DESIGN OF ORAL INSULIN DELIVERY SYSTEM BASED PEPTIDES AND PHOSPHOLIPIDS

• Main Author: RAHMAWATI FUADAH (NIM: 20515007), NANIK
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/29541
• Institution: Institut Teknologi Bandung

<p align="justify">The development of oral insulin as a therapy for Diabetes Mellitus I is limited by the low bioavailability of oral insulin, that evantually become less than 1% in the human body. Degradation of insulin due to low pH and protease enzymes in the digestive system, as well as the large molecular size of insulin to be absorbed by the intestinal epithelial cells, are among factors contribute to the low bioavailability of oral insulin. A delivery system is a promising approach to protect and improve the bioavailability of oral insulin. This system is generally an ampiphatic molecule, which has a polar and nonpolar moieties. Therefore, phospholipids are commonly applied to construct a delivery system including for oral insulin that either in the form of solid lipid nanoparticles, liposomes, or microemulsions. However, the success rate of using phospholipid as the delivery system of oral insulin is low. It has been reported in the previous study that the administration of oral insulin requires twenty times higher than the injection dosage. Therefore, a new delivery system is needed to enhance the bioavailability of oral insulin. One of the emerging candidates is a peptide because this molecule also can be constructed to have ampiphatic properties by adjusting it’s sequence through the combination of hydrophobic and hydrophilic amino acid residues. The aims of the presence study is to perform in silico design using phospholipids and peptides as main materials and evalute their effectiveness as a delivery system for insulin by using molecular dynamics (MD) simulation. The phospholipid-based delivery system was constructed by choosing phosphatydilcholine as a basic material because it has been studied by in vivo and in vitro methods in the previous study. DPPC; OPPC; LPC; and combine of DPPC-LPC were among phosphatydilcholine groups used to construct some in silico models for a delivery system of insulin. In case for the peptide-based delivery system, we constructed three groups of peptides i.e. negative charge peptides (I6D, V6D, L6D); positive charge peptides (I6K, V6K, L6K); and their combinations. The initial structure of both phospholipid and peptide based delivery system for MD simulations was prepared by randomly mixing the base materials in a water box containing an insulin molecule. All MD simulations were carried out with a GROMACS 5.0.4 program using NPT ensemble with the setting temperature and pressure were 310 K and 1 atm, respectively. While nonbonding interactions were calculated based <br /> <br /> vi <br /> <br /> on parameters in GROMOS 53a6 force fields with a cut-off 1.0 nm and the simulation was running for 150 by maintaining temperature and pressure with a V-rescale and a Parrinello-Rahman algorithms, respectively. The MD simulations result showed that among all phospholipid based materials only DPPC and LPC, which were able to maintain the secondary and tertiary structures of insulin within the time range of simulation. However, all phospholipid (DPPC, OPPC, LPC, DPPC-LPC) based materials failed to completely encapsulate insulin within 150 ns simulation and hence only partial part of the protein structure that protected by these systems. On the contrary, a relatively complete encapsulation of insulin was observed when peptide based materials. Among all peptide models constructed in our study, only V6D peptide that can maintain the structure of insulin. Further analysis showed that contact number between insulin and V6D peptide were relatively higher compare to the other peptides and also steady until the end of simulation. This study thus revealed that the peptide based material is better than a phospholipid one to be developed as an oral delivery system for insulin.<p align="justify">