Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent
- Kara M. HarmatysKara M. HarmatysPrincess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, CanadaDepartment of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, CanadaMore by Kara M. Harmatys,
- Marta OverchukMarta OverchukPrincess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, CanadaInstitute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, Ontario M5S 3G9, CanadaMore by Marta Overchuk,
- Juan ChenJuan ChenPrincess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, CanadaMore by Juan Chen,
- Lili DingLili DingPrincess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, CanadaMore by Lili Ding,
- Ying ChenYing ChenJohns Hopkins Medical School, 1550 Orleans Street, 492 CRB II, Baltimore, Maryland 21287, United StatesMore by Ying Chen,
- Martin G. PomperMartin G. PomperJohns Hopkins Medical School, 1550 Orleans Street, 492 CRB II, Baltimore, Maryland 21287, United StatesMore by Martin G. Pomper, and
- Gang Zheng*Gang Zheng*E-mail: [email protected]Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, CanadaInstitute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, Ontario M5S 3G9, CanadaDepartment of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, CanadaMore by Gang Zheng
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.
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- Marta Overchuk, Kara M. Harmatys, Martha P. Damen, Juan Chen, Martin G. Pomper, Gang Zheng, . Long-circulating prostate-specific membrane antigen-targeted NIR phototheranostic agent. 2019,,, 137. https://doi.org/10.1117/12.2525622
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