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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

Molecular Pharmaceutics

ISSN

1543-8384

e-ISSN

—

Svazek periodika

17

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

98-108

Kód UT WoS článku

000506713600010

EID výsledku v databázi Scopus

2-s2.0-85077116403