ki value measurements; Deborah Scollard, Teesha Komal, and Dr. Nicholas Bernards for help with PET/CT image acquisition and reconstruction and Dr. Warren Folz for MR images (STTARR Innovation Centre); Dr. Raymond Reilly, Dr. Zhongli Cai, and Dr. Conrad Chan for the assistance with radio-HPLC. This study was funded by the Terry Fox Research Institute (PPG#1075), the Canadian Institute of Health Research (Foundation Grant #154326), the Canadian Cancer Society Research Institute (704718), the Vanier Canada Graduate Scholarship, the Canada Foundation for Innovation, the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research, Prostate Cancer Canada, Natural Sciences, and Engineering Research Council of Canada, the Princess Margaret Cancer Foundation, and NIH grants CA134675, CA184228, CA202199, and EB024495.
Funding Information:
This study was funded by the Terry Fox Research Institute (PPG#1075) the Canadian Institute of Health Research (Foundation Grant #154326) the Canadian Cancer Society Research Institute (704718), the Vanier Canada Graduate Scholarship, the Canada Foundation for Innovation the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research, Prostate Cancer Canada, Natural Sciences, and Engineering Research Council of Canada, the Princess Margaret Cancer Foundation and NIH grants CA134675, CA184228, CA202199, and EB024495.
Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/11/21
Y1 - 2018/11/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056253573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056253573&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.8b00636
DO - 10.1021/acs.bioconjchem.8b00636
M3 - Article
C2 - 30350576
AN - SCOPUS:85056253573
VL - 29
SP - 3746
EP - 3756
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
SN - 1043-1802
IS - 11
ER -