title: Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle.
abstract: Therapeutic nanoparticles (TNPs) have shown heterogeneous responses in human clinical trials, raising questions of whether imaging should be used to identify patients with a higher likelihood of NP accumulation and thus therapeutic response. Despite extensive debate about the enhanced permeability and retention (EPR) effect in tumors, it is increasingly clear that EPR is extremely variable; yet, little experimental data exist to predict the clinical utility of EPR and its influence on TNP efficacy. We hypothesized that a 30-nm magnetic NP (MNP) in clinical use could predict colocalization of TNPs by magnetic resonance imaging (MRI). To this end, we performed single-cell resolution imaging of fluorescently labeled MNPs and TNPs and studied their intratumoral distribution in mice. MNPs circulated in the tumor microvasculature and demonstrated sustained uptake into cells of the tumor microenvironment within minutes. MNPs could predictably demonstrate areas of colocalization for a model TNP, poly(d,l-lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG), within the tumor microenvironment with >85% accuracy and circulating within the microvasculature with >95% accuracy, despite their markedly different sizes and compositions. Computational analysis of NP transport enabled predictive modeling of TNP distribution based on imaging data and identified key parameters governing intratumoral NP accumulation and macrophage uptake. Finally, MRI accurately predicted initial treatment response and drug accumulation in a preclinical efficacy study using a paclitaxel-encapsulated NP in tumor-bearing mice. These approaches yield valuable insight into the in vivo kinetics of NP distribution and suggest that clinically relevant imaging modalities and agents can be used to select patients with high EPR for treatment with TNPs.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Miles A
authors.initials: MA
authors.lastname: Miller
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Gadde
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Pfirschke
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Camilla
authors.initials: C
authors.lastname: Engblom
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Sprachman
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Kohler
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Yang
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Laughney
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Wojtkiewicz
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nazila
authors.initials: N
authors.lastname: Kamaly
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sushma
authors.initials: S
authors.lastname: Bhonagiri
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Pittet
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. King Abdulaziz University, Jeddah, Saudi Arabia. rweissleder@mgh.harvard.edu ofarokhzad@bwh.harvard.edu.
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. rweissleder@mgh.harvard.edu ofarokhzad@bwh.harvard.edu.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D004249:DNA Damage; D018450:Disease Progression; D005260:Female; D052203:Ferrosoferric Oxide / Q000737:chemistry / Q000378:metabolism*; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008280:Magnetics / Q000379:methods*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*; D011098:Polyglactin 910 / Q000737:chemistry / Q000378:metabolism*; D011237:Predictive Value of Tests; D013997:Time Factors; D014018:Tissue Distribution; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D017239:Paclitaxel; D052203:Ferrosoferric Oxide