Structure-performance Relationship In Chemical Product Design: Sustained Drug Delivery Systems

Based on the theories and methods of chemical product engineering, novel drug/gene delivery systems were designed and developed, which can meet the requirement of desired drug/gene. The releationship between micro-/meso-structure and performance of drug carriers was also investigated using multi-scale methods. Due to the complexity of drug delivery system (DDS), the desired performance of DDS is decided not only by the formulation of systems, but the most important by the micro-structure and compatibility of carriers and drugs, which is remarkably influenced by the molecular structure of carrier and the formulation of systems. Thus, the relationship between structure and performance is significant to chemical product design and development in DDS.Doxorubicin (DOX) was selected as the model drug. Based on the character of DOX and the pH difference between inside and outside of celles, cholesterol conjugated His10Arg10 (HR20) and His10Arg5 (HR15) were designed and synthesized as the drug carriers. These amphiphilic peptides are able to self-assemble into cationic micelles in aqueous solution. Cholesterol, an essential constituent in mammalian cell membranes, is selected as the hydrophobic core for carrying drugs. The pH-sensitive histidine residues distribute in the middle layer of micelles. This layer is hydrophobic at the physiological environment (pH 7.4) to prevent the release of DOX. However, it converses to hydrophilic ones by protonation of imidazole groups once internalized and transferred to a lysosome (pH 5.0), leadiing to the faster release of DOX. The cell-penetrating arginine residues were selected as the outer layer, which can improve the bioavailability of DOX. The interaction between peptides and DOX, effect of pH on the micelle structure, etc, were investigated using mesoscale simulation. DOX-loaded micelles were prepared and characterized by experimental techniques, such as particle size, zeta potential, SEM, AFM, drug release profiles, cytotoxicity, etc. In addition, the mechanism of drug release was also investigated using mathematics modelling.The development of gene delivery system is an important theme due to its safety and the cost of manufacture. In this work, the micelles self-assembled from HR15-Chol and HR20-Chol were also used for gene delivery. Cholesterol was used for improving the stability of core/shell structure, histidine was employed for endolysosomal release of genes, and cell penetrating arginine is for DNA binding. In addition, peptides with alpha-helical structure were designed and synthesized for gene delivery. The backbone of alpha-helical peptides was CKHLAKALAKALAC, in which, the two cysteine residues could be self-crosslinked to di, tri- and tetra-peptides. The branch was composed of histidine, lysine, asparagines, and RGD group. The lysine residues were used for DNA binding, histidine residues were employed for endolysosomal release of genes, asparagines residues could provide the spacer for RGD targeting group. The peptides/DNA complexes were prepared and characterized by a variety of experimental techniques, such as particle size, zeta potential, SEM, DNA binding, gene expression efficiency, cytotoxicity, etc.The relationship between structure and performance was investigated using mesoscale simulation method. Paclitaxel (PTX) was selected as a model drug. The phase behavior of PTX-loaded poly(ethylene oxide)-b-poly(L-lactide) (PEO-b-PLA) in mixed solvent (water and N,N-dimethylformamide (DMF)) was studied. And a phase diagram of PTX-loaded PEO-b-PLA in the sovent was mapped. The effect of chirality and molecular weight of PLA segments on the micro-structure of PTX loaded nanoparticles were also studied. Another hydrophobic drug, nifedipine, was also selected as a model drug. The effect of composition on the formation of PLA microsphers was studied, based on which a phase diagram for the formation of spherical microparticles was mapped. Finally, the mechanism of spherical microparticles was proposed, which can guide the developing of DDS.In this work, experimental research, computer simulation, and theoretical analysis were employed to investigate the relationship between structure and performance with several case studies, which provided a novel technique and method for designing chemical products in drug/gene delivery systems.