Dendrimer-based Drug Delivery Systems: From Theory To Practice

Dendrimers are a class of artificial macromolecules that have a topological structure like a tree. They are hyperbranched, monodisperse, three-dimensional molecules with well-defined shapes, molecular weights, sizes, branched layers, hydrophobic pockets, and surface functionalities. Due to these structural properties, dendrimers have been widely applied in many fields, such as supramolecular chemistry or host-guest chemistry, electrochemistry, photochemistry, nanoparticle synthesis, pollution management, dye decolorization, preparation of monomolecular membranes, curing of epoxy resins, catalysis, drug delivery, gene transfection, and cancer diagnosis. Recently, the applications of dendrimers in drug delivery systems have received a great deal of attention in the field of nanomedicine, drug delivery systems, and pharmaceutical sciences.The research in this dissertation focuses on the design and development of dendrimer-based drug delivery systems, and their applications in pre-clinical trails. The effect of dendrimers on the solubility, dissolution, release, pharmacodynamic and pharmacokinetic behaviors of non-covalently attached drugs is investigated. General rules on dendrimer and drug interactions are proposed. Potential administration routes of these dendrimer-based drug formulations are discussed. Also, a nano-platform based on dendrimers and biotin molecules is established for cancer targeting therapy and diagnosis.The dissertation comprises seven chapters. Chapter 1 begins with a summary on dendrimer history, structure, synthesis, physico-chemical properties, and applications in different fields. The definition of drug delivery systems and nanomedicine is introduced. On the basis of the summary, the importance of the development of dendrimer-based drug delivery systems is given.Chapter 2 systematically introduces the effect of poly(amidoamine) (PAMAM) dendrimers on the solubility, in vitro release rate, pharmacodynamic behaviors of drugs. Several classes of drugs including non-steroidal anti-inflammatory drugs, sulfonamide antimicrobials, quinolone antimicrobials, anti-cancer drugs, and anti-epileptic drugs are limited in clinical trials due to their extremely low solubility in water, short half-life time in blood, and serious gastrointestinal side effects when administrated in oral route. The water-soluble dendrimer-drug complexes can overcome these disadvantages by significantly enhancing the solubility of drugs, decreasing in vitro and in vivo release rate of the drugs from dendrimer matrixes, and increasing their bio-activity. These data provide a platform for the development of drug formulations in intravenous injection and ocular administration route.In Chapter 3, multi-dimensional nuclear magnetic response (NMR) techniques were employed to investigate the interactions between PAMAM dendrimers and drugs. In combination with solubility results, several rules are deduced. The results suggest that there are three types of interactions between dendrimers and drugs in the complexes: electrostatic interactions between cationic dendrimers and negatively charged drugs, hydrophobic interactions between relative non-polar cavities of dendrimer and hydrophobic drugs, and hydrogen-bond interactions between the cavities and drug molecules. Among these interaction mechanisms, the electrostatic interaction contributes more to the solubility enhancement of the drugs than hydrophobic interaction and hydrogen-bond interaction. Besides, higher generation dendrimers are more capable of encapsulating drugs than lower generation ones, while lower generation ones are much easier for the electrostatic attachment of drugs than higher generation ones.The interactions between PAMAM dendrimers and surfactants are investigated in Chapter 4. A new interaction model is proposed. Evidence from the multi-dimensional NMR studies suggests that the surfactant penetrate into the interior cavities of dendrimers. The dendrimer-surfactant-drug ternary systems are evaluated in drug delivery systems. The results show that dendrimer-surfactant aggregates enhance the drug loading efficiency of dendrimers, decrease the high cost of dendrimers, and release the drugs from the aggregate in a controllable manner. The new drug formulations based on dendrimer-surfactant aggregates is promising in transdermal and nasal administration routes in clinical trails.Chapter 5 deals with the potential administration routes of the dendrimer-based drug formulations. Take non-steroidal anti-inflammatory drugs for example, the in vitro release, pharmacodynamic and pharmacokinetic behaviors of the dendrimer-drug complexes are compared when administrated in oral route and transdermal route, respectively. The results show that the dendrimer-drug complexes are more suitable in transdermal route than in oral route, and can further increase the bioavailability of the drugs, prolong the effective time of drugs in blood, and enhance the patient compliance. Furthermore, the potential of dendrimers to be administrated in different routes with particular reference to oral, intravenous, transdermal, ocular, and nasal delivery systems are discussed.In Chapter 6, polymeric nano-platforms based on PAMAM dendrimers and biotin molecules are synthesized for cancer targeting therapy and diagnosis. As revealed by flow cytometry and confocal microscopy, the dendrimer-biotin conjugate exhibits much higher cellular uptake into Hela cells than the conjugate without biotin. The uptake is dose-dependent, incubation time-dependent, energy-dependent, and can be effectively blocked by biotin molecules. The results indicate that the biocompatible nano-platform is promising in cancer therapy and diagnosis. In addition, the advantages and disadvantages of several targeting ligand mediated targeting delivery systems are discussed, and an optimized biotechnology is proposed to enhance the targeting efficiency of small molecules such as folic acid and biotin, and to shorten the synthesis period of dendrimer-antibody conjugates.Chapter 7 summarizes the full dissertation and gives perspectives of dendrimers in biomedical fields. Although dendrimer-mediated drug delivery is in its infancy, it offers a number of attractive features. These nanomaterials are expected to play a key role in the fields of biomedicine, nanomedicine, and clinical therapy and diagnosis in the 21^st century. They provide uniform platforms for bioactive molecule attachment and have the ability to encapsulate or bind drugs through several mechanisms. They are useful additives in drug formulations for increasing the solubility, stability, bioavailability, cellular uptake, targeting ability and patient compliance of the administrated drugs, and for decreasing the drug resistance and irritation. Scientists in this field are now in the process of conducting preclinical tests to evaluate the safety of dendrimers in animals and human. We will really benefit from the dendrimer-based drug delivery systems in a near future.