Cellular Delivery of Bioorthogorral Pretargeting Therapeutics in PSMA-Positive Prostate Cancer

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F20%3A00541311" target="_blank" >RIV/86652036:_____/20:00541311 - isvavai.cz</a>

Result on the web

<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944582/" target="_blank" >https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944582/</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.molpharmaceut.9b00788" target="_blank" >10.1021/acs.molpharmaceut.9b00788</a>

Result language

angličtina

Original language name

Cellular Delivery of Bioorthogorral Pretargeting Therapeutics in PSMA-Positive Prostate Cancer

Original language description

Prostate cancer is primarily fatal after it becomes metastatic and castration-resistant despite novel combined hormonal and chemotherapeutic regimens. Hence, new therapeutic concepts and drug delivery strategies are urgently needed for the eradication of this devastating disease. Here we report the highly specific, in situ click chemistry driven pretargeted delivery of cytotoxic drug carriers to PSMA(+) prostate cancer cells. Anti-PSMA 5D3 mAb and its F(ab')(2) fragments were functionalized with trans-cyclooctene (TCO), labeled with a fluorophore, and used as pretargeting components. Human serum albumin (ALB) was loaded with the DM1 antitubulin agent, functionalized with PEGylated tetrazine (PEG4-Tz), labeled with a fluorophore, and used as the drug delivery component. The internalization kinetics of components and the therapeutic efficacy of the pretargeted click therapy were studied in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu control cells. The F(ab')(2) fragments were internalized faster than 5D3 mAb in PSMA(+) PC3-PIP cells. In the two-component pretargeted imaging study, both components were colocalized in a perinuclear location of the cytoplasm of PC3-PIP cells. Better colocalization was achieved when 5D3 mAb was used as the pretargeting component. Consecutively, the in vitro cell viability study shows a significantly higher therapeutic effect of click therapy in PC3-PIP cells when 5D3 mAb was used for pretargeting, compared to its F(ab')(2) derivative. 5D3 mAb has a longer lifetime on the cell surface, when compared to its F(ab')(2) analogue, enabling efficient crosslinking with the drug delivery component and increased efficacy. Pretargeting and drug delivery components were crosslinked via multiple bioorthogonal click chemistry reactions on the surface of PSMA(+) PC cells forming nanoclusters, which undergo fast cellular internalization and intracellular transport to perinuclear locations.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30104 - Pharmacology and pharmacy

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Molecular Pharmaceutics

ISSN

1543-8384

e-ISSN

—

Volume of the periodical

17

Issue of the periodical within the volume

1

Country of publishing house

US - UNITED STATES

Number of pages

11

Pages from-to

98-108

UT code for WoS article

000506713600010

EID of the result in the Scopus database

2-s2.0-85077116403