Click Chemistry with Polymers,Dendrimers, and Hydrogels for Drug Delivery

During the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagnosis. In addition, polymeric hydrogels with the ability to encapsulate drugs and cells have been developed for drug delivery and tissue engineering applications. In the long road to this successful story, pharmaceutical sciences have been accompanied by parallel advances in synthetic methodologies allowing the preparation of precise polymeric materials with enhanced properties. In this context, the introduction of the click concept by Sharpless and coworkers in 2001 focusing the attention on modularity and orthogonality has greatly benefited polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. The purpose of this Expert Review is to discuss the impact of click chemistry in the preparation and functionalization of polymers, dendrimers, and hydrogels of interest in drug delivery.     

Surface engineered and drug releasing pre-fabricated scaffolds for tissue engineering

A wide range of polymeric scaffolds have been intensively studied for use as implantable and temporal devices in tissue engineering. Biodegradable and biocompatible scaffolds having a highly open porous structure and good mechanical strength are needed to provide an optimal microenvironment for cell proliferation, migration, and differentiation, and guidance for cellular in-growth from host tissue. A variety of natural and synthetic polymeric scaffolds can be fabricated in the form of a solid foam, nanofibrous matrix, microsphere, or hydrogel. Biodegradable porous scaffolds can be surface engineered to provide an extracellular matrix mimicking environment for better cell adhesion and tissue in-growth. Furthermore, scaffolds can be designed to release bioactive molecules, such as growth factors, DNA, or drugs, in a sustained manner to facilitate tissue regeneration. This paper reviews the current status of surface engineered and drug releasing scaffolds for tissue engineering.     

Nanofiber technology: designing the next generation of tissue engineering scaffolds

Tissue engineering is an interdisciplinary field that has attempted to utilize a variety of processing methods with synthetic and natural polymers to fabricate scaffolds for the regeneration of tissues and organs. The study of structure-function relationships in both normal and pathological tissues has been coupled with the development of biologically active substitutes or engineered materials. The fibrillar collagens, types I, II, and III, are the most abundant natural polymers in the body and are found throughout the interstitial spaces where they function to impart overall structural integrity and strength to tissues. The collagen structures, referred to as extracellular matrix (ECM), provide the cells with the appropriate biological environment for embryologic development, organogenesis, cell growth, and wound repair. In the native tissues, the structural ECM proteins range in diameter from 50 to 500 nm. In order to create scaffolds or ECM analogues, which are truly biomimicking at this scale, one must employ nanotechnology. Recent advances in nanotechnology have led to a variety of approaches for the development of engineered ECM analogues. To date, three processing techniques (self-assembly, phase separation, and electrospinning) have evolved to allow the fabrication of nanofibrous scaffolds. With these advances, the long-awaited and much anticipated construction of a truly "biomimicking" or "ideal" tissue engineered environment, or scaffold, for a variety of tissues is now highly feasible. This review will discuss the three primary technologies (with a focus on electrospinning) available to create tissue engineering scaffolds that are capable of mimicking native tissue, as well as explore the wide array of materials investigated for use in scaffolds.     

Natural polymers for gene delivery and tissue engineering

Although the field of gene delivery is dominated by viral vectors and synthetic polymeric or lipid gene carriers, natural polymers offer distinct advantages and may help advance the field of non-viral gene therapy. Natural polymers, such as chitosan, have been successful in oral and nasal delivery due to their mucoadhesive properties. Collagen has broad utility as gene activated matrices, capable of delivering large quantities of DNA in a direct, localized manner. Most natural polymers contain reactive sites amenable for ligand conjugation, cross-linking, and other modifications that can render the polymer tailored for a range of clinical applications. Natural polymers also often possess good cytocompatibility, making them popular choices for tissue engineering scaffolding applications. The marriage of gene therapy and tissue engineering exploits the power of genetic cell engineering to provide the biochemical signals to influence proliferation or differentiation of cells. Natural polymers with their ability to serve as gene carriers and tissue engineering scaffolds are poised to play an important role in the field of regenerative medicine. This review highlights the past and present research on various applications of natural polymers as particulate and matrix delivery vehicles for gene delivery.     

Surface-functionalized electrospun nanofibers for tissue engineering and drug delivery

Electrospun nanofibers with a high surface area to volume ratio have received much attention because of their potential applications for biomedical devices, tissue engineering scaffolds, and drug delivery carriers. In order to develop electrospun nanofibers as useful nanobiomaterials, surfaces of electrospun nanofibers have been chemically functionalized for achieving sustained delivery through physical adsorption of diverse bioactive molecules. Surface modification of nanofibers includes plasma treatment, wet chemical method, surface graft polymerization, and co-electrospinning of surface active agents and polymers. A variety of bioactive molecules including anti-cancer drugs, enzymes, cytokines, and polysaccharides were entrapped within the interior or physically immobilized on the surface for controlled drug delivery. Surfaces of electrospun nanofibers were also chemically modified with immobilizing cell specific bioactive ligands to enhance cell adhesion, proliferation, and differentiation by mimicking morphology and biological functions of extracellular matrix. This review summarizes surface modification strategies of electrospun polymeric nanofibers for controlled drug delivery and tissue engineering.     

Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery

This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer-drug conjugates, as a function of physicochemical properties will further need to be assessed.     

Pharmaceutical and biomedical potential of surface engineered dendrimers

Dendrimers are hyperbranched, globular, monodisperse, nanometric polymeric architecture, having definite molecular weight, shape, and size (which make these an inimitable and optimum carrier molecule in pharmaceutical field). Dendritic architecture is having immense potential over the other carrier systems, particularly in the field of drug delivery because of their unique properties, such as structural uniformity, high purity, efficient membrane transport, high drug pay load, targeting potential, and good colloidal, biological, and shelf stability. Despite their enormous applicability in different areas, the inherent cytotoxicity, reticuloendothelial system (RES) uptake, drug leakage, immunogenicity, and hemolytic toxicity restricted their use in clinical applications, which is primarily associated with cationic charge present on the periphery due to amine groups. To overcome this toxic nature of dendrimers, some new types of nontoxic, biocompatible, and biodegradable dendrimers have been developed (e.g., polyester dendrimer, citric acid dendrimer, arginine dendrimer, carbohydrate dendrimers, etc.). The surface engineering of parent dendrimers is graceful and convenient strategy, which not only shields the positive charge to make this carrier more biomimetic but also improves the physicochemical and biological behavior of parent dendrimers. Thus, surface modification chemistry of parent dendrimers holds promise in pharmaceutical applications (such as solubilization, improved drug encapsulation, enhanced gene transfection, sustained and controlled drug release, intracellular targeting) and in the diagnostic field. Development of multifunctional dendrimer holds greater promise toward the biomedical applications because a number of targeting ligands determine specificity in the same manner as another type of group would secure stability in biological milieu and prolonged circulation, whereas others facilitate their transport through cell membranes. Therefore, as a consequence of ideal hyperbranched architecture and the biocompatible nature of engineered dendrimers, their utilization has been included in the scope of this review, which focuses on current surface alteration strategies of dendrimers for their potential use in drug delivery and explains the possible beneficial applications of these engineered dendrimers in the biomedical field.     

Design, synthesis and potent pharmaceutical applications of glycodendrimers: a mini review

Dendrimers are a new class of artifical macromolecules with well-defined hyperbranched structures which endue these promising materials with a wide variety of applications. They are useful tools in drug discovery and allow bio-active molecules to be presented in a highly multi-valent fashion on the surface. Recently, the use of dendrimers as scaffolds of carbohydrates to synthesize glycodendrimers with high and specific affinities to various receptors has made it possible for these dendritic materials to participate in extracellular and intracellular biochemical processes. References on synthesis and biological applications of glycodendrimers in the literatures demonstrate that dendrimers are suitable candidates as scaffolds of these bioactive carbohydrates. In this mini-review, different approaches to construct glycodendrimers as well as their promising applications in biological systems are fully discussed.     

Improved biomaterials for tissue engineering applications: surface modification of polymers

Tissue engineering approaches that combine biomaterial-based scaffolds with protein delivery systems have provided a potential strategy for improved regeneration of damaged tissue. The success of polymeric scaffolds is determined by the response it elicits from the surrounding biological environment. This response is governed, to a large extent, by the surface properties of the scaffold. Surfaces of polymeric scaffolds have a significant effect on protein and cell attachment. Multiple approaches have been developed to provide micrometer to nanometer scale alterations in surface architecture of scaffolds to enable improved protein and cell interactions. Chemical modification of polymeric scaffold surfaces is one of the upcoming approaches that enables enhanced biocompatibility while providing a delivery vehicle for proteins. Similarly, physical adsorption, radiation mediated modifications, grafting, and protein modifications are other methods that have been employed successfully for alterations of surface properties of polymeric scaffolds. The goal of this review is to provide an overview of the role of surface properties /chemistry in tissue engineering and briefly discuss some of the methods of surface modification that can provide improved cell and protein interactions. It is hoped that these improved polymeric scaffolds will lead to accelerated and functional tissue regeneration.     

The Diels–Alder reaction: A powerful tool for the design of drug delivery systems and biomaterials

Click reactions have the potential to greatly facilitate the development of drug delivery systems and biomaterials. These reactions proceed under mild conditions, give high yields, and form only inoffensive by-products. The Diels–Alder cycloaddition is one of the click reactions that do not require any metal catalyst; it is one of the most useful reactions in synthetic organic chemistry and material design. Herein, we highlight possible applications of the Diels–Alder reaction in pharmaceutics and biomedical engineering. Particular focus is placed on the synthesis of polymers and dendrimers for drug delivery, the preparation of functionalized surfaces, bioconjugation techniques, and applications of the Diels–Alder reaction in nanotechnology. Moreover, applications of the reaction for the preparation of hydrogels for drug delivery and tissue engineering are reviewed. A general introduction to the Diels–Alder reaction is presented, along with a discussion of potential pitfalls and challenges. At the end of the article, we provide a set of tools that may facilitate the application of the Diels–Alder reaction to solve important pharmaceutical or biomedical problems.     

Electrospun materials as potential platforms for bone tissue engineering

Nanofibrous materials produced by electrospinning processes have attracted considerable interest in tissue regeneration, including bone reconstruction. A range of novel materials and processing tools have been developed to mimic the native bone extracellular matrix for potential applications as tissue engineering scaffolds and ultimately to restore degenerated functions of the bone. Degradable polymers, bioactive inorganics and their nanocomposites/hybrids nanofibers with suitable mechanical properties and bone bioactivity for osteoblasts and progenitor/stem cells have been produced. The surface functionalization with apatite minerals and proteins/peptides as well as drug encapsulation within the nanofibers is a promising strategy for achieving therapeutic functions with nanofibrous materials. Recent attempts to endow a 3D scaffolding technique to the electrospinning regime have shown some promise for engineering 3D tissue constructs. With the improvement in knowledge and techniques of bone-targeted nanofibrous matrices, bone tissue engineering is expected to be realized in the near future.     

Poly(amidoamine) polymers: soluble linear amphiphilic drug-delivery systems for genes, proteins and oligonucleotides

Polymer-drug and polymer-protein conjugates are emerging as a robust and well-characterized class of therapeutic entity. Although there are no low-molecular-weight soluble polymer conjugates in routine clinical use, there are many examples of routinely used high-molecular-weight drugs conjugated to soluble polymers (e.g., Oncospar). Advances in synthetic polymer chemistry have fostered the development of linear poly(amidoamine)s (PAA)s that impart both biodegradability, 'smart' (pH responsive) biological activity and biocompatibility. In their linear form, such as hyper-branched poly(amidoamine) (PAMAM) dendrimers, linear PAAs can be used to deliver large therapeutic entities such as peptides, proteins and genes to either the cytosol or nucleus. Furthermore, these polymers offer great potential in vivo due to their ability to either target the liver or be directed away from the liver and enter tumor mass via the enhanced permeability and retention (EPR) effect. PAAs also exhibit minimal toxicity (dependent upon backbone chemistry), relative to well-characterized polymers used for gene delivery. The propensity of PAAs to modulate intracellular trafficking resulting in their cytosolic translocation has also recently been quantified in vivo and is the primary focus of this article.     

Interpenetrating Polymer Networks polysaccharide hydrogels for drug delivery and tissue engineering

The ever increasing improvements of pharmaceutical formulations have been often obtained by means of the use of hydrogels. In particular, environmentally sensitive hydrogels have been investigated as “smart” delivery systems capable to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. At the same time the progress in the tissue engineering research area was possible because of significant innovations in the field of hydrogels. In recent years multicomponent hydrogels, such as semi-Interpenetrating Polymer Networks (semi-IPNs) and Interpenetrating Polymer Networks (IPNs) have emerged as innovative biomaterials for drug delivery and as scaffolds for tissue engineering. These interpenetrated hydrogel networks, which can be obtained by either chemical or physical crosslinking, in most cases show physico-chemical properties that can remarkably differ from those of the macromolecular constituents. Among the synthetic and natural polymers that have been used for the preparation of semi-IPNs and IPNs, polysaccharides represent a class of macromolecules of particular interest because they are usually abundant, available from renewable sources and have a large variety of composition and properties that may allow appropriately tailored chemical modifications. Sometimes both macromolecular systems are based on polysaccharides but often also synthetic polymers are present together with polysaccharide chains.     

Synthesis of dendrimers and drug-dendrimer conjugates for drug delivery

Dendrimers constitute a class of polymers that possess a well-defined structure allowing the precise control of size, shape and terminal group functionality. Their utility has been explored for a wide range of pharmaceutical applications. There is growing interest in the design and synthesis of novel biocompatible dendrimers and a number of novel dendrimer architectures are discussed in this review. Recently, there has also been interest in the design of drug-dendrimer prodrugs and several of these systems are described, with emphasis on how the properties of such carriers may be tailored via surface engineering.     

Recent progress in dendrimer-based nanocarriers

A large number of drug delivery systems--mostly in the form of liposomes, microspheres, nanoparticles and hydrogels--have been designed to achieve targeted delivery and sustained release of drugs by exploiting the inherent properties of polymers. The size, shape, and surface properties of the polymer are used to modulate the pharmacokinetic and pharmacodynamic behavior of drugs conjugated with or encapsulated in the polymeric carrier. Recently, a class of well-defined, monodisperse, and tree-like polymers called dendrimers has attracted attention because of the flexibility they offer in terms of their size, shape, branching, length, and surface functionality. A unique characteristic of dendrimers is that they can act as a particulate system while retaining the properties of a polymer. Drugs and diagnostic agents can be encapsulated in the central core or bound to the surface of the dendrimer by noncovalent or covalent interaction. Dendritic polymers can significantly improve pharmacokinetic and pharmacodynamic properties of low molecular weight and protein-based therapeutic agents. Furthermore, fluorescent antibodies and imaging contrast agents can be bound to these new polymers and the resulting complexes can be used for analyzing biological fluids and for diagnosis. Because of their size, shape, and ability to conjugate with a wide range of chemical entities, dendrimers have found many applications in the pharmaceutical and biomedical sciences. This review focuses on the unique carrier properties of biomimetic dendrimers and discusses a wide range of applications of dendrimers in drug delivery, including their use as drug solubilizers, absorption enhancers, release modifiers, and carriers for targeting drugs and diagnostic agents.     

The use of PAMAM dendrimers in the efficient transfer of genetic material into cells

Polyamidoamine (PAMAM) dendrimers have steadily grown in popularity in the past decade in a variety of disciplines, ranging from materials science to biomedicine. This can be attributed in part to their use in applications that range from computer toners to medical diagnostics. PAMAM dendrimers are safe and nonimmunogenic, and can function as highly efficient cationic polymer vectors for delivering genetic material into cells. They have been shown to be as efficient or more efficient than either cationic liposomes or other cationic polymers (e.g. polyethylenimine, polylysine) for in vitro gene transfer. This article will focus on the application of PAMAM dendrimers as a nonviral gene delivery vector from the initial discovery of this capacity to the most recent experimental findings.     

Recent progress in dendrimer-based nanomedicine development

Dendrimers offer well-defined nanoarchitectures with spherical shape, high degree of molecular uniformity, and multiple surface functionalities. Such unique structural properties of dendrimers have created many applications for drug and gene delivery, nanomedicine, diagnostics, and biomedical engineering. Dendrimers are not only capable of delivering drugs or diagnostic agents to desired sites by encapsulating or conjugating them to the periphery, but also have therapeutic efficacy in their own. When compared to traditional polymers for drug delivery, dendrimers have distinct advantages, such as high drug-loading capacity at the surface terminal for conjugation or interior space for encapsulation, size control with well-defined numbers of peripheries, and multivalency for conjugation to drugs, targeting moieties, molecular sensors, and biopolymers. This review focuses on recent applications of dendrimers for the development of dendrimer-based nanomedicines for cancer, inflammation, and viral infection. Although dendrimer-based nanomedicines still face some challenges including scale-up production and well-characterization, several dendrimer-based drug candidates are expected to enter clinical development phase in the near future.     

New intelligent and targetted drug delivery systems. Pharmaceutical and biomedical applications

Biomaterials are widely used in numerous medical applications. Chemical engineering has played a central role in this research and development. We review herein polymers as biomaterials, materials and approaches used in drug and protein delivery systems, materials used as scaffolds in tissue engineering, and nanotechnology and microfabrication techniques applied to biomaterials.     

Functional electrospun nanofibrous scaffolds for biomedical applications

Functional nanofibrous scaffolds produced by electrospinning have great potential in many biomedical applications, such as tissue engineering, wound dressing, enzyme immobilization and drug (gene) delivery. For a specific successful application, the chemical, physical and biological properties of electrospun scaffolds should be adjusted to match the environment by using a combination of multi-component compositions and fabrication techniques where electrospinning has often become a pivotal tool. The property of the nanofibrous scaffold can be further improved with innovative development in electrospinning processes, such as two-component electrospinning and in-situ mixing electrospinning. Post modifications of electrospun membranes also provide effective means to render the electrospun scaffolds with controlled anisotropy and porosity. In this article, we review the materials, techniques and post modification methods to functionalize electrospun nanofibrous scaffolds suitable for biomedical applications.     

The role of surface energy of technical polymers in serum protein adsorption and MG-63 cells adhesion

Polymeric materials are widely used as supports for cell culturing in medical implants and as scaffolds for tissue regeneration. However, novel applications in the biosensor field require materials to be compatible with cell growth and at the same time be suitable for technological processing. Technological polymers are key materials in the fabrication of disposable parts and other sensing elements. As such, it is essential to characterize the surface properties of technological polymers, especially after processing and sterilization. It is also important to understand how technological polymers affect cell behavior when in contact with polymer materials. Therefore, the aim of this research was to study how surface energy and surface roughness affect the biocompatibility of three polymeric materials widely used in research and industry: poly(methyl methacrylate), polystyrene, and poly(dimethylsiloxane). Glass was used as the control material.From the Clinical EditorPolymeric materials are widely used as supports for cell culturing in medical implants and as scaffolds for tissue regeneration. The aim of this research is to study how surface energy and surface roughness affect the biocompatibility of three polymeric materials widely used in research and industry: poly(methylmethacrylate) (PMMA), polystyrene (PS), and poly(dimethylsiloxane) (PDMS).