Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide
Authors: Shreya Goel
Mauro Ferrari
Zhenhua Hu
Louis E Hinkle
Sara Nizzero
Haifa Shen
Chao Li
Xiaoyan Wu
Journal: Science Advances (2020)
Discipline: Multidisciplinary
Keywords: oral bioavailability; peptide drugs; FATP4 transporter; long-chain fatty acid (LCFA); enterocytic membrane
Affiliations: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA., Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA., Department of Pediatric Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China., The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China., Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA., Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.

Abstract:  Low oral bioavailability of peptide drugs has limited their application to parenteral administration, which suffers from poor patient compliance. Here, we show that molecular targeting of the FATP4 transporter is an effective approach to specifically transport long-chain fatty acid (LCFA)-conjugated peptides across the enterocytic membrane and, thus, enables oral delivery of drug peptides. We packaged LCFA-conjugated exendin-4 (LCFA-Ex4) into liposomes and coated with chitosan nanoparticles to form an orally deliverable Ex4 (OraEx4). OraEx4 protected LCFA-Ex4 from damage by the gastric fluid and released LCFA-Ex4 in the intestinal cavity, where LCFA-Ex4 was transported across the enterocyte membrane by the FAPT4 transporter. OraEx4 had a high bioavailability of 24.8% with respect to subcutaneous injection and exhibited a substantial hypoglycemic effect in murine models of diabetes mellitus. Thus, molecular targeting of the FATP4 transporter enhances oral absorption of therapeutic peptides and provides a platform for oral peptide drug development. 

Retracted: Yes

PubPeer comments:
 Figure 5F appears to have 2 sets of images which overlap. I thought I saw something similar in the liver images, but can t find it now. *** ![file] *** Full Figure ![file] , 
 Figure S18 ![file] , 
 ![file] , 
 Figure 3C. The Jejunum and Ileum panels appear to show areas of overlap, as highlighted here with orange, yellow, and pink boxes. Note that the red boxes belong to the original figure, and that the LCFA-Ex4 aspect ratio is very different between the two anatomical locations. ![file] , 
 Figure S12.  Major organs were collected from C57BL 6 mice 1, 2, 4, 8 and 12 hours after administration of OraEx4, and images were captured with an IVIS-200 imaging system. Representative images are shown. The 1h and 8h set of organs look surprisingly similar, except for the amount of signal captured (shown with green boxes). Could the authors clarify if some of the mice had two sets of major organs, please? ![file] , 
 Ad #2: Some additional findings in Figure S18. ![file] , 
 As I noted on Twitter: **Funding**: This work was partially supported by NIH grants R01CA193880, R01CA222959, and U54CA210181, U.S. Department of Defense grant W81XWH-17-1-0389, and an internal grant of Houston Methodist Research Institute. , 
 #3 ![file] , 
 Retracted. In the research article, u201cMolecular targeting of FATP4 transporter for oral delivery of therapeutic peptideu201d (1), we reported development of a chitosan nanoparticle-coated liposome for oral delivery of long-chain fatty acid (LCFA)-conjugated peptide drugs, promoting absorption through the FATP4 transporter. After publication, readers identified duplicated image regions in multiple figure panels. Alerted to these concerns, the corresponding authoru2019s institution performed a review of the supporting data and research records and determined that the research was not performed according to expected standards and was not reliable. Therefore, we wish to retract this research article promptly. We apologize that these errors were not discovered before the manuscript was published. All of the authors have agreed the paper should be retracted, except Dr. Zhenhua Hu who did not respond to our communications. https: advances.sciencemag.org content 6 26 eabc9572 See also: https: retractionwatch.com 2020 06 26 drug-delivery-study-with-duplicated-images-is-retracted ,