A corrole nanobiologic elicits tissue-activated MRI contrast enhancement and tumor-targeted toxicity.
Water-soluble corroles with inherent fluorescence can form stable self-assemblies with tumor-targeted cell penetration proteins, and have been explored as agents for optical imaging and photosensitization of tumors in pre-clinical studies. However, the limited tissue-depth of excitation wavelengths limits their clinical applicability. To examine their utility in more clinically-relevant imaging and therapeutic modalities, here we have explored the use of corroles as contrast enhancing agents for magnetic resonance imaging (MRI), and evaluated their potential for tumor-selective delivery when encapsulated by a tumor-targeted polypeptide. We have found that a manganese-metallated corrole exhibits significant T1 relaxation shortening and MRI contrast enhancement that is blocked by particle formation in solution but yields considerable MRI contrast after tissue uptake. Cell entry but not low pH enables this. Additionally, the corrole elicited tumor-toxicity through the loss of mitochondrial membrane potential and cytoskeletal breakdown when delivered by the targeted polypeptide. The protein-corrole particle (which we call HerMn) exhibited improved therapeutic efficacy compared to current targeted therapies used in the clinic. Taken together with its tumor-preferential biodistribution, our findings indicate that HerMn can facilitate tumor-targeted toxicity after systemic delivery and tumor-selective MR imaging activatable by internalization.
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Jessica D
JD
Sims
Daegu Gyeongbuk Institute of Science & Technology, Daegu, Republic of Korea.
Jae Youn
JY
Hwang
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Shawn
S
Wagner
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Felix
F
Alonso-Valenteen
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Chris
C
Hanson
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Jan Michael
JM
Taguiam
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Richard
R
Polo
Translational Biomedical Imaging Laboratory, Department of Radiology, The Saban Reseach Institute, Children's Hospital, Keck Medical School of USC, Los Angeles, USA.
Ira
I
Harutyunyan
Translational Biomedical Imaging Laboratory, Department of Radiology, The Saban Reseach Institute, Children's Hospital, Keck Medical School of USC, Los Angeles, USA.
Gevorg
G
Karapetyan
Translational Biomedical Imaging Laboratory, Department of Radiology, The Saban Reseach Institute, Children's Hospital, Keck Medical School of USC, Los Angeles, USA.
Karn
K
Sorasaenee
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Ahmed
A
Ibrahim
Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Eduardo
E
Marban
Translational Biomedical Imaging Laboratory, Department of Radiology, The Saban Reseach Institute, Children's Hospital, Keck Medical School of USC, Los Angeles, USA.
Rex
R
Moats
Department of Chemistry, California Institute of Technology, Pasadena, CA, USA.
Harry B
HB
Gray
Schulich Faculty of Chemistry, Technion-Israel Institute, Haifa, Israel.
Zeev
Z
Gross
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Geffen School of Medicine, University of California-Los Angeles, USA. Electronic address: Medinal@cshs.org.
Lali K
LK
Medina-Kauwe
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008345:Manganese / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011166:Porphyrins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D003287:Contrast Media; D020890:Neuregulin-1; D011166:Porphyrins; D011993:Recombinant Fusion Proteins; C431863:corrole; D008345:Manganese
Corrole; MRI; Manganese; Nanoparticle; Tumor-targeting