Biomedical Properties 61 Introduction

Recently, much interest has been generated by colloidal drug delivery systems such as nanocapsules because of the possibilities for controlled release, increased drug efficacy, and reduced toxicity after parenteral administration. Nano-capsules can be formulated into a variety of useful dosage forms including oral liquid suspensions, lotions, creams, ointments, powders, capsules, tablets, and injections. Nano-encapsulation has been applied to solve problems in the development of pharmaceutical dosage forms as well as in cosmetics for several purposes. These include conversion of liquids to solids, separation of incompatible components in a dosage form, taste masking, reduction of gastrointestinal irritation, protection of the core materials against atmospheric deterioration, enhancement of stability, and controlled release of active ingredients.

Nanoparticles used in drug delivery are solid, colloidal particles consisting of macromolecular substances that vary in size from 10 to 1000 nm. The drug is dissolved, entrapped, adsorbed, attached, or encapsulated in the macromolecular materials. Nanoparticles, also called nanopellets or nano-capsules, can have a shell-like wall, called a nanosphere, or a polymer lattice. However, it is often difficult to determine whether nanoparticles have a shell-like wall or a continuous matrix. Nanocapsules present a liquid core surrounded by a polymeric shell, while so-called nanospheres consist of a dense polymeric matrix, in which the drug can be dispersed. Compared to other colloidal carriers, polymeric nanocapsules present a higher stability when in contact with biological fluids, and their polymeric nature allows one to obtain the desired controlled and sustained drug release. Nanocapsules represent drug delivery systems suitable for most of the administration routes, even if rapid recognition by the immune system limits their use as injectable carriers.

Different approaches to preparing biodegradable nano-capsules, consisting of biodegradable polymers, have been described, as well as the methods for preparing surface-modified sterically stabilized particles [643-654]. Nano-capsules can be prepared either from preformed polymers, such as polyesters (i.e., polylactic acid), or from a monomer during its polymerization, as in the case of alkylcyanoacry-lates. Most of the methods based on the polymerization of monomers (i.e., alkylcyanoacrylates) consist of adding a monomer into the dispersed phase of an emulsion or an inverse microemulsion or dissolving it in a nonsolvent of the polymer. Starting from preformed polymers, nanoparticles are formed by the precipitation of synthetic polymers or by denaturation or gelification of natural macromolecules. Two main approaches have been proposed for the preparation of nanocapsules of synthetic polymers. The first one is based on the emulsification of the water-immiscibile organic solution of the polymer by an aqueous phase containing the surfactant, followed by solvent evaporation. The second approach is based on the precipitation of a polymer after addition of a nonsolvent of the polymer. Concerning nanocapsules formed of natural macromolecules, the nano-capsules can be obtained by thermal denaturation of proteins (such as albumin) or by a gelification process, as in the case of alginates. The attachment of certain hydrophilic polymers on the surface of the carriers reduces the uptake by the immune system, therefore prolonging the blood half-life of the nanospheres and thus allowing their intravenous administration. Characterization of sterically stabilized nanospheres allows the establishment of parameters that govern the in vivo behavior. In particular particle size and surface properties, such as chemical composition, charge, and hydrophobic, etc., are directly correlated with the nanoparticle fate. A drug or any biologically active compound can be dissolved, entrapped, or encapsulated into the nanocapsules or simply adsorbed onto its surface. It has been well known that polymeric particulate nanocarriers, able to deliver drugs or other compounds to specific sites of action for a prolonged time, represent a potential therapeutic approach for several diseases [643-654].

The pioneers in this field discovered that the nano-capsules could be used as new type of lysosomotropic carrier [6, 7], as new dosage forms [2, 655], or for controlled release of drugs [1]. Early work also focused on the preparation and characterization of hemolysate-loaded poly(N-a, N-e-L-lysinediylterephthaloyl) [3], gelatin [4], and poly-isobutylcyanoacrylate nanocapsules [8-10, 656]. It was found that the polyalkylcyanoacrylate nanocapsules increased the intestinal absorption of a lipophilic drug [5, 11]. Since the mid 1980s, many different active molecules, such as anti-inflammatory agents, anticancer drugs, immunostimulating compounds, anti-infectious agents, antiglaucomatous drugs, and even peptides have been encapsulated and as a result their pharmacological effect has been improved or their secondary effects reduced compared with free drugs after administration by oral, parenteral, or ocular routes. The nanocapsules have been found also to be suitable as a biodegradable drug carrier for the administration and controlled release of drugs, like insulin, indomethacin, calci-tonin, doxorubicine, gangliosides, oligonucleotides, etc.

One of the major obstacles to the targeted delivery of colloidal carriers (nanocapsules) is the body's own defense mechanism in capturing foreign particles by the reticu-loendothelial system. Following intravenous administration, practically all nanometer size particles are captured by the reticuloendothelial system (mainly the liver). The design of "macromolecular homing devices" seems to disguise nonoparticles from the reticuloendothelial system, which is of potential interest for the targeted delivery of nanocapsu-lar carriers [657]. The idea is based on a graft copolymer model embodying a link site for attachment (binding) to the carrier, a floating pad for maintaining the particles afloat in the bloodstream, an affinity ligand for site-specific delivery, and a structural tune for balancing the overall structure of the homing device.

Although the oral route is preferred route for drug delivery, numerous drugs remain poorly available when administered by the oral route. In order to circumvent this problem, some drugs are associated with colloidal polymeric particle systems. Orally administered nano and microparti-cles can follow at least three different pathways: (i) capture by gut-associated lymphoid tissue; (ii) mucoadhesion; and (iii) direct fecal elimination. Mucoadhesion of colloidal par-ticulate systems in the gastrointestinal tract was emphasized [658]. On the one hand, in vitro adsorption and desorption studies showed that particles could be captured to a considerable extent by the mucous gel layer lining the gastrointestinal tract through a mucoadhesion mechanism. On the other hand, the in vivo behavior of the particle in the intestinal limen was accurately investigated by means of radiolabelled particles.

Recently a major breakthrough has been achieved in the formulation of polymeric artificial nanocapsules, which can be made in a reproducible manner having a specific size and shape and in reasonable quantities. This opens a new field of intelligent material with possible sophisticated applications. To achieve the goal to bring this research field from the level of basic science to possible application, the necessary techniques have been developed and expertise from different fields and laboratories has been combined [659674]. The first step to allow specific applications is to func-tionalize the nanocapsules by coating the surface with active sites or to inserting them into the wall. One direction is to cover them with lipid membranes providing an artificial cell. These techniques have been combined with recent developments in molecular biology. The advantage of natural proteins already optimized by nature has been taken for specific tasks, which could be modified by genetic engineering to adopt them for purposes (e.g., such nanospheres can harvest specific substrates or release at a specific site encapsulated materials). A second aspect is that these nanocapsules provide a new class of surfaces which allows study of molecular interactions of surface attached proteins. These studies have permited new types of measurements and thus provided new insights into protein-protein or protein-ligand interaction. Artificial cells for pharmaceutical and therapeutic applications have been expanded up to the higher range of macrocapsules and down to the nanometer range of nano-capsules and even to the macromolecular range of cross-linked hemoglobin as a blood substitute. Artificial cells have been being prepared by bioencapsulation in the laboratory for medical and biotechnological applications. Advances in molecular biology have resulted in the availability of non-pathogenic genetically engineered microorganisms that can effectively use uremic metabolites for cell growth. The three generations of blood substitutes have been developed based on an original idea of a completely artificial red blood cell.

In Section 6.2, we will focus on the advances in the area of artificial cell and red blood cell substitutes, most of which are based on Chang's concept [675-679]. In Section 6.3, various types of the drug delivery and controlled release are reviewed.

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