Nanotechnology in Therapeutics: Current Technology and Applications Chapter Abstracts

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Chapter 1
Concepts of Medical Chronobiology, Chronopharmacology and Chronotherapeutics as the Basis for Applications of Drug Delivery Technology
Nicholas A. Peppas

Chrono-pharmacological drug delivery systems are able to match the delivery of therapeutic agents with the biological rhythm. Such systems are very important especially in the area of endocrinology and in delivery of vaccines. For example, the treatment of hypopituitary dwarfism by administration of human growth hormone releasing hormone is more effective when the hormone is administered in a pulsatile manner. Analysis of perceived problems in protein delivery in systems exhibiting chronobiology has led to the design of novel drug nanodelivery systems to achieve a physiological pulsatile pattern desired for the treatment of diseases as well as for achievement of a high bioavailability.

Chapter 2
Feedback Control in Drug Delivery
Jeffry A. Florian, Jr. and Robert S. Parker

The use of feedback principles to aid drug dosing and treatment decision-making is reviewed in this chapter. Drug delivery is considered in the context of treating four diseases: (i) glucose control in diabetic patients; (ii) hemodynamic control during surgery; (iii) HIV viral load management; and (iv) reduction of cancerous tumor burden. The characteristics of the underlying treatment problem and the degree to which feedback control principles are directly relevant is discussed. The clinical implementation of automated control algorithms for treatment actuation or design ranges from immediately possible in standard frameworks (hemodynamic regulation) to an open research and development problem (cancer).

Chapter 3
Advances in Drug Delivery Technologies for Nanoparticulates
Robert O. Williams III and Kirk A. Overhoff

A growing number of therapeutic compounds currently being developed by pharmaceutical companies are poorly water soluble leading to limited and/or erratic bioavailability. Nanoparticle formation has been exploited as a method to improve the bioavailability of these poorly water soluble active pharmaceutical ingredients (API). Two strategies have been proposed for formation of nanoparticles, particle reduction and particle nucleation and stabilization. Particle reduction technologies include milling and homogenization, while nucleation and stabilization technologies include solvent evaporation, rapid freezing, and antisolvent technologies. Both strategies have the ability to enhance dissolution of the API leading to increased bioavailability. Examples of nanoparticle compositions have shown enhanced uptake across biological membranes due to their small size. Surface modification of nanoparticles has also proven beneficial by allowing for site specific targeting, increasing residence time, and protecting against degradation. Examples using these nanoparticle technologies introduced within this chapter focus on oral and pulmonary delivery of the API.

Chapter 4
Synthetic Ligand-Receptor Interactions In Delivery Systems
David B. Henthorn, Youyou Zheng and Nicholas A. Peppas

Biomaterials design has undergone a pronounced shift where the goal is no longer production of passive, inert structures, but instead materials which interact with their environment. The enabling technology for production of active biomaterials has been molecular recognition - the ability for a structure to interact with one specific chemical compound. Addition of molecular recognition to a material may be done through various means, ranging from the immobilization of various natural biomolecules to the creation of wholly synthetic ligand-receptor pairs. The design, construction, and evaluation of synthetic receptor-ligand pairs have been the subject of much research. Design may be done through experiment, with computational tools, or a mixture of both. Strategies for successful synthetic ligand-receptor construction are discussed, as are evaluation techniques which aim to characterize receptor affinity and specificity.

Chapter 5
Nanoscale Analysis of Mucus-Carrier Interactions for Improved Drug Absorption
Yanbin Huang and Nicholas A. Peppas

Mucous layers cover epithelial surfaces throughout the body and provide protection and lubrication of the underlying epithelium. They are also the primary sites with which drug delivery nanodevices interact. Mucoadhesive drug delivery exploits the attraction between mucous layers and drug carriers. The main advantages of mucoadhesive drug carriers include localization of the carriers within the specific body site and prolonged residence time of delivery devices. These features greatly enhance the bioavailability of drugs, especially for peptide and protein delivery. Understanding of mucin/polymer interactions in the physiological environment is essential for the rational design of mucoadhesive delivery systems. We describe the structure of the mucous layer and its main component mucin molecules, and discuss the interaction between mucins and synthetic polymers.

Chapter 6
Polymeric Gene Delivery Vectors
Han Chang Kang, Minhyung Lee and You Han Bae

Gene therapy is a bioengineering technology where genetic materials are delivered into the body for disease treatment. It can be achieved by the efficient delivery of genes to the tissues or cells of interest. Effective gene delivery using delivery vectors can prevent the loss of DNA during the delivery process. In general, viral gene carriers show higher gene transfection efficiency than non-viral vectors. However, safety concerns over the use of viral vectors have stimulated remarkable interest in developing alternative carriers using polymers, because polymeric carriers have low cytotoxicity and no immunogenicity. Interest in polymeric carriers has prompted several strategies for enhancing transfection and biocompatibility of the gene delivery vehicles. These strategies aim to solve current problems related to extracellular and intracellular transfection barriers: the bloodstream, the cellular membrane, endosomes, and the nuclear membrane. In this review, we introduce current issues in gene therapy, and some solutions in terms of transfection and biocompatibility. In addition, we discuss future gene technology and propose some requirements for the next-generation of polymeric gene delivery carriers. Effective polymeric gene carriers may have the potential to extend and improve patients' lives.

Section B. Therapeutic Micro- and Nanodevices

Chapter 7
Biohybrid Materials for Therapeutic Devices
Elizabeth A. Moschou, Leonidas G. Bachas and Sylvia Daunert

One of the key issues concerning the development of successful autonomous therapeutic devices relates to the need of addressing individualized therapy. The term individualized therapy or responsive drug delivery is defined as the response to metabolic changes in the body of each individual patient by delivering the appropriate amount of drug at the appropriate time. To that end, "smart" biohybrid materials have been developed that integrate the functions of analyte sensing and responsive actuation for drug release toward the development of closed-loop drug delivery systems. These "smart" biohybrid materials are based on a variety of natural biological recognition elements, such as enzymes, lectins, binding proteins, peptides and antibodies. Different strategies have been employed thus far to create a link in the communication between their sensing and actuating components. These strategies mostly include the translation of the pH responsive signal of the sensor into a mechanical action by the pH-triggered actuator or the transformation of the change in the binding event of the sensor into chemomechanical work by the actuator. In this chapter, we overview the progress in the development of smart biohybrid materials that are suitable for applications in responsive drug delivery and in the fabrication of therapeutic devices.

Chapter 8
Biomimetic Systems: A Synergy of Scientific and Engineering Approaches
Mark E. Byrne and Siddarth Venkatesh

As medicine enters a new era, that of molecular medical therapy, the authors focus on the principles that have led us to this juncture, and their implications for the future. Intense scrutiny at the cellular level has led to the cognition of signal cascades, binding mechanisms, innate and adaptive immunity, and responses to extracellular stimuli. As a result, there has been an explosion in biodesign, utilizing these principles to engineer biomimetic structures and devices, which follow the fundamental laws of molecular recognition. Here, we focus on the concept of "biomimetic systems" and examples are provided which demonstrate that these systems are now part of current streams of vibrant research, providing solutions to biomedical issues. This chapter is presented to range the spectrum of length scales beginning with the gene up to the microscale, first concentrating on biological recognition and mechanisms and then transitioning into current biomimetic principles with particular emphasis being laid on the identification of therapeutic strategies. Biomimetic systems can be designed by extraction of the biological principles that govern them, which is possible only by a synergy of the basic and applied sciences.

Chapter 9
Nanostructured Scaffolds for Tissue Engineering
Danielle S.W. Benoit and Kristi S. Anseth

Biomaterial scaffolds play a critical role in guiding the regeneration of functional tissues by serving as a temporary extracellular matrix. A major opportunity in the advancement of the tissue engineering field is understanding how the scaffold's nanoscale chemistry and architecture influence cell function and tissue regeneration. Such knowledge could facilitate the development of highly controlled chemical, biological, and physical properties. This chapter reviews current strategies to create nanofiber scaffolds, as well as approaches to control the nanoscale topography and biological hierarchy. Nanostructured scaffolds for uses in tissue engineering can be formed through methods such as electrospinning, self-assembly, and phase separation, all of which have been utilized as three-dimensional cell culture environments toward the end of tissue engineering. In addition, nanomodifications to bulk properties include topographical cues such as roughness, nonspecific material modifications such as charged molecules, proteins, peptides, and others, in order to affect cell function and tissue evolution. As new approaches emerge that exploit nanotechnology to synthesize elegantly tailored biomaterial scaffolds, scales that are important to tissue engineering will become clear. These revelations will have important implications in the future of biomaterial design for tissue regeneration.

Section C. Nanostructured Therapeutic Materials

Chapter 10
Hydrogel Nanocomposites for Intelligent Therapeutics
Reynolds A. Frimpong and J. Zach Hilt

Although polymer composites have been an area of research for many years, it is only recently that nanocomposites have garnered much attention due to the unique properties that the nanoscale structures can provide. For example, nanomaterials have been shown to exhibit unique mechanical (e.g., carbon nanotubes), optical (e.g., gold colloids), magnetic (e.g., superparamagnetic particles) properties, and these properties are being exploited in composite systems. By combining hydrogels with nanoscale systems, it is possible to create novel biomaterials with enhanced properties. In particular, environmentally responsive hydrogels that have swelling states dependent on external stimuli (e.g., pH and temperature) can be integrated with various nanomaterials to create intelligent composite system. Recently, hydrogel nanocomposites have been demonstrated as remote controlled actuators, which have great potential as remote controlled drug delivery systems. In this chapter, we highlight the recent activity in hydrogel nanocomposites, while focusing on the potential of these systems as intelligent therapeutics.

Chapter 11
Nanotechnology for Treating Bone Disorders
Ganesan Balasundaram, Grace Park and Thomas J. Webster

Nanotechnology has already begun to revolutionize many traditional science and engineering fields. However, the use of nanotechnology in biological applications still remains largely uninvestigated despite some promising preliminary evidence. This chapter will provide specific applications of nanotechnology towards treating bone ailments (both from a drug delivery and implant perspective). First, fundamentals of bone biology and diseases (such as osteoporosis and bone cancer) will be covered to orient the reader. Then, applications of nanomaterials in treating these diseases will be emphasized. Applications involve the use of nanoparticles of ceramics, polymers, metals, and composites thereof to regenerate bone. In doing so, this chapter provides strong evidence for the continued study of nanotechnology in orthopedic applications.

Chapter 12
Nanotechnology and Cancer Therapy
James O. Blanchette and Nicholas A. Peppas

The following chapter addresses the role of nanotechnology in new treatments for cancer therapy with a focus on environmentally-sensitive hydrogel nanospheres for oral delivery of chemotherapeutics. Cancer as a disease is discussed from carcinogenesis to tumor development as are current chemotherapeutic treatments options. The advantages of oral administration are presented and the potential role of complexation hydrogels as an oral chemotherapeutic carrier is presented.

Section D. Nanoparticulate Systems in Intelligent Therapy

Chapter 13
Star Polymers and Dendrimers in Nanotechnology and Drug Delivery
Stephanie Seidlits and Nicholas A. Peppas

In recent years, star polymers and dendrimers have attracted immense interest for application in many fields due to their unique regularly branched, and sometimes monodisperse structure and the presence of several modifiable functional groups on their surface. Capable of carrying small molecules in a protective microenvironment either peripherally or in the interior, star polymers and dendrimers are used for drug and gene delivery, for chromophore encapsulation for imaging applications, as modifiers of surface interactions with proteins or cells and as cellularly-active structures in microfabricated devices. In drug delivery, highly reproducible delivery profiles can be achieved due to the controlled architecture and low polydispersity of dendrimers. Furthermore, the excess of modifiable functional groups on the surface can be used to attach soluble or targeting moieties, or a wide variety of other desirable molecules. The size of these systems and the often globular structure of dendrimers have allowed creation of synthetic proteins and in particular enzymes, since the interior of higher generation dendrimers resembles enzymatic active sites. Very recently, the ability of immobilized star polymers and dendrimers as scaffolds for anchorage-dependent cells has been reported.

Chapter 14
Ionic Nanoparticulate Systems for Drug Delivery
Petr Bures and Nicholas A. Peppas

Nanoparticle-based systems are preferred for delivery applications because of their uniform drug distribution, ability to interact with drug absorption sites due to their high surface to volume ratio, and efficacy of drug absorption. Such nanoparticulate systems are also rendered efficient by surface modification with selective functional groups. Of particular interest are nanoparticulate structures based on ionic homo- and copolymers because of their ability to respond to physiological and abnormal conditions. These swelling/deswelling changes can be used as transmitting elements in intelligent systems to provide significant acceleration/deceleration of the associated drug delivery. Here, we analyze the structural principles of such systems.

Chapter 15
Nanospheres of Intelligent Networks for Biomedical and Drug Delivery Applications
Nicholas A. Peppas and Daphne N. Robinson

Nanotechnology has entered the field of drug delivery in a variety of ways including the development of targeted and intelligent nanoparticulate systems. Most of these systems are based on hydrophilic, physiologically-responsive nanoparticles. We review here methods of preparation of such systems as well as their characterization methods.

Chapter 16
Shell Crosslinked Nanoparticles: A Progress Report of their Design for Drug Delivery
Yali Li, Guorong Sun, Jinqi Xu and Karen L. Wooley

This review emphasizes advances that have been made primarily over the past five years toward the development of SCKs as sophisticated hosts for the controlled uptake and release of guests, with special attention upon their potential for application in drug delivery. The formation of SCKs based upon amphiphilic block copolymers is introduced, and is followed by detailed discussions of the subsequent internal and/or external functionalization of SCKs through varying methodologies. Excavation of SCK core domains to produce nanocages, and the implications of various morphologies assembled from similar block copolymers, are described as future directions to increase the levels of complexity in composition, structure and function.

Chapter 17
Nanoparticulate Structures in Diabetes Treatment
Nicholas A. Peppas and C. Donini

Since its initial administration to humans, insulin has been the cornerstone of type I diabetes. Conventional administration of exogenous insulin is a replacement therapy which mimics, as close as possible, secretion of insulin by healthy pancreas. However, this route of insulin administration has a risk of factors, such as hyperinsulinemia and localized deposition of insulin that lead to local hypertrophy and fat deposits at injection sites. Among all the routes for the administration of insulin, the oral route is the most convenient. In addition, because orally administered insulin undergoes a first hepatic pass, it will produce a similar effect as pancreas-secreted insulin by inhibiting the hepatic gluconeogenesis and suppressing the hepatic glucose production. Unfortunately, chemical instability, susceptibility to proteolysis, and inability to transverse biological barriers due to their large size, reduce the bioavailability of the peptides and proteins such as insulin. Transport of therapeutic agents or proteins across the intestinal gut wall may take place via various pathways. The transport of the molecules can take place through the cell membrane of the enterocytes (transcellular transport) or via the tight junctions between the cells (paracellular transport). The transcellular pathway can be further classified as carrier-mediated, passive diffusion and receptor-mediated endocytosis. Various methods have been explored to improve the oral bioavailability of insulin. Nanoparticulate gels have been designed to protect the insulin in the harsh, acidic environment of the stomach before releasing the bioactive agent in the small intestine.

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