Nanoemulsion-based delivery of fluorescent PARP inhibitors in mouse models of small cell lung cancer

Junior Gonzales, Susanne Kossatz, Sheryl Roberts, Giacomo Pirovano, Christian Brand, Carlos Pérez-Medina, Patrick Donabedian, M. Jason de la Cruz, Willem J.M. Mulder, Thomas Reiner

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The preclinical potential of many diagnostic and therapeutic small molecules is limited by their rapid washout kinetics and consequently modest pharmacological performances. In several cases, these could be improved by loading the small molecules into nanoparticulates, improving blood half-life, in vivo uptake and overall pharmacodynamics. In this study, we report a nanoemulsion (NE) encapsulated form of PARPi-FL. As a proof of concept, we used PARPi-FL, which is a fluorescently labeled sensor for olaparib, a FDA-approved small molecule inhibitor of the nuclear enzyme poly(ADP-ribose)polymerase 1 (PARP1). Encapsulated PARPi-FL showed increased blood half-life, and delineated subcutaneous xenografts of small cell lung cancer (SCLC), a fast-progressing disease where efficient treatment options remain an unmet clinical need. Our study demonstrates an effective method for expanding the circulation time of a fluorescent PARP inhibitor, highlighting the pharmacokinetic benefits of nanoemulsions as nanocarriers and confirming the value of PARPi-FL as an imaging agent targeting PARP1 in small cell lung cancer.

LanguageEnglish
Pages3776-3782
Number of pages7
JournalBioconjugate Chemistry
Volume29
Issue number11
DOIs
StatePublished - 24 Oct 2018

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Small Cell Lung Carcinoma
Half-Life
Administrative data processing
Poly(ADP-ribose) Polymerases
Cells
Molecules
Enzyme Inhibitors
Blood
Heterografts
Pharmacodynamics
Pharmacokinetics
Pharmacology
Enzymes
Imaging techniques
Kinetics
Sensors
Poly(ADP-ribose) Polymerase Inhibitors
Poly (ADP-Ribose) Polymerase-1
Therapeutics
olaparib

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Gonzales, J., Kossatz, S., Roberts, S., Pirovano, G., Brand, C., Pérez-Medina, C., ... Reiner, T. (2018). Nanoemulsion-based delivery of fluorescent PARP inhibitors in mouse models of small cell lung cancer. Bioconjugate Chemistry, 29(11), 3776-3782. DOI: 10.1021/acs.bioconjchem.8b00640
Gonzales, Junior ; Kossatz, Susanne ; Roberts, Sheryl ; Pirovano, Giacomo ; Brand, Christian ; Pérez-Medina, Carlos ; Donabedian, Patrick ; de la Cruz, M. Jason ; Mulder, Willem J.M. ; Reiner, Thomas. / Nanoemulsion-based delivery of fluorescent PARP inhibitors in mouse models of small cell lung cancer. In: Bioconjugate Chemistry. 2018 ; Vol. 29, No. 11. pp. 3776-3782
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Gonzales, J, Kossatz, S, Roberts, S, Pirovano, G, Brand, C, Pérez-Medina, C, Donabedian, P, de la Cruz, MJ, Mulder, WJM & Reiner, T 2018, 'Nanoemulsion-based delivery of fluorescent PARP inhibitors in mouse models of small cell lung cancer' Bioconjugate Chemistry, vol. 29, no. 11, pp. 3776-3782. DOI: 10.1021/acs.bioconjchem.8b00640

Nanoemulsion-based delivery of fluorescent PARP inhibitors in mouse models of small cell lung cancer. / Gonzales, Junior; Kossatz, Susanne; Roberts, Sheryl; Pirovano, Giacomo; Brand, Christian; Pérez-Medina, Carlos; Donabedian, Patrick; de la Cruz, M. Jason; Mulder, Willem J.M.; Reiner, Thomas.

In: Bioconjugate Chemistry, Vol. 29, No. 11, 24.10.2018, p. 3776-3782.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Gonzales,Junior

AU - Kossatz,Susanne

AU - Roberts,Sheryl

AU - Pirovano,Giacomo

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AU - Pérez-Medina,Carlos

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N2 - The preclinical potential of many diagnostic and therapeutic small molecules is limited by their rapid washout kinetics and consequently modest pharmacological performances. In several cases, these could be improved by loading the small molecules into nanoparticulates, improving blood half-life, in vivo uptake and overall pharmacodynamics. In this study, we report a nanoemulsion (NE) encapsulated form of PARPi-FL. As a proof of concept, we used PARPi-FL, which is a fluorescently labeled sensor for olaparib, a FDA-approved small molecule inhibitor of the nuclear enzyme poly(ADP-ribose)polymerase 1 (PARP1). Encapsulated PARPi-FL showed increased blood half-life, and delineated subcutaneous xenografts of small cell lung cancer (SCLC), a fast-progressing disease where efficient treatment options remain an unmet clinical need. Our study demonstrates an effective method for expanding the circulation time of a fluorescent PARP inhibitor, highlighting the pharmacokinetic benefits of nanoemulsions as nanocarriers and confirming the value of PARPi-FL as an imaging agent targeting PARP1 in small cell lung cancer.

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Gonzales J, Kossatz S, Roberts S, Pirovano G, Brand C, Pérez-Medina C et al. Nanoemulsion-based delivery of fluorescent PARP inhibitors in mouse models of small cell lung cancer. Bioconjugate Chemistry. 2018 Oct 24;29(11):3776-3782. Available from, DOI: 10.1021/acs.bioconjchem.8b00640