Construction And Application Of An Oral Protein Drug Delivery System Based On Polymer Nanocapsules

Biologic drugs such as peptides and proteins have unique advantages including small side effects and strong target specificity,which play an important role in the treatment of diabetes,cancer,and other major diseases.Due to poor absorption and swift enzymatic degradation in the gastrointestinal tract,biologic drugs are mainly administered by injection to achieve the required dose and pharmacokinetics.However,there are obvious deficiencies in injection administration such as poor convenience and low patient compliance.The development of the oral delivery system for biologic drugs can greatly improve the convenience and compliance of drug delivery and is also a hot direction in the field of biomolecular drug research and development.The physiological barriers in the process from oral administration to absorption in the small intestine mainly include biochemical barriers composed of p H environment and various proteases,mucus barriers covering the intestinal epithelial cells,and intestinal epithelial cell barriers composed of cells.How to cross a series of barriers is the key to developing the oral delivery system for these drugs.In this paper,protein molecules were encapsulated in crosslinked polymer shells by aqueous phase in situ free radical polymerization to prepare a nanoparticle for the oral delivery of protein drugs.The cross-linked polymer shell is mainly composed of 3-acrylamidephenylboronic acid(PBA)and 2-methylacryloxyethyl phosphatidylcholine(MPC).The crosslinked polymer shell of the nanocapsules can protect protein molecules from the p H environment and protease in the biochemical barrier.PBA monomer can improve the retention ability of nanocapsules in the intestinal mucus layer by interacting with mucin.MPC monomer can mediate the transmembrane transport of nanocapsules through choline transporter on the cell membrane.The main findings are as follows:In this paper,bovine serum albumin(BSA)was used as a model protein to construct an oral delivery platform.By optimizing the synthesis conditions of nanocapsules,the optimal ratio of BSA to polymerized monomer was determined to be 1:7200;under this condition,The encapsulation efficiency of n(BSA)p MPC-PBA is about 71%;the synthesized nanocapsule is a spherical particle with a particle size of about 25 nm;the measurement results of Zeta potential show that the nanocapsule shell will mask the electronegativity of the model protein itself,leading to potential The decrease of the value;the polymerization process conditions are mild,which can largely avoid the influence on the protein activity.The characterization of the mucus adhesion ability proved that the introduction of PBA in the nanocapsules increased the mucin adhesion ability of the carrier;the intestinal epithelial cell delivery model composed of Caco-2 cells verified the intestinal epithelial cell barrier penetration ability of the newly synthesized nanocapsules,which was consistent with the intestinal epithelial cell barrier penetration ability of the newly synthesized nanocapsules.Compared with the pure BSA control,the permeability of the nanocapsules increased by about 20%;finally,it was proved by observing the distribution of BSA in the body that the nanocapsules can enhance the delivery effect of protein drugs in the oral route,thereby improving the process of drugs entering the blood circulation and increasing the bioavailability of drugs Spend.On this basis,insulin was selected as the research drug to explore the oral delivery effect of the nanocapsules.To improve the degradation ability of the nanocapsules in vivo and realize the controllable release of their contents,PLA-PEG-PLA dimethacrylate was used instead as the cross-linking agent;the in vitro characterization experiments proved that the introduction of the nanocapsule shell would confer insulin resistance.The ability of hydrolase to degrade;the results of animal experiments show that,compared with oral free insulin,nanocapsule n(INS)p MPC-PBA can reduce the blood sugar level of type I diabetic rats with blood glucose value greater than 16.7 mmol/L.The blood glucose level proves that the introduction of nanocapsules can improve the oral bioavailability of insulin;the tissue damage evaluation proves that the nanocapsules will not cause tissue damage,and the nanocapsules have good biological safety.The overall research results show that the oral delivery system based on polymer nanocapsules constructed in this subject can improve insulin resistance to a certain extent,depending on the adhesion ability of PBA monomers to mucin and the functional properties of MPC monomers to mediate transmembrane transport.Oral bioavailability provides a new idea for the subsequent construction of oral delivery systems for different peptide and protein drugs.