Preparation And Drug Carrier Studies Of Bifunctional Nanoparticles Towards Oral Insulin Delivery

In recent years,diabetes has become one of the three diseases that threaten human health.Insulin is a peptide and is an effective drug for the treatment of diabetes.Oral delivery of higher molecular weight polypeptide drugs such as insulin faces two currently yet to be resolved problems,namely,instability of peptides exposed to the acidic and enzymatic environment of the gastrointestinal tract,and poor membrane permeability of higher molecular weight molecules in Intestinal environment.Overcoming these obstacles has been the object of a number of research activities,using functional polymers as drug carriers that have properties ranging from pH-sensitive,glucose-sensitive to membrane-adherent.In the present work,a dual-functional amphiphilic block co-polymer P(MMA-co-MAA)-b-P(AEMA)with both pH sensitivity and membrane adhesion properties were designed and synthesized by ARGET ATRP as a carrier vehicle for oral drug delivery,with insulin being investigated as a model drug.Insulin was dissolved in dilute aqueous HCl and mixed with a DMF solution of the block co-polymer.An insulin-loaded nanomicelle material was formed after removal of the organic solvent by dialysis.The PMMA and PMAA portions of the block co-polymer of a micelle form an inner core encapsulating insulin.Hydrophilic P(AEMA)portions of the block co-polymer stretch outside the core,forming a shell or whiskers keeping the micelle stable in solution.The pKa of the PMAA portion of the block co-polymer is 5.0-6.0,enabling PMAA to be responsive to the change of pH from the stomach to the intestines,for targeted release of the encapsulated insulin.Membrane adhesion and tight junction-opening properties of the P(AEMA)portions extend residence time of the micelle in the intestines and enhance para-cellular transport of released insulin.In experimental work,prepared micelles were subjected to characterization by particle size,Zeta potential,drug loading,and insulin-encapsulation efficiency.Preparation conditions were optimized.In vitro drug release and cytotoxicity studies were conducted on micelles prepared under optimal preparation conditions.Under these conditions,drug loading and encapsulation efficiency of prepared micelles were found to be 10.01%and 86.56%,respectively.Cytotoxicity was found to be small.Cumulative release amount reached 65%in 24 h under simulated intestinal drug release conditions,while under simulated gastric drug release conditions,the cumulative release amount was found to be less than 35%in 24 h.In this paper,a insulin-loaded and dual-functional nanomicelles with both pH sensitivity and membrane adhesion properties were designed and synthesized to solve two major obstacles in the process of insulin delivery,Besides,the insulin-loaded and dual-functional nanomicelles did not exhibit cytotoxicity.And it have potential for application to the improving of oral bioavailability of insulin.