Delivery of polymeric nanostars for molecular imaging and endoradiotherapy through the enhanced permeability and retention (EPR) effect

• Published in: Theranostics 2020, Vol.10 (2), p.567-584
• Main Authors: Goos, Jeroen A C M, Cho, Andrew, Carter, Lukas M, Dilling, Thomas R, Davydova, Maria, Mandleywala, Komal, Puttick, Simon, Gupta, Abhishek, Price, William S, Quinn, John F, Whittaker, Michael R, Lewis, Jason S, Davis, Thomas P
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; Cancer; Cell Line, Tumor; Colonic Neoplasms - blood supply; Colonic Neoplasms - diagnostic imaging; Colonic Neoplasms - radiotherapy; Contrast agents; Humans; Magnetic fields; Magnetic resonance imaging; Medical research; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Imaging - methods; Molecular weight; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Permeability; Polymers; Polymers - chemistry; Positron-Emission Tomography - methods; Radiopharmaceuticals - pharmacokinetics; Research Paper; Theranostic Nanomedicine - methods; Tissue Distribution; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.36777

Expression levels of biomarkers are generally unknown at initial diagnosis. The development of theranostic probes that do not rely on biomarker availability would expand therapy options for cancer patients, improve patient selection for nanomedicine and facilitate treatment of inoperable patients or patients with acquired therapy resistance. Herein, we report the development of star polymers, also known as nanostars, that allow for molecular imaging and/or endoradiotherapy based on passive targeting the enhanced permeability and retention (EPR) effect. We synthesised a star copolymer, consisting of 7-8 centre-cross-linked arms that were modified with Gd for magnetic resonance imaging (MRI), and functionalised either with Zr for quantification and positron emission tomography (PET) imaging, or with Lu for endoradiotherapy. H longitudinal relaxivities were determined over a continuum of magnetic field strengths ranging from 0.24 mT - 0.94 T at 37 °C (nuclear magnetic relaxation dispersion (NMRD) profile) and -weighted MRI contrast enhancement was visualized at 3 T and 7 T. PET imaging and biodistribution studies were performed in mice bearing tumours with high EPR (CT26) or low EPR (BxPC3) characteristics. Therapy studies were performed in mice with high EPR tumours and mean absorbed organ doses were estimated for a standard human model. The star copolymer with Gd displayed a significantly superior contrast enhancement ability ( = 0.60 s) compared to the standard clinical contrast agent Gadovist ( = 1.0 s). Quantification of tumour accumulation using the radiolabelled nanostars in tumour-bearing mice demonstrated an exceptionally high uptake in tumours with high EPR characteristics (14.8 - 21.7 %ID/g). Uptake of the star polymers in tumours with low EPR characteristics was significantly lower (