Design And Application Of Stimuli-responsive Drug Delivery System

Chemotherapy is one of the most common treatment in cancer therapy. Although with enormous needs, it cannot reach an ideal curative effect. The main challenges are the toxic and side effects, low bioavailability, and absence of specific recognition ability. In novel stimuli-responsive drug delivery system, endogenous stimuli (such as pH, redox environment, and enzymes) and exogenous stimuli (such as temperature, magnetic fields, ultrasounds, electric fields, and light) can be taken advantage to trigger drug release. By this mean, the on-demand drug release can be implemented, also with lower side effects and better therapeutic effect.The research in this dissertation focus on the design and development of novel stimuli responsive drug delivery system. The dissertation is comprised of five chapters.Chapter 1 summarizes the significance, history, and present status of drug delivery system. We also give a brief introduction of key technologies and problems in stimuli-responsive drug delivery system. Finally, the design concepts and main contents of this dissertation are given.Dendrimers load drugs by surface conjugation or physical interactions in general. However, surface conjugated drugs maybe interacted with biomolecules in blood circulation. Drugs loaded in interior of dendrimers by physical interactions are not stable in physiological condition. In chapter 2, dendrimer-encapsulated gold nanoparticles (DEGNPs) were synthesized and used as carriers of thiolated drugs. The drugs can be loaded in interior of dendrimers by Au-S bond which is stable in physiological condition. Thiol-containing drugs such as captopril and 6-mercaptopurine loaded within DEGNPs showed an "Off-On" release behavior in the presence of thiol-reducing agents such as glutathione and dithiothreitol. Thiolated doxorubicin and cisplatin, loaded within the nanoparticle, showed much reduced cytotoxicity as compared to the free anticancer compounds. The toxicity of drug-loaded DEGNPs can be enhanced by improving the intracellular glutathione. Glutathione- triggered release of thiolated doxorubicin within cancer cells is further confirmed by flow cytometry and confocal laser scan microscopy studies. In addition, DEGNPs showed excellent biocompatibility on several cell lines. This study provides a new insight into tumor microenvironment responsive drug delivery system.Most photo-responsive hydrogels for drug delivery were responsive to UV or visible light. The light with such wavelength cannot penetrate into deep tissue compared with NIR light, which restrict the biomedical application of these hydrogels. In chapter 3, we developed a near infrared (NIR) light-responsive supramolecular hydrogel composed of poly(ethylene glycol)-modified dendrimer-encapsulated with platinum nanoparticles (DEPt-PEG) and α-cyclodextrin (a-CD). Upon NIR irradiation, the hydrogel underwent a photothermo-sensitive degradation to release the entrapped therapeutic agents in an on-demand and dose-tunable fashion, and thus could conduct the controlled drug release. In addition, this supramolecular hydrogel showed excellent biocompatibility. This study provided a new concept and demonstration of NIR light-responsive hydrogel that skillfully integrated the photothermal nanoparticles in the structure of a thermo-sensitive supramolecular hydrogel to conduct a NIR-responsive degradation and drug release, which can be further explored for the delivery of diverse therapeutic agents such as chemotherapeutic drugs, nucleic acids, proteins, and the combined chemo-photothermal therapy.In chapter 4, polyethylene glycol-modified polydopamine nanoparticles (PDA-PEG) were synthesized and used as anticancer drug carriers. Polydopamine possesses excellent biocompatibility and photothermal effect. Polydopamine can be modified with functional groups easily. The degradation products of polydopamine is nontoxic. All these merits make polydopamine an ideal carrier for drug delivery. PDA-PEG could easily load anticancer drugs such as doxorubicin and 7-ethyl-10-hydroxycamptothecin via π-π stacking and/or hydrogen binding. Moreover, the drug-loaded PDA-PEG showed great stability and drug-retaining capability in physiological condition, and could respond to multiple stimuli including near infrared light, pH and reactive oxygen species to trigger the release of loaded anticancer drugs. The in vitro and in vivo studies demonstrated that PDA-PEG-mediated photothermal-chemotherapy showed synergetic effect for cancer therapy with less toxic and side effect.Chapter 5 summarizes the full dissertation and gives perspectives of stimuli-responsive drug delivery systems. Although stimuli-responsive drug delivery systems have not been approved for clinical application, some of these systems have been tested in a clinical trial. For example, the Thermodox(?) that responsive to temperature may breakthrough of "zero" in clinical application of stimuli-responsive drug delivery systems. It can be believed that in the near future, more and more stimuli-responsive drug delivery systems can be used in clinical application, solving the troubles in drug delivery and making benefit for human being.