Synthesis and characterization of a novel peptide-grafted Cs and evaluation of its nanoparticles for the oral delivery of insulin, in vitro, and in vivo study
Authors: Fateme Atyabi
Farid Dorkoosh
Saeed Balalaie
Mohammad Sharifzadeh
Niyousha Rafiee Tehrani
Mohsen Amini
Ghullam Reza Barbari
Nika Bahari Javan
Morteza Rafiee Tehrani
Journal: International Journal of Nanomedicine (2018)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: cell-penetrating peptide; oral delivery; penetratin; peptide grafted.
Affiliations: Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran, ., Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran., Department of Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran., Department of Chemistry, Khajeh Nasir Toosi University, Tehran, Iran., School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Abstract:  Background: Despite years of experience and rigorous research, injectable insulin is the sole trusted treatment method to control the blood glucose level in diabetes type 1 patients, but injection of insulin is painful and poses a lot of stress to the patients, especially children, therefore, development of a non-injectable formulation of insulin is a major breakthrough in the history of medicine and pharmaceutical sciences. Methods: In this study, a novel peptide grafted derivative of chitosan (CPP-g- chitosan) is synthesized and its potential for oral delivery of proteins and peptides is evaluated. Drug-loaded nanoparticles were developed from this derivative using ionic gelation method with application of sodium tripolyphosphate (TPP) as a cross-linking agent. Human insulin was used as the model protein drug and release kinetic was studied at gastrointestinal pH. Finally the developed nanoparticles were filled into very tiny enteric protective capsules and its effects on blood glucose level are evaluated in laboratory animals. Results: Presence of the positively charged cell-penetrating peptide moiety in the structure of chitosan polymer had slight inhibitory effects on the release of insulin from the nanoparticles in simulated gastric fluid (pH 1.2) comparing to native chitosan. The nanoparticles were positively charged in gastrointestinal pH with size ranging from 180 nm to 326 nm. The polypeptide grafted to chitosan is a novel analog of Penetratin, presenting both the hydrophilic and hydrophobic characteristics altering the release behavior of the nanoparticles and significantly increase the absorption of insulin into the rat epithelium comparing to nanoparticles from simple chitosan. In-vivo results in diabetic rat proved that this nanoparticulate system can significantly lower the blood glucose levels in diabetic rats and remain effective for a duration of 9-11 hours. Conclusion: The results indicate that nanoparticles developed from this new peptide conjugated derivative of chitosan are very promising for oral delivery of proteins and peptides. 

Retracted: Yes

PubPeer comments:
 Does the MSK-TMB cohort described in paper 1 include the cohorts described in papers 2-4? If so, then verification is invalid. [1] Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet (2019) [2] Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell (2018) [3] Mutational landscape determines sensitivity to PD-1 blockade in nonu2013small cell lung cancer. Science (2015) [4] Molecular Determinants of Response to Antiu2013Programmed Cell Death (PD)-1 and Antiu2013Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Nonu2013Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. JCO (2018) ,