title: Kinetic quantification of protein polymer nanoparticles using non-invasive imaging.
abstract: Protein polymers are repetitive amino acid sequences that can assemble monodisperse nanoparticles with potential applications as cancer nanomedicines. Of the currently available molecular imaging methods, positron emission tomography (PET) is the most sensitive and quantitative; therefore, this work explores microPET imaging to track protein polymer nanoparticles over several days. To achieve reliable imaging, the polypeptides were modified by site-specific conjugation using a heterobifunctional sarcophagine chelator, AmBaSar, which was subsequently complexed with (64)Cu. AmBaSar/(64)Cu was selected because it can label particles in vivo over periods of days, which is consistent with the timescales required to follow long-circulating nanotherapeutics. Using an orthotopic model of breast cancer, we observed four elastin-like polypeptides (ELPs)-based protein polymers of varying molecular weight, amino acid sequence, and nanostructure. To analyze this data, we developed a six-compartment image-driven pharmacokinetic model capable of describing their distribution within individual subjects. Surprisingly, the assembly of an ELP block copolymer (78 kD) into nanoparticles (R(h) = 37.5 nm) minimally influences pharmacokinetics or tumor accumulation compared to a free ELP of similar length (74 kD). Instead, ELP molecular weight is the most important factor controlling the fate of these polymers, whereby long ELPs (74 kD) have a heart activity half-life of 8.7 hours and short ELPs (37 kD) have a half-life of 2.1 hours. These results suggest that ELP-based protein polymers may be a viable platform for the development of multifunctional therapeutic nanoparticles that can be imaged using clinical PET scanners.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033-9121, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Janib
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: R
authors.initials: R
authors.lastname: Park
authors.forename: M K
authors.initials: MK
authors.lastname: Pastuszka
authors.forename: P
authors.initials: P
authors.lastname: Shi
authors.forename: A S
authors.initials: AS
authors.lastname: Moses
authors.forename: M M
authors.initials: MM
authors.lastname: Orosco
authors.forename: Y-A
authors.initials: YA
authors.lastname: Lin
authors.forename: H
authors.initials: H
authors.lastname: Cui
authors.forename: P S
authors.initials: PS
authors.lastname: Conti
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: J A
authors.initials: JA
authors.lastname: MacKay
mesh_terms: D001565:Benzoates / Q000737:chemistry*; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D003301:Copper Radioisotopes / Q000737:chemistry*; D007700:Kinetics; D057054:Molecular Imaging / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000648:ultrastructure; D019275:Radiopharmaceuticals / Q000737:chemistry
chemical_list: C543149:4-((8-amino-3,6,10,13,16,19-hexaazabicyclo(6.6.6)icosane-1-ylamino)methyl)benzoic acid; D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003301:Copper Radioisotopes; D011506:Proteins; D019275:Radiopharmaceuticals