Layer-by-Layer Assembled Polymeric Films For Controlled Drug Delivery

Recently, layer-by-layer (LbL) assembly technique has attracted increasing attention due to its unique advantages in the field of controlled drug delivery:mild preparation conditions (in aqueous solution) compatible for maintaining bioactivity of drug molecules, various loading methods of drugs into films with finely controlled loading amount of drugs, stimulus-responsive release profile and so on. In previous works, LbL assembled multilayer films are directly deposited on the surface of implant materials for controlled drug delivery. The exploration of LbL assembled multilayer films as independent functional materials for controlled drug release has not been reported. Moreover, LbL assembled multilayer films are usually used for loading and releasing of one type of drug molecules, which sometimes cannot achieve good therapeutic treatment of disease. The design of advanced platforms that can delivery two or more kinds of drug molecules (multi-agent delivery) to realize combination therapy remains a challenge. Based on the problems mentioned above, this thesis aims at (1) exploring the free-standing multilayer films as novel biomedical functional materials for unidirectional drug delivery;(2) developing new types of drug delivery polymeric films that can co-deliver two types of drug molecules and release them in a controlled way.In chapter1, we overview briefly the latest developments challenges of the LbL assembled multilayer films in controlled drug delivery. In almost all of the recent works LbL assembled polymeric films were deposited on the surface of implanted materials which limited the potential application of these films as independent functional materials in biomedical field. The research about the LbL assembled polymeric films for delivering one kind of drug molecules has been very mature. However, novel drug delivery films that can release two or more kinds of drug molecules in different ways to realize the combination therapy are still highly desirable.In chapter2, we have fabricated a robust and flexible free-standing film with a sandwich structure consisting of a barrier layer of PLGA, a drug loading layer of (PAH-D/HA)*10and a capping layer of PLGA. The PAH-D/HA films were fabricated by LbL assembly of chemically cross-linked poly(allylamine hydrochloride)(PAH) and dextran (named PAH-D) with hyaloplasm acid (HA). The barrier and capping layers are spin-coating poly(lactide-co-glycolide)(PLGA), which can be degraded under physiological conditions. The resulting free-standing film exhibits unique "unidirectional releasing" feature that guarantees bioactivity and low side-effect of therapeutic agents. The unidirectional release of anticancer drug methotrexate disodium(MTX) in such free-standing films was verified and its controlled release was realized by using a PLGA capping layer, providing a sustained release profile of MTX over5days.In chapter3, a "tissue-repair plaster" has been developed by fabricating a bilayer free-standing film that can release recombinant human basic fibroblast growth factor (bFGF). Cationic biodegradable polymer poly(β-amino ester), negatively charged alginic acid (ALG) and bFGF are sequentially deposited to fabricate a LbL assembled tetralayer (PAE/ALG/bFGF/ALG)*n film. The PLGA supporting layer is spin-coated on the surface of PAE/ALG/bFGF/ALG multilayer films. The free-standing PLGA/(PAE/ALG/bFGF/ALG)*n films are obtained by directly peeling them off from a solid substrate by tweezers. The as-prepared free-standing films have a satisfactory mechanical stability as endowed by the PLGA supporting layer. Such kinds of free-standing films can adhere strongly on the surface of human skin and biological tissues. The bFGF can be released over a period of15days in vitro. The released bFGF retains its bioactivity, as it can accelerated closure of a scratch in L929cell cultures.In chapter4, macromolecular drug chondroitin sulfate sodium (CSS) and small drug molecule ceftriaxone sodium (CTX) are coloaded into one multilayer film and released in different ways for wound healing purpose. CSS molecules are loaded into multilayer film by first complexing with polycationic chitosan hydrochloride to produce CHI-CSS polyelectrolyte complexes (noted as CHI-CSS) and then LbL assembled with HA to fabricate CHI-CSS/HA films. CTX molecules are loaded into CHI-CSS/HA multilayer film by a post-diffusion process. The CTX molecules are released in a relatively fast way which exhibit antimicrobial effect and can effectively avoid wound infection. The CSS molecules are released in a relatively slow way, which can accelerate the cell migration and promote the wound healing.In chapter5, two kinds of anticancer drug molecules methotrexate disodium salt (MTX) and doxorubicin hydrochloride(DOX)are coloaded into one multilayer film. These two kinds of anticancer drugs loaded in multilayer films show pH-controlled release behavior. DOX molecules are first conjugated to HA through pH-sensitive hydrazone bond to prepare HA-DOX conjugate and then HA-DOX conjugate is LbL assembled with chitosan quaternary ammonium salt (CHI) to incorporate DOX into CHI/HA-DOX multilayer films. MTX molecules are loaded into CHI/HA-DOX films by a post-diffusion process. Both MTX and DOX show pH-dependent release profiles. The MTX molecules are released in a relatively fast way to inhibit the proliferation of cancer cells, while the DOX molecules are released in a relatively slow way to kill the cancer cells completely. Our results indicate that the differential release profiles of MTX and DOX increase the antitumor efficacy remarkably as a result of combination cancer therapy.