title: IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer.
abstract: Overcoming resistance to chemotherapy is a major and unmet medical challenge in the treatment of pancreatic cancer. Poor drug delivery due to stromal barriers in the tumor microenvironment and aggressive tumor biology are additional impediments toward a more successful treatment of pancreatic cancer. In attempts to address these challenges, we developed IGF1 receptor (IGF1R)-directed, multifunctional theranostic nanoparticles for targeted delivery of therapeutic agents into IGF1R-expressing drug-resistant tumor cells and tumor-associated stromal cells. These nanoparticles were prepared by conjugating recombinant human IGF1 to magnetic iron oxide nanoparticles (IONPs) carrying the anthracycline doxorubicin (Dox) as the chemotherapeutic payload. Intravenously administered IGF1-IONPs exhibited excellent tumor targeting and penetration in an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer featuring enriched tumor stroma and heterogeneous cancer cells. IGF1R-targeted therapy using the theranostic IGF1-IONP-Dox significantly inhibited the growth of pancreatic PDX tumors. The effects of the intratumoral nanoparticle delivery and therapeutic responses in the orthotopic pancreatic PDX tumors could be detected by magnetic resonance imaging (MRI) with IONP-induced contrasts. Histological analysis showed that IGF1R-targeted delivery of Dox significantly inhibited cell proliferation and induced apoptotic cell death of pancreatic cancer cells. Therefore, further development of IGF1R-targeted theranostic IONPs and MRI-guided cancer therapy as a precision nanomedicine may provide the basis for more effective treatment of pancreatic cancer.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Weiping
authors.initials: W
authors.lastname: Qian
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles , Los Angeles, California 90027, United States.
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.affiliation: Ocean Nanotech, LLC , San Diego, California 92126, United States.
authors.forename: Y Andrew
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Ocean Nanotech, LLC , San Diego, California 92126, United States.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Kooby
authors.forename: Qian
authors.initials: Q
authors.lastname: Yu
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Lipowska
authors.forename: Charles A
authors.initials: CA
authors.lastname: Staley
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.forename: Lily
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D015870:Gene Expression; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000737:chemistry / Q000627:therapeutic use* / Q000648:ultrastructure; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000068936:Theranostic Nanomedicine / Q000379:methods*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D003287:Contrast Media; D005290:Ferric Compounds; D058185:Magnetite Nanoparticles; D011994:Recombinant Proteins; C000499:ferric oxide; D007334:Insulin-Like Growth Factor I; D004317:Doxorubicin; D017526:Receptor, IGF Type 1
keywords: IGF1R-targeted cancer therapy; MRI; image-guided cancer therapy; orthotopic pancreatic cancer patient tissue derived xenografts; theranostic nanoparticles