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Advanced Drug Delivery Reviews (v.64, #)

Editorial Board (pp. ii).

An introduction to the most cited papers in the history of Advanced Drug Delivery Reviews (1987–2012) by Nicholas A. Peppas (pp. 1-3).

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings by Christopher A. Lipinski; Franco Lombardo; Beryl W. Dominy; Paul J. Feeney (pp. 4-17).

Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting ‘the rule of 5’ predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP>4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.

Keywords: Rule of 5; Computational alert; Poor absorption or permeation; MWT; MLogP; H-Bond donors and acceptors; Turbidimetric solubility; Thermodynamic solubility; Solubility calculation

Hydrogels for biomedical applications by Allan S. Hoffman (pp. 18-23).

This article reviews the composition and synthesis of hydrogels, the character of their absorbed water, and permeation of solutes within their swollen matrices. The most important properties of hydrogels relevant to their biomedical applications are also identified, especially for use of hydrogels as drug and cell carriers, and as tissue engineering matrices.

Keywords: Abbreviations; CD; cyclodextrin; DX; p; -dioxanone; EG; ethylene glycol; EGDMA; ethylene glycol dimethacrylate; HA; hyaluronic acid; HEMA; hydroxyethyl methacrylate; IPN; inter-penetrating network; MBAAm; methylene-bis-acrylamide; P(…); poly(…); PAAc; poly(acrylic acid); PAAm; polyacrylamide; PAGE; polyacrylamide gel electrophoresis; PAN; polyacrylonitrile; PBO; poly(butylene oxide); PCL; polycaprolactone; PEG; poly(ethylene glycol); PEI; poly(ethylene imine); PEO; poly(ethylene oxide); PEMA; poly(ethyl methacrylate); PF; propylene fumarate; PGEMA; poly(glucosylethyl methacrylate); PHB; poly(hydroxy butyrate); PHEMA; poly(hydroxyethyl methacrylate); PHPMA; poly(hydroxypropyl methacrylamide); PLA; poly(lactic acid); PLGA; poly(lactic-co-glycolic acid); PMMA; poly(methyl methacrylate); PNIPAAm; poly(; N; -isopropyl acrylamide); PNVP; poly(; N; -vinyl pyrrolidone); PPO; poly(propylene oxide); PVA; poly(vinyl alcohol); PVAc; poly(vinyl acetate); PVamine; poly(vinyl amine)Hydrogels; Drug delivery; Water; Pores; Tissue engineering

Nanoparticles in cancer therapy and diagnosis by Irène Brigger; Catherine Dubernet; Patrick Couvreur (pp. 24-36).

Numerous investigations have shown that both tissue and cell distribution profiles of anticancer drugs can be controlled by their entrapment in submicronic colloidal systems (nanoparticles). The rationale behind this approach is to increase antitumor efficacy, while reducing systemic side-effects. This review provides an update of tumor targeting with conventional or long-circulating nanoparticles. The in vivo fate of these systems, after intravascular or tumoral administration, is discussed, as well as the mechanism involved in tumor regression. Nanoparticles are also of benefit for the selective delivery of oligonucleotides to tumor cells. Moreover, certain types of nanoparticles showed some interesting capacity to reverse MDR resistance, which is a major problem in chemotherapy. The first experiments, aiming to decorate nanoparticles with molecular ligand for ‘active’ targeting of cancerous cells, are also discussed here. The last part of this review focus on the application of nanoparticles in imaging for cancer diagnosis.

Keywords: Nanoparticles; Nanospheres; Nanocapsules; Conventional or long-circulating carriers; Passive or active tumor targeting; EPR effect; Multidrug resistance (MDR); Oligonucleotide delivery; Tumor imaging

Block copolymer micelles for drug delivery: Design, characterization and biological significance by Kazunori Kataoka; Atsushi Harada; Yukio Nagasaki (pp. 37-48).

Recently, colloidal carrier systems have been receiving much attention in the field of drug targeting because of their high loading capacity for drugs as well as their unique disposition characteristics in the body. This paper highlights the utility of polymeric micelles formed through the multimolecular assembly of block copolymers as novel core–shell typed colloidal carriers for drug and gene targeting. The process of micellization in aqueous milieu is described in detail based on differences in the driving force of core segregation, including hydrophobic interaction, electrostatic interaction, metal complexation, and hydrogen bonding of constituent block copolymers. The segregated core embedded in the hydrophilic palisade is shown to function as a reservoir for genes, enzymes, and a variety of drugs with diverse characteristics. Functionalization of the outer surface of the polymeric micelle to modify its physicochemical and biological properties is reviewed from the standpoint of designing micellar carrier systems for receptor-mediated drug delivery. Further, the distribution of polymeric micelles is described to demonstrate their long-circulating characteristics and significant tumor accumulation, emphasizing their promising utility in tumor-targeting therapy. As an important perspective on carrier systems based on polymeric micelles, their feasibility as non-viral gene vectors is also summarized in this review article.

Keywords: Polymeric micelle; Drug targeting; Gene vector; Block copolymer; Polyion complex; Tumor targeting; Poly(ethylene glycol); Poly(amino acid); Polylactide; Poly(ethyleneimine); Poly(dimethylaminoethylmethacrylate)

Environment-sensitive hydrogels for drug delivery by Yong Qiu; Kinam Park (pp. 49-60).

Environmentally sensitive hydrogels have enormous potential in various applications. Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive and/or temperature-sensitive hydrogels can be used for site-specific controlled drug delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. Light-sensitive, pressure-responsive and electro-sensitive hydrogels also have the potential to be used in drug delivery and bioseparation. While the concepts of these environment-sensitive hydrogels are sound, the practical applications require significant improvements in the hydrogel properties. The most significant weakness of all these external stimuli-sensitive hydrogels is that their response time is too slow. Thus, fast-acting hydrogels are necessary, and the easiest way of achieving that goal is to make thinner and smaller hydrogels. This usually makes the hydrogel systems too fragile and they do not have mechanical strength necessary in many applications. Environmentally sensitive hydrogels for drug delivery applications also require biocompatibility. Synthesis of new polymers and crosslinkers with more biocompatibility and better biodegradability would be essential for successful applications. Development of environmentally sensitive hydrogels with such properties is a formidable challenge. If the achievements of the past can be extrapolated into the future, however, it is highly likely that responsive hydrogels with a wide array of desirable properties can be made.

Keywords: Abbreviations; IPN; interpenetrating polymer network; LCST; lower critical solution temperature; PAAm; poly(acrylamide); BMA; butyl methacrylate; PNIAAm; poly(; N; -isopropylacrylamide); PDEAAm; poly(; N,N; -diethylacrylamide); PEG; poly(ethylene glycol); PEO; poly(ethylene oxide); PPO; poly(propylene oxide); poly(acrylic acid); poly(acrylic acid); PMA; poly(methacrylic acid); PLA; poly(; l; -lactic acid); PDEAEM; poly(; N,N; ′-diethylaminoethyl methacrylate); DMAEM; N,N; ′-dimethylaminoethyl methacrylate; PVD; poly(vinylacetaldiethylaminoacetate); PVA; poly(vinylalcohol); Con A; concanavalin AEnvironment-sensitive hydrogels; Drug delivery; Stimuli-sensitive hydrogels; Smart hydrogels

Biodegradable nanoparticles for drug and gene delivery to cells and tissue by Jayanth Panyam; Vinod Labhasetwar (pp. 61-71).

Biodegradable nanoparticles formulated from poly (d,l-lactide- co-glycolide) (PLGA) have been extensively investigated for sustained and targeted/localized delivery of different agents including plasmid DNA, proteins and peptides and low molecular weight compounds. Research about the mechanism of intracellular uptake of nanoparticles, their trafficking and sorting into different intracellular compartments, and the mechanism of enhanced therapeutic efficacy of nanoparticle-encapsulated agent at cellular level is more recent and is the primary focus of the review. Recent studies in our laboratory demonstrated rapid escape of PLGA nanoparticles from the endo-lysosomal compartment into cytosol following their uptake. Based on the above mechanism, various potential applications of nanoparticles for delivery of therapeutic agents to the cells and tissue are discussed.

Keywords: Nanotechnology; Sustained release; Biodegradable polymers; Protein delivery; Gene therapy

Biodegradation and biocompatibility of PLA and PLGA microspheres by James M. Anderson; Matthew S. Shive (pp. 72-82).

A fundamental understanding of the in vivo biodegradation phenomenon as well as an appreciation of cellular and tissue responses which determine the biocompatibility of biodegradable PLA and PLGA microspheres are important components in the design and development of biodegradable microspheres containing bioactive agents for therapeutic application. This chapter is a critical review of biodegradation, biocompatibility and tissue/material interactions, and selected examples of PLA and PLGA microsphere controlled release systems. Emphasis is placed on polymer and microsphere characteristics which modulate the degradation behaviour and the foreign body reaction to the microspheres. Selected examples presented in the chapter include microspheres incorporating bone morphogenetic protein (BMP) and leuprorelin acetate as well as applications or interactions with the eye, central nervous system, and lymphoid tissue and their relevance to vaccine development. A subsection on nanoparticles and nanospheres is also included. The chapter emphasizes biodegradation and biocompatibility; bioactive agent release characteristics of various systems have not been included except where significant biodegradation and biocompatibility information have been provided.

Keywords: Inflammatory response; Foreign body response; Macrophages; Foreign body giant cells; Hydrolytic degradation; Therapeutic agent release; In vivo tissue response

Solid lipid nanoparticles by Wolfgang Mehnert; Karsten Mäder (pp. 83-101).

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.

Keywords: Abbreviations; CFC; critical flocculation temperature; HPH; high pressure homogenization; PCS; photon correlation spectroscopy; RT; room temperature; SLN; solid lipid nanoparticles; TEM; transmission electron microscopyColloidal drug carriers; Stability; Drug incorporation; Coexistence of different colloidal species; Administration routes; SLN quality and structure; Production parameters

Dendrimers in biomedical applications—reflections on the field by Sönke Svenson; Donald A. Tomalia (pp. 102-115).

The formation of particulate systems with well-defined sizes and shapes is of eminent interest in certain medical applications such as drug delivery, gene transfection, and imaging. The high level of control possible over the architectural design of dendrimers; their size, shape, branching length/density, and their surface functionality, clearly distinguishes these structures as unique and optimum carriers in those applications. The bioactive agents may be encapsulated into the interior of the dendrimers or chemically attached/physically adsorbed onto the dendrimer surface, with the option of tailoring the carrier to the specific needs of the active material and its therapeutic applications. In this regard, the high density of exo-presented surface groups allows attachment of targeting groups or functionality that may modify the solution behavior or toxicity of dendrimers. Quite remarkably, modified dendrimers have been shown to act as nano-drugs against tumors, bacteria, and viruses. Recent successes in simplifying and optimizing the synthesis of dendrimers such as the ‘lego’ and ‘click’ approaches, provide a large variety of structures while at the same time reducing the cost of their production. The reflections on biomedical applications of dendrimers given in this review clearly demonstrate the potential of this new fourth major class of polymer architecture and indeed substantiate the high hopes for the future of dendrimers.

Keywords: Dendrimers; PAMAM; Dendrimer synthesis; Drug delivery; Gene transfection; Imaging agents; Encapsulation; Drug release; Biocompatibility; MRI; Cytotoxicity; Artificial proteins; Targeting; Folate receptor

Chemistry for peptide and protein PEGylation by M.J. Roberts; M.D. Bentley; J.M. Harris (pp. 116-127).

Poly(ethylene glycol) (PEG) is a highly investigated polymer for the covalent modification of biological macromolecules and surfaces for many pharmaceutical and biotechnical applications. In the modification of biological macromolecules, peptides and proteins are of extreme importance. Reasons for PEGylation (i.e. the covalent attachment of PEG) of peptides and proteins are numerous and include shielding of antigenic and immunogenic epitopes, shielding receptor-mediated uptake by the reticuloendothelial system (RES), and preventing recognition and degradation by proteolytic enzymes. PEG conjugation also increases the apparent size of the polypeptide, thus reducing the renal filtration and altering biodistribution. An important aspect of PEGylation is the incorporation of various PEG functional groups that are used to attach the PEG to the peptide or protein. In this paper, we review PEG chemistry and methods of preparation with a particular focus on new (second-generation) PEG derivatives, reversible conjugation and PEG structures.

Keywords: PEGylation; PEG-protein; PEG conjugation; PEG chemistry

Penetration enhancers by Adrian C. Williams; Brian W. Barry (pp. 128-137).

One long-standing approach for improving transdermal drug delivery uses penetration enhancers (also called sorption promoters or accelerants) which penetrate into skin to reversibly decrease the barrier resistance. Numerous compounds have been evaluated for penetration enhancing activity, including sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common excipient in topically applied dosage forms), surfactants (also common in dosage forms) and terpenes. Many potential sites and modes of action have been identified for skin penetration enhancers; the intercellular lipid matrix in which the accelerants may disrupt the packing motif, the intracellular keratin domains or through increasing drug partitioning into the tissue by acting as a solvent for the permeant within the membrane. Further potential mechanisms of action, for example with the enhancers acting on desmosomal connections between corneocytes or altering metabolic activity within the skin, or exerting an influence on the thermodynamic activity/solubility of the drug in its vehicle are also feasible, and are also considered in this review.

Keywords: Penetration enhancers; Accelerants; Skin; Lipids; Azone; Dimethylsulphoxide; Terpenes

Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview by Alfred H. Schinkel; Johan W. Jonker (pp. 138-153).

Active drug efflux transporters of the ATP binding cassette (ABC)-containing family of proteins have a major impact on the pharmacological behavior of most of the drugs in use today. Pharmacological properties affected by ABC transporters include the oral bioavailability, hepatobiliary, direct intestinal, and urinary excretion of drugs and drug-metabolites and -conjugates. Moreover, the penetration of drugs into a range of important pharmacological sanctuaries, such as brain, testis, and fetus, and the penetration into specific cell- and tissue compartments can be extensively limited by ABC transporters. These interactions with ABC transporters determine to a large extent the clinical usefulness, side effects and toxicity risks of drugs. Many other xenotoxins, (pre-)carcinogens and endogenous compounds are also influenced by the ABC transporters, with corresponding consequences for the well-being of the individual. We aim to provide an overview of properties of the mammalian ABC transporters known to mediate significant transport of clinically relevant drugs.

Keywords: Drug efflux transporter; ATP binding cassette; Pharmacokinetics; Multidrug resistance; Blood–brain barrier; Sanctuary sites; Oral bioavailability; Placenta; Drug excretion; Toxicology

Thermosensitive sol–gel reversible hydrogels by Byeongmoon Jeong; Sung Wan Kim; You Han Bae (pp. 154-162).

Aqueous polymer solutions that are transformed into gels by changes in environmental conditions, such as temperature and pH, thus resulting in in situ hydrogel formation, have recently attracted the attention of many investigators for scientific interest and for practical biomedical or pharmaceutical applications. When the hydrogel is formed under physiological conditions and maintains its integrity for a desired period of time, the process may provide various advantages over conventional hydrogels. Because of the simplicity of pharmaceutical formulation by solution mixing, biocompatibility with biological systems, and convenient administration, the pharmaceutical and biomedical uses of the water-based sol–gel transition include solubilization of low-molecular-weight hydrophobic drugs, controlled release, labile biomacromolecule delivery, such as proteins and genes, cell immobilization, and tissue engineering. When the formed gel is proven to be biocompatible and biodegradable, producing non-toxic degradation products, it will provide further benefits for in vivo applications where degradation is desired. It is timely to summarize the polymeric systems that undergo sol–gel transitions, particularly due to temperature, with emphasis on the underlying transition mechanisms and potential delivery aspects. This review stresses the polymeric systems of natural or modified natural polymers, N-isopropylacrylamide copolymers, poly(ethylene oxide)/poly(propylene oxide) block copolymers, and poly(ethylene glycol)/poly(d,l-lactide-co-glycolide) block copolymers.

Keywords: Aqueous polymer solution; Sol–gel transition; In situ hydrogel formation; Temperature; Drug delivery

Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC) by J. Siepmann; N.A. Peppas (pp. 163-174).

The objective of this article is to review the spectrum of mathematical models that have been developed to describe drug release from hydroxypropyl methylcellulose (HPMC)-based pharmaceutical devices. The major advantages of these models are: (i) the elucidation of the underlying mass transport mechanisms; and (ii) the possibility to predict the effect of the device design parameters (e.g., shape, size and composition of HPMC-based matrix tablets) on the resulting drug release rate, thus facilitating the development of new pharmaceutical products. Simple empirical or semi-empirical models such as the classical Higuchi equation and the so-called power law, as well as more complex mechanistic theories that consider diffusion, swelling and dissolution processes simultaneously are presented, and their advantages and limitations are discussed. Various examples of practical applications to experimental drug release data are given. The choice of the appropriate mathematical model when developing new pharmaceutical products or elucidating drug release mechanisms strongly depends on the desired or required predictive ability and accuracy of the model. In many cases, the use of a simple empirical or semi-empirical model is fully sufficient. However, when reliable, detailed information are required, more complex, mechanistic theories must be applied. The present article is a comprehensive review of the current state of the art of mathematical modeling drug release from HPMC-based delivery systems and discusses the crucial points of the most important theories.

Keywords: Controlled drug delivery; HPMC; Hydrophilic matrices; Hydroxypropyl methylcellulose; Modeling; Release mechanism

Microemulsion-based media as novel drug delivery systems by M. Jayne Lawrence; Gareth D. Rees (pp. 175-193).

Microemulsions are clear, stable, isotropic mixtures of oil, water and surfactant, frequently in combination with a cosurfactant. These systems are currently of interest to the pharmaceutical scientist because of their considerable potential to act as drug delivery vehicles by incorporating a wide range of drug molecules. In order to appreciate the potential of microemulsions as delivery vehicles, this review gives an overview of the formation and phase behaviour and characterization of microemulsions. The use of microemulsions and closely related microemulsion-based systems as drug delivery vehicles is reviewed, with particular emphasis being placed on recent developments and future directions.

Protein release from alginate matrices by Wayne R. Gombotz; Siow Fong Wee (pp. 194-205).

There are a variety of both natural and synthetic polymeric systems that have been investigated for the controlled release of proteins. Many of the procedures employed to incorporate proteins into a polymeric matrix can be harsh and often cause denaturation of the active agent. Alginate, a naturally occurring biopolymer extracted from brown algae (kelp), has several unique properties that have enabled it to be used as a matrix for the entrapment and/or delivery of a variety of biological agents. Alginate polymers are a family of linear unbranched polysaccharides which contain varying amounts of 1,4′-linked β-d-mannuronic acid and α-l-guluronic acid residues. The residues may vary widely in composition and sequence and are arranged in a pattern of blocks along the chain. Alginate can be ionically crosslinked by the addition of divalent cations in aqueous solution. The relatively mild gelation process has enabled not only proteins, but cells and DNA to be incorporated into alginate matrices with retention of full biological activity. Furthermore, by selection of the type of alginate and coating agent, the pore size, degradation rate, and ultimately release kinetics can be controlled. Gels of different morphologies can be prepared including large block matrices, large beads (>1mm in diameter) and microbeads (<0.2mm in diameter). In situ gelling systems have also been made by the application of alginate to the cornea, or on the surfaces of wounds. Alginate is a bioadhesive polymer which can be advantageous for the site specific delivery to mucosal tissues. All of these properties, in addition to the nonimmunogenicity of alginate, have led to an increased use of this polymer as a protein delivery system. This review will discuss the chemistry of alginate, its gelation mechanisms, and the physical properties of alginate gels. Emphasis will be placed on applications in which biomolecules have been incorporated into and released from alginate systems.

Keywords: Bioadhesion; Biodegradable polymer; Cell encapsulation; Diffusion controlled release; DNA encapsulation; Hydrogel; Mucosal delivery; Natural polymer; Vaccine delivery

Nanoparticle and targeted systems for cancer therapy by Lisa Brannon-Peppas; James O. Blanchette (pp. 206-212).

This review explores recent work directed towards more targeted treatment of cancer, whether through more specific anti-cancer agents or through methods of delivery. These areas include delivery by avoiding the reticuloendothelial system, utilizing the enhanced permeability and retention effect and tumor-specific targeting. Treatment opportunities using antibody-targeted therapies are summarized. The ability to treat cancer by targeting delivery through angiogenesis is also discussed and antiangiogenic drugs in clinical trials are presented. Delivery methods that specifically use nanoparticles are also highlighted, including both degradable and nondegradable polymers.

Keywords: Targeted delivery; Nanoparticles; Cancer therapy; Angiogenesis; Antibodies

Nanoparticulate systems for brain delivery of drugs by Jörg Kreuter (pp. 213-222).

The blood–brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics, antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, especially neuropeptides. One of the possibilities to overcome this barrier is a drug delivery to the brain using nanoparticles. Drugs that have successfully been transported into the brain using this carrier include the hexapeptide dalargin, the dipeptide Kyotorphin, loperamide, tubocurarine, the NMDA receptor antagonist MRZ 2/576, and doxorubicin. The nanoparticles may be especially helpful for the treatment of the disseminated and very aggressive brain tumors. Intravenously injected doxorubicin-loaded polysorbate 80-coated nanoparticles were able to lead to a 40% cure in rats with intracranially transplanted glioblastomas 101/8. The mechanism of the nanoparticle-mediated transport of the drugs across the blood–brain barrier at present is not fully elucidated. The most likely mechanism is endocytosis by the endothelial cells lining the brain blood capillaries. Nanoparticle-mediated drug transport to the brain depends on the overcoating of the particles with polysorbates, especially polysorbate 80. Overcoating with these materials seems to lead to the adsorption of apolipoprotein E from blood plasma onto the nanoparticle surface. The particles then seem to mimic low density lipoprotein (LDL) particles and could interact with the LDL receptor leading to their uptake by the endothelial cells. After this the drug may be released in these cells and diffuse into the brain interior or the particles may be transcytosed. Other processes such as tight junction modulation or P-glycoprotein (Pgp) inhibition also may occur. Moreover, these mechanisms may run in parallel or may be cooperative thus enabling a drug delivery to the brain.

Keywords: Nanoparticles; Blood–brain barrier; Drug delivery to the brain; Brain tumors; Glioblastomas

Novel crosslinking methods to design hydrogels by W.E. Hennink; C.F. van Nostrum (pp. 223-236).

Hydrogels are presently under investigation as matrices for the controlled release of bioactive molecules, in particular pharmaceutical proteins, and for the encapsulation of living cells. For these applications, it is often required that the gels degrade under physiological conditions. This means that the originally three-dimensional structure has to disintegrate preferably in harmless products to ensure a good biocompatibility of the hydrogel. In this overview, different chemical and physical crosslinking methods used for the design of biodegradable hydrogels are summarized and discussed. Chemical crosslinking is a highly versatile method to create hydrogels with good mechanical stability. However, the crosslinking agents used are often toxic compounds, which have been extracted from the gels before they can be applied. Moreover, crosslinking agents can give unwanted reactions with the bioactive substances present in the hydrogel matrix. Such adverse effects are avoided with the use of physically crosslinked gels.

Keywords: Hydrogel; Crosslinking; Drug release; Tissue engineering; Degradation

Block copolymer micelles as long-circulating drug vehicles by Glen S. Kwon; Kazunori Kataoka (pp. 237-245).

The development of block copolymer micelles as long-circulating drug vehicles is described. As well, a recent fundamental study of block copolymer micelles, where much insight into their structures and properties has been realized, is briefly summarized in order to shed light on their properties in vivo. There is emphasis on block copolymer micelles having poly(ethylene oxide) as the hydrophilic block and poly(l-amino acid) as the hydrophobic block, with some discussion on the properties of poly(ethylene oxide). Comparisons are drawn with other drug vehicles and with micelles formed from low molecular weight surfactants. Micelle-forming, block copolymer-drug conjugates are described. Hydrophobic drugs, such as doxorubicin, distribute into block copolymer micelles, and details of several examples are given. Finally, the paper presents studies that evidence the long circulation times of block copolymer micelles. Like long-circulating liposomes, block copolymers that form micelles accumulate passively at solid tumors and thus have great potential for anti-cancer drug delivery.

Keywords: Drug delivery system; AB block copolymer; ABA block copolymer; Poly(ethylene oxide); Poly(; l; -amino); Polymer-drug conjugate; Doxorubicin

PEGylated nanoparticles for biological and pharmaceutical applications by Hidenori Otsuka; Yukio Nagasaki; Kazunori Kataoka (pp. 246-255).

The utility of polymeric micelles formed through the multimolecular assembly of block copolymer was comprehensively described as novel core–shell typed colloidal carriers for drug and gene targeting. Particularly, novel approaches for the formation of functionalized poly(ethylene glycol) (PEG) layers as hydrophilic outer shell were focused to attain receptor-mediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. Surface organization of block copolymer micelles with cross-linking core was also described from a standpoint of the preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Furthermore, the potential utility of multimolecular assembly derived from heterobifunctional PEGs and block copolymers were explored to systematically modify the properties of metal and semiconductor nanostructures by controlling their structure and their surface properties, making them extremely attractive for use in biological and biomedical applications.

Keywords: Poly(ethylene glycol); Block copolymers; Biological and biomedical applications

Genetic contribution to variable human CYP3A-mediated metabolism by Jatinder K. Lamba; Yvonne S. Lin; Erin G. Schuetz; Kenneth E. Thummel (pp. 256-269).

The human CYP3A subfamily plays a dominant role in the metabolic elimination of more drugs than any other biotransformation enzyme. CYP3A enzyme is localized in the liver and small intestine and thus contributes to first-pass and systemic metabolism. CYP3A expression varies as much as 40-fold in liver and small intestine donor tissues. CYP3A-dependent in vivo drug clearance appears to be unimodally distributed which suggests multi-genic or complex gene–environment causes of variability. Interindividual differences in enzyme expression may be due to several factors including: variable homeostatic control mechanisms, disease states that alter homeostasis, up- or down-regulation by environmental stimuli (such as smoking, drug intake, or diet), and genetic mutations. This review summarizes the current understanding and implications of genetic variation in the CYP3A enzymes. Unlike other human P450s (CYP2D6, CYP2C19) there is no evidence of a ‘null’ allele for CYP3A4. More than 30 SNPs (single nucleotide polymorphisms) have been identified in the CYP3A4 gene. Generally, variants in the coding regions of CYP3A4 occur at allele frequencies <5% and appear as heterozygous with the wild-type allele. These coding variants may contribute to but are not likely to be the major cause of inter-individual differences in CYP3A-dependent clearance, because of the low allele frequencies and limited alterations in enzyme expression or catalytic function. The most common variant, CYP3A4*1B, is an A-392G transition in the 5′-flanking region with an allele frequency ranging from 0% (Chinese and Japanese) to 45% (African-Americans). Studies have not linked CYP3A4*1B with alterations in CYP3A substrate metabolism. In contrast, there are several reports about its association with various disease states including prostate cancer, secondary leukemias, and early puberty. Linkage disequilibrium between CYP3A4*1B and another CYP3A allele ( CYP3A5*1) may be the true cause of the clinical phenotype. CYP3A5 is polymorphically expressed in adults with readily detectable expression in about 10–20% in Caucasians, 33% in Japanese and 55% in African-Americans. The primary causal mutation for its polymorphic expression ( CYP3A5*3) confers low CYP3A5 protein expression as a result of improper mRNA splicing and reduced translation of a functional protein. The CYP3A5*3 allele frequency varies from approximately 50% in African-Americans to 90% in Caucasians. Functionally, microsomes from a CYP3A5*3/*3 liver contain very low CYP3A5 protein and display on average reduced catalytic activity towards midazolam. Additional intronic or exonic mutations ( CYP3A5*5, *6, and *7) may alter splicing and result in premature stop codons or exon deletion. Several CYP3A5 coding variants have been described, but occur at relatively low allelic frequencies and their functional significance has not been established. As CYP3A5 is the primary extrahepatic CYP3A isoform, its polymorphic expression may be implicated in disease risk and the metabolism of endogenous steroids or xenobiotics in these tissues (e.g., lung, kidney, prostate, breast, leukocytes). CYP3A7 is considered to be the major fetal liver CYP3A enzyme. Although hepatic CYP3A7 expression appears to be significantly down-regulated after birth, protein and mRNA have been detected in adults. Recently, increased CYP3A7 mRNA expression has been associated with the replacement of a 60-bp segment of the CYP3A7 promoter with a homologous segment in the CYP3A4 promoter ( CYP3A7*1C allele). This mutational swap confers increased gene transcription due to an enhanced interaction between activated PXR:RXRα complex and its cognate response element (ER-6). The genetic basis for polymorphic expression of CYP3A5 and CYP3A7 has now been established. Moreover, the substrate specificity and product regioselectivity of these isoforms can differ from that of CYP3A4, such that the impact of CYP3A5 and CYP3A7 polymorphic expression on drug disposition will be drug dependent. In addition to genetic variation, other factors that may also affect CYP3A expression include: tissue-specific splicing (as reported for prostate CYP3A5), variable control of gene transcription by endogenous molecules (circulating hormones) and exogenous molecules (diet or environment), and genetic variations in proteins that may regulate constitutive and inducible CYP3A expression (nuclear hormone receptors). Thus, the complex regulatory pathways, environmentally susceptible milieu of the CYP3A enzymes, and as yet undetermined genetic haplotypes, may confound evaluation of the effect of individual CYP3A genetic variations on drug disposition, efficacy and safety.

Keywords: Abbreviations; CV; coefficient of variation; CYP; cytochrome P450Cytochrome P450; Pharmacogenetics; Genetic polymorphism; Drug metabolism; Biotransformation; Toxicogenetics

Advanced drug delivery devices via self-assembly of amphiphilic block copolymers by Annette Rösler; Guido W.M. Vandermeulen; Harm-Anton Klok (pp. 270-279).

Amphiphilic block copolymers are well established as building blocks for the preparation of micellar drug carriers. Over the past decade, the effectiveness of such self-assembled drug delivery devices has been demonstrated numerous times. This review will discuss two approaches that can be used to further improve the effectiveness of amphiphilic block copolymer-based drug delivery systems. The first approach involves the chemical modification of the block copolymer building blocks. Several examples will be discussed of amphiphilic block copolymers modified with crosslinkable groups in order to increase the stability of the micellar drug carriers, or of block copolymers containing specific ligands that could ultimately allow targeted drug delivery. The second approach to improve the performance of micellar drug carriers is the addition of auxiliary agents. To illustrate this approach, the feasibility of channel proteins and metal (nano)particles to improve temporal control over the drug release process is discussed.

Keywords: Block copolymer micelle; Nanocapsule; Crosslinking; Targeted drug delivery; Auxiliary agent; Channel Protein; Metal particle

Caco-2 monolayers in experimental and theoretical predictions of drug transport by Per Artursson; Katrin Palm; Kristina Luthman (pp. 280-289).

This review examines the use of Caco-2 monolayers in the prediction of intestinal drug absorption. First, the different routes of drug transport in Caco-2 monolayers are compared with those seen in vivo. Second, the prediction of drug absorption in vivo from transport experiments in cell monolayers is discussed for different classes of drugs. Finally, the use of Caco-2 monolayers as a reference model in physico-chemical and theoretical predictions of drug absorption is discussed. We conclude that Caco-2 monolayers can be used to identify drugs with potential absorption problems, and possibly also to select drugs with optimal passive absorption characteristics from series of pharmacologically active molecules generated in drug discovery programs.

Keywords: Drug transport; Drug absorption; Intestinal epithelium; Caco-2; Cell monolayer; Partition coefficient; Hydrogen bonding potential; Desolvation energy; Molecular surface area; In vitro-in vivo correlation

Long circulating microparticulate drug carriers by S. Stolnik; L. Illum; S.S. Davis (pp. 290-301).

To exert its activity a drug must reach its pharmacological site(s) of action(s) within the body. One of the current approaches to achieve site specific delivery utilises the use of a carrier. This review focuses on the physicochemical and biological properties of polymeric particulate carriers in the nanometre size range surface modified by poly(ethylene oxide) (PEO). Such systems are able to bypass the normal physiological defence processes occurring after the intravenous injection of particulates and, depending on the particle size and PEO layer properties, remain for a prolonged period of time in the systemic circulation, or have a degree of selectivity for sites of deposition within the body.

Keywords: Particulate (colloid) drug delivery system; Poloxamer; Poloxamine; Poly(ethylene oxide); PEG copolymer; Drug targeting; Biodegradable material; Protein adsorption; Biodistribution

Multifunctional nanocarriers by Vladimir P. Torchilin (pp. 302-315).

Currently used pharmaceutical nanocarriers, such as liposomes, micelles, nanoemulsions, polymeric nanoparticles and many others demonstrate a broad variety of useful properties, such as longevity in the blood allowing for their accumulation in pathological areas with compromised vasculature; specific targeting to certain disease sites due to various targeting ligands attached to the surface of the nanocarriers; enhanced intracellular penetration with the help of surface-attahced cell-penetrating molecules; contrast properties due to the carrier loading with various contrast materials allowing for direct carrier visualization in vivo; stimuli-sensitivity allowing for drug release from the carriers under certain physiological conditions, and others. Some of those pharmaceutical carriers have already made their way into clinic, while others are still under preclinical development. What could be seen much more rare, however, are the pharmaceutical nanocarriers combining several from the listed abilities. Long-circulating immunoliposomes capable of prolonged residence in the blood and specific target recognition represent one of few examples of this kind. At the same time, the enginnering of multifunctional pharmaceutical nanocarriers combinig several useful preoperties in one particle can significantly enhance the efficacy of many therapeutic and diagnostic protocols. This paper considers current status and possible future directions in the emerging area of multifunctional nanocarriers with primary attention on the combination of such properties as longevity, targetability, intracellular penetration and contrast loading.

Keywords: Nanomedicine; Pharmaceutical carriers; Drug delivery; Drug targeting; Long-circulating drug carriers; Imaging; Intracellular drug delivery; Liposomes; Micelles; Polymeric nanoparticles

The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres by R. Gref; A. Domb; P. Quellec; T. Blunk; Muller R.H. Müller; J.M. Verbavatz; R. Langer (pp. 316-326).

Injectable blood persistent particulate carriers have important therapeutic application in site-specific drug delivery or medical imaging. However, injected particles are generally eliminated by the reticulo-endothelial system within minutes after administration and accumulate in the liver and spleen. To obtain a coating that might prevent opsonization and subsequent recognition by the macrophages, sterically stabilized nanospheres were developed using amphiphilic diblock or multiblock copolymers. The nanospheres are composed of a hydrophilic polyethylene glycol coating and a biodegradable core in which various drugs were encapsulated. Hydrophobic drugs, such as lidocaine, were entrapped up to 45wt% and the release kinetics were governed by the polymer physico-chemical characteristics. Plasma protein adsorption was drastically reduced on PEG-coated particles compared to non-coated ones. Relative protein amounts were time-dependent. The nanospheres exhibited increased blood circulation times and reduced liver accumulation, depending on the coating polyethylene glycol molecular weight and surface density. They could be freeze-dried and redispersed in aqueous solutions and possess good shelf stability. It may be possible to tailor “optimal” polymers for given therapeutic applications.

Keywords: Long-circulating nanoparticles; Biodegradable polymers; Polyethylene glycol; Hydrophilic coating; Reduced liver accumulation; Intravenous drug administration

Responsive polymeric delivery systems by Joseph Kost; Robert Langer (pp. 327-341).

This paper discusses the state of the art in a relatively new approach in the field of controlled drug delivery–responsive polymeric drug delivery systems. Such systems are capable of adjusting drug release rates in response to a physiological need. The fundamental principles of externally and self-regulated delivery systems are examined. Special attention is paid to specific clinical settings such as diabetes, presenting the advantages and disadvantages of different approaches.

Keywords: Abbreviations; AIBN; azobisisobutyronitrile; Con A; concanavalin A; DMA,; N; N; -dimethylaminoethylmethacrylate; EE; ethinylestradiol; EVAc; ethylenevinylacetate; HCG; human chronic gonadotropin; HEA; hydroxyethylacrylate; HEMA; hydroxyethylmethacrylate; IVGTT; intravenous glucose tolerance test; LCST; lower critical solution temperature; MBAAm; methylenebisacrylamide; MMA; methylmethacrylate; NIPAAm; N; -isopropylacrylamide; PAH; para; -aminohippuric acid; PHEMA; poly(2-hydroxyethylmethacrylate); PMMA; poly(methylmethacrylate); PVA; poly(vinyl alcohol); QA; quinaldic acid; RIA; radioimmunoassay; SAPG-insulin; phenyl-α-; d; -glucopyranoside insulin; SHBG; sex-hormone-binding globulin; TEGDMA; tetraethyleneglycoldimethacrylate; TMS; trimethylsilystyrene; 5-FU; 5-fluorouracilControlled release; Controlled drug delivery; Self-regulated drug delivery; Externally regulated drug delivery; Pulsatile drug delivery; Environmentally sensitive polymer; Insulin delivery

Folate-mediated delivery of macromolecular anticancer therapeutic agents by Yingjuan Lu; P.S. Philip S. Low (pp. 342-352).

The receptor for folic acid constitutes a useful target for tumor-specific drug delivery, primarily because: (1) it is upregulated in many human cancers, including malignancies of the ovary, brain, kidney, breast, myeloid cells and lung, (2) access to the folate receptor in those normal tissues that express it can be severely limited due to its location on the apical (externally-facing) membrane of polarized epithelia, and (3) folate receptor density appears to increase as the stage/grade of the cancer worsens. Thus, cancers that are most difficult to treat by classical methods may be most easily targeted with folate-linked therapeutics. To exploit these peculiarities of folate receptor expression, folic acid has been linked to both low molecular weight drugs and macromolecular complexes as a means of targeting the attached molecules to malignant cells. Conjugation of folic acid to macromolecules has been shown to enhance their delivery to folate receptor-expressing cancer cells in vitro in almost all situations tested. Folate-mediated macromolecular targeting in vivo has, however, yielded only mixed results, largely because of problems with macromolecule penetration of solid tumors. Nevertheless, prominent examples do exist where folate targeting has significantly improved the outcome of a macromolecule-based therapy, leading to complete cures of established tumors in many cases. This review presents a brief mechanistic background of folate-targeted macromolecular therapeutics and then summarizes the successes and failures observed with each major application of the technology.

Keywords: Folate receptor; Macromolecular drug targeting; Liposomal therapeutic agents; Gene therapy vectors; Prodrug-activating enzymes; Immunotherapeutic agents

Delivery of molecular and cellular medicine to solid tumors by Rakesh K. Jain / (pp. 353-365).

To reach cancer cells in a tumor, a blood-borne therapeutic molecule or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium, and finally migrate through the interstitium. Unfortunately, tumors often develop in ways that hinder each of these steps. Our research goals are to analyze each of these steps experimentally and theoretically, and then integrate the resulting information in a unified theoretical framework. This paradigm of analysis and synthesis has allowed us to obtain a better understanding of physiological barriers in solid tumors, and to develop novel strategies to exploit and/or to overcome these barriers for improved cancer detection and treatment.

Keywords: Tumor microcirculation; Angiogenesis; Blood flow; Vascular permeability; Diffusion and convection; Receptor-ligand binding; Interstitial pressure; Lymphatics; Cell adhesion and deformation; Cancer detection and treatment

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