Is Bioorthogonal Pretargeting Superior to Conventional Targeted Photosensitizers? A Comparative Study of Chlorin Delivery Using Biotin Vectors
- 1Lobachevsky State University of Nizhny Novgorod, Gagarina av. 23, Nizhny Novgorod, Russian Federation, 603950
- 2Chemistry Department of Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow, Russia, 119991
Abstract
Bioorthogonal pretargeting offers a modular approach to targeted photodynamic therapy (PDT), but its advantages over conventional ligand-photosensitizer conjugates remain insufficiently explored. Here, we aimed to directly compare preformed biotin-containing conjugates with sequential biotin-mediated bioorthogonal delivery. DFT calculations were used to guide the design of new tetrazine dienes with tuned electronic properties for inverse-electron-demand Diels-Alder (IEDDA) chemistry. The selected tetrazines were synthesized and paired with BCN- and s-TCO-functionalized chlorin photosensitizers, and their reactivity was characterized by second-order rate constants and photophysical measurements. In vitro, sequential pretargeting produced substantially higher intracellular fluorescence than administration of preformed 1:1 ligation products; however, this advantage did not translate into enhanced photodynamic activity. Moreover, neither accumulation nor PDT efficacy consistently correlated with SLC5A6 expression in SMVT-high SK-BR-3 versus SMVT-low MDA-MB-231 cells. Free-biotin competition produced heterogeneous, combination-dependent effects, indicating that SMVT is unlikely to be the sole determinant of uptake.
Related
- Evaluation of Tooth Shade Selection With Conventional Methods and Artificial Intelligence-Integrated Methods: A Comparative Study
- Comparison of Hockey-Stick and Conventional Linear Ultrasound Transducers for Detection of Non-Displaced Dentoalveolar Fractures: An Ex Vivo Paired Comparative Study
- Muscle-Preserving Versus Conventional Midline Expansive Open-Door Laminoplasty for Multilevel Cervical Spondylotic Myelopathy: A 10-Year Comparative Cohort Study
- Comparative outcomes of conventional follitropin delta 15 µg/day versus follitropin alfa 225 IU/day for ovarian stimulation: results from an exploratory post hoc analysis of Spanish participants from the ADAPT-1 randomized controlled trial
- Comparative evaluation of the antipyretic and analgesic efficacy and safety of a fast-release paracetamol 650 mg formulation vs. conventional paracetamol formulations in adults with acute febrile or febrile-pain conditions: a multicenter randomized controlled trial
BibTeX
@misc{jankovic2026bioorthogonal,
title = {{Is Bioorthogonal Pretargeting Superior to Conventional Targeted Photosensitizers? A Comparative Study of Chlorin Delivery Using Biotin Vectors}},
author = {Petar Jankovic and Anastasia A. Gorokhova and Ilya A. Shmyrov and Jana M. Svetlova and Natalia S. Kuzmina and Alexander V. Nyuchev and Sergey S. Nikolashin and Maxim N. Miheenko and Elena G. Zavyalova and Elizaveta M. Pnachina and Lubov V. Krylova and Irina V. Balalaeva and Alexey Yu. Fedorov and Vasilii F. Otvagin},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008548/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008548/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Is Bioorthogonal Pretargeting Superior to Conventional Targeted Photosensitizers? A Comparative Study of Chlorin Delivery Using Biotin Vectors
AU - Petar Jankovic
AU - Anastasia A. Gorokhova
AU - Ilya A. Shmyrov
AU - Jana M. Svetlova
AU - Natalia S. Kuzmina
AU - Alexander V. Nyuchev
AU - Sergey S. Nikolashin
AU - Maxim N. Miheenko
AU - Elena G. Zavyalova
AU - Elizaveta M. Pnachina
AU - Lubov V. Krylova
AU - Irina V. Balalaeva
AU - Alexey Yu. Fedorov
AU - Vasilii F. Otvagin
PY - 2026
DA - 2026/09/09
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008548/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008548/v1
AB - Bioorthogonal pretargeting offers a modular approach to targeted photodynamic therapy (PDT), but its advantages over conventional ligand-photosensitizer conjugates remain insufficiently explored. Here, we aimed to directly compare preformed biotin-containing conjugates with sequential biotin-mediated bioorthogonal delivery. DFT calculations were used to guide the design of new tetrazine dienes with tuned electronic properties for inverse-electron-demand Diels-Alder (IEDDA) chemistry. The selected tetrazines were synthesized and paired with BCN- and s-TCO-functionalized chlorin photosensitizers, and their reactivity was characterized by second-order rate constants and photophysical measurements. In vitro, sequential pretargeting produced substantially higher intracellular fluorescence than administration of preformed 1:1 ligation products; however, this advantage did not translate into enhanced photodynamic activity. Moreover, neither accumulation nor PDT efficacy consistently correlated with SLC5A6 expression in SMVT-high SK-BR-3 versus SMVT-low MDA-MB-231 cells. Free-biotin competition produced heterogeneous, combination-dependent effects, indicating that SMVT is unlikely to be the sole determinant of uptake.
ER -