Research On Drug Delivery System And Tissue Scaffold Construct From Functional Polypeptide-Copolymer And Polymer Hydrogel

Functional drug delivery systems based on polymer materials have attracted much attention recentely. It is a highly interdisciplinary field of science covering the material science, pharmaceutics, clinical medicine, etc. With the development of polymerization technology, novel functional polymer materials are constantly emerging, which provides an anchor for the development of "smart" drug delivery system such as environmental sensitive systems and targeting drug delivery systems. These functional drug delivery systems have broad applications on the life science, medicine, biology and other fields, which can enormously promote the development of material science. In this paper, a number of drug delivery systems and tissue scaffolds were prepared. In the study of drug delivery systems, environmental sensitive dual-drug delivery systems have been prepared from the composites of peptide micelles and polymer hydrogels. These dual-drug delivery systems can encapsulate both hydrophilic and hydrophobic drugs simultaneously, and control the release behaviors of the two drugs indenpendtly. While in the study of tissue scaffold, functional scaffolds for controllable cell growth have been developed by incorporating drug-loaded carriers into the hydrogel scaffolds. Additionally, data of drug release and degradation has been fitted and analyzed by related equations for understanding the inherent mechanisms of drug release and degredation processes.(1) A novel dual-drug delivery system from polypeptide micelle/hydrogel composite has been prepared. Aspirin (Asp) is dissolved directly in the water phase of polyvinyl alcohol (PVA) hydrogel, and doxorubicin (DOX) is encapsulated in poly(L-glutamate acid)-b-poly(propylene oxide)-b-poly(L-glutamate acid) (GPG) micelle. Different release behaviors of the two drugs in the system are achieved. Asp shows a short-term release while DOX shows a sustained long-term release. Moreover, the release behavior of DOX shows pH and temperature sensitive. With adding chitosan (CS) to the system, the pH controlled release behavior of Asp can be observed. The obtained release profiles are well fitted by the classical empirical power law. According to the release-exponent n, the release of DOX follows Fickian-diffusion and Asp follows anomalous-transport in PVA/micelle DDDS. However, the release of DOX is anomalous-transport and Asp is close to case-Ⅱtransport in CS/PVA/micelle DDDS.(2) We presented a novel hydrogel scaffold for controllable cell growth. The resulting structure of the scaffold is PVA hydrogel network containing paclitaxel (PTX)-loaded micelles and VEGF165-loaded alginate hydrogel microparticles. VEGF165 shows a short-term release to encourage cell growth in the early period, and PTX shows a sustained long-term release to inhibit the growth of cells in late period. In addition, the in-vitro release study shows an interesting phenomenon that the existence of Ca-alginate microparticles (Alg-MPs) in PVA hydrogel can decrease the release rate of PTX due to the reduced hydrogel network pore size when adding Alg-MPs. MTT assay shows the viabilities of endothelial cells (ECs) and L929 cells are high in the early period and low in late period. And the smooth muscle cells (SMCs) shows a delayed inhibited growth in late period on the scaffold. It is consistent with the requirements of clinical applications of vascular surgery.(3) We have prepared the lysozyme-carrier/chitosan composite films to resist the variation of degradation rate from environment change. The degradation activity of lysozyme shows the environmental dependence, which is increased at lower pH value or higher temperature. Therefore, the degradation time period of chitosan scaffolds could be misjudged when the surrounding condition of implantation site changes. We use the pH-sensitive carriers of Ca-alginate hydrogel micro-particles to encapsulate lysozyme. These carriers can fast release large amount of lysozyme at high pH value to compensate the decrease of enzyme activity, and control the release amount of lysozyme in the opposite condition when lysozyme presents a high activity. In vitro degradation tests show that the degradation profiles of lysozyme-loaded Ca-alginate microparticle/chitosan films are overlapped at various pH values, indicating an anti-pH interference effect. Meanwhile, the anti-temperature interference degradable films constructed from lysozyme-loaded poly(N-isopropylacrylamide) (PNIPAM) microparticle/chitosan composites were also prepared. The result of degradation test shows a weaker anti-temperature interference effect, comparing with the lysozyme-alginate/chitosan systems. The Peppas’s power law equation is used to analyze the release mechanism of these lysozyme-loaded environmental sensitive microparticles. And the Michaelis equation is used to analyze the effect of the release amount of lysozyme on the degradation rate of chitosan film. Fluorescence microscopy observation and MTT assay show a good biocompatibility and cell proliferation on these lysozyme-carrier/chitosan composite films.(4) We have prepared a dual-drug loaded system based on the conjugates of Asp-loaded CS nano-particles and DOX-loaded GPG micelles. The CS nano-particles are cationic hydrogels, while the GPG micelles have anionic poly(L-glutamate acid) shells. Therefore, the two kinds of polyelectrolyte nano-carriers can electrostatic self-assemble into micro-conjugates. We have investigated the range of CS/GPG ratio for CS nano-particle and GPG micelle to electrostatic self-assemble into a sustained CS/GPG nano-conjugates solution. We have studied the in vitro drug release behaviors of the Asp-CS/DOX-GPG conjugates as a function of pH value. Asp and DOX both show the pH sensitive release behaviors. Moreover, the release rate of Asp shows a dramatic decrease in the Asp-CS/DOX-GPG system, as compared with the Asp-CS nanoparticles, which caused by the aggragation of GPG micelles on the CS nono-particle surfaces.