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

TitleDelivery of polymeric nanostars for molecular imaging and endoradiotherapy through the enhanced permeability and retention (EPR) effect.
Publication TypeJournal Article
Year of Publication2020
AuthorsGoos JACM, Cho A, Carter LM, Dilling TR, Davydova M, Mandleywala K, Puttick S, Gupta A, Price WS, Quinn JF, Whittaker MR, Lewis JS, Davis TP
JournalTheranostics
Volume10
Issue2
Pagination567-584
Date Published2020
ISSN1838-7640
Abstract

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 (<0.001), suggesting passive tumour accumulation of the nanostars the EPR effect. Survival of mice treated with high dose Lu-labelled star polymers was significantly higher than survival of mice treated with lower therapy doses or control mice (=0.001), demonstrating the utility of the Lu-labelled star polymers as platforms for endoradiotherapy. Our work highlights the potential of star polymers as probes for the molecular imaging of cancer tissue or for the passive delivery of radionuclides for endoradiotherapy. Their high functionalisability and high tumour accumulation emphasises their versatility as powerful tools for nanomedicine.

DOI10.7150/thno.36777
Alternate JournalTheranostics
PubMed ID31903138
PubMed Central IDPMC6929988

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