LbL Self-Assembly Of Hepatic-Targeting Drug Microcapsules And Their Properties

LbL self-assembled microcapsules fabricated on removable templates are under extensive investigation in sustained drug release owing to the facile preparation and possibility to tune the properties of film thickness, permeability, and responsiveness to external stimuli. The optimal drug release requires the drug not only to be released with controlled rate but also transported to the target site with less loss. Hence it is very necessary to embed some target functions to modify traditional multilayered drug delivery systems which were rarely been concerned in previous reports. In this dissertation, D-galactose was incorporated as a targeting ligand directing to the hepatic cells through strongly binding with large numbers of asialoglycoprotein receptors (ASGPR) which are exclusively expressed by liver parenchymal cells. The encapsulation and controlled release via hepatic-targeting multilayered microcapsules towards different drugs were investigated.LbL self-assembled hepatic-targeting microcapsules based on electrostatic attraction were constructed by alternately depositing galactose-branched polycation (PGEDMC) with poly(styrenesulfonate) (PSS). Film properties such as assembled amount and film surface roughness were finely controlled by varying polyelectrolyte concentration, ionic strength, counter anion type and organic solvent ratio. Integrate hollow capsules used for drug delivery were formed after the removal of polystyrene (PS) or CaCO3 particles verified by TEM and SEM.LbL self-assembled hepatic-targeting microcapsules based on electrostatic attractions were constructed by alternately depositing galactose-branched polyanion (PGESS) with polycations such as chitosan (CHI), poly(allylamine hydrochloride) (PAH) and polyethyleneimine (PEI). The film thickness evolution followed an exponential growth mode observed by spectroscopic ellipsometry. The amount of targeting ligand was controlled by using PGESS with different monomer ratios determined by UV-vis. Multilayers with double targeting ligands were designed by conjugating folic acid (FA) as second ligand onto CHI/PGESS films, and surface density of FA could be tuned via variation of crosslinking reagent and FA matrix concentrations, crosslinking time and CHI layer number.Novel targetable and biodegradable polycation/protein microcapsules were designed by LbL self-assembly of PGEDMC with anionized hemoglobin (Hb), in which Hb acted as a main degradable component. The in vitro biodegradability of fabricated multilayers via proteases was evaluated in detail on both planar substrates and CaCO3 particles followed by UV-vis, SEM, and AFM characterizations, and a drastic mass loss, surface roughness leap, and integrity destruction were observed. The degradation course approximately follows an exponential decay evolution and the relation between the kinetic constant k in degradation process and deposited bilayer number n is well approximated with a power equation. The films deposited with two bilayers remains the least Hb amount of no more than 10% after 12 h of degradation, in contrast with that of 50% for eight bilayers.Three types of LbL assembled targeting drug microcapsules were formed. Hydrophilic drugs such as propranolol hydrochloride (PRH) and doxorubicin hydrochloride (DOX) were loaded from feeding solution into pre-formed hollow capsules doped with PSS interior. A drastic thermal shrinkage response was observed by SEM, and heating after drug loading could seal PGEDMC or PSS-capped capsule shell, enhancing the loading capacity and reducing the release rate significantly. Alternate deposition of PGEDMC and PSS was carried out on hydrophobic drug such as acyclovir, and the drug release rate decreases with the increase of coated layer number and a microcapsule-drying treatment would enhance the sustained release effect probably because of a multilayer shrink and tightness during the process. Macromolecular drug such as protein drug was first deposited on porous templates (e.g. CaCO3) and then alternately coated with PGEDMC and Hb to form biodegradable targeting drug microcapules. Remarkable drug release was observed once the enzymatic degradation of capsule shells has occurred.Biotargetability of assembled multilayers and microcapusles were investigated by specific lectin binding and cancer cell adhesion. Galactose-contained multilayered films showed good biocompatibility via methylthiozol tetrazolium (MTT) test. It was shown that PGEDMC as well as PGESS-capped multilayers could specifically bindβ-D galactose binding lectin and HepG2 cancer cells while their binding to nonspecific lectin and A549 cancer cell was rather weak. The specific adhesion could be controlled by changing surface targeting ligand density. The targetability of galactose-contained LbL self assembly multilayers to hepatocytes was preliminarily confirmed in vitro.