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

doi:10.1021/acs.bioconjchem.8b00640

Nanoemulsion-Based Delivery of Fluorescent PARP Inhibitors in Mouse Models of Small Cell Lung Cancer

Bioconjug Chem. 2018 Nov 21;29(11):3776-3782. doi: 10.1021/acs.bioconjchem.8b00640. Epub 2018 Nov 7.

Authors

Affiliations

¹ Department of Radiology , Memorial Sloan Kettering Cancer Center , New York , New York 10065 , United States.
² Translational and Molecular Imaging Institute, Department of Radiology , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
³ Structural Biology Program, Sloan Kettering Institute , Memorial Sloan Kettering Cancer Center , New York , New York 10065 , United States.
⁴ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems , Eindhoven University of Technology , Eindhoven , The Netherlands.
⁵ Department of Radiology , Weill Cornell Medical College , New York , New York 10065 , United States.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Disease Models, Animal
Emulsions / chemistry
Female
Fluorescent Dyes / administration & dosage*
Fluorescent Dyes / pharmacokinetics
Fluorescent Dyes / therapeutic use
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / pathology
Mice
Mice, Nude
Nanostructures / chemistry
Pharmaceutical Vehicles / chemistry
Phthalazines / administration & dosage*
Phthalazines / pharmacokinetics
Phthalazines / therapeutic use
Piperazines / administration & dosage*
Piperazines / pharmacokinetics
Piperazines / therapeutic use
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacokinetics
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Small Cell Lung Carcinoma / drug therapy*
Small Cell Lung Carcinoma / pathology

Substances

Antineoplastic Agents
Emulsions
Fluorescent Dyes
Pharmaceutical Vehicles
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Poly (ADP-Ribose) Polymerase-1
olaparib

Abstract

Publication types

MeSH terms

Substances

Grants and funding