Current Pharmaceutical Design - Volume 12, Issue 36, 2006

A new interdisciplinary field of nanomedicine that promises breakthrough advances to human health has emerged over last years. This field develops innovative nanomaterials, tools and devices operating at the nanoscale to diagnose, treat, prevent and monitor diseases and traumatic injury, relieve pain, and, overall, preserve and improve the human health [1]. This field joins physical and engineering sciences with pharmaceutics and medicine to translate newest discoveries in nanoscience into clinical practice. The “next generation” therapies must be able to deliver drugs, radionuclides, therapeutic proteins and recombinant DNA to focal areas of disease or to tumors to maximize clinical benefit while limiting untoward side effects. It is not surprising therefore that the drug delivery field has attracted great attention of the biomedical community. The development of multifunctional, spatially ordered, architecturally varied nanosystems for targeted drug delivery is also seen as a priority in nanomedicine [1]. The knowledge and experience in interactions of nanosized drug delivery systems is invaluable for the nanomedicine researchers. Several nanosized drug delivery systems have already been approved for clinical use and more nanomaterials are being evaluated in clinics [2]. Thus nanomedicine is not only “futuristic” but also “realistic” field with a near-term prospective to improve human health. A symposium series focusing on the problems of nanomedicine and drug delivery has started several years ago - the Fourth International Nanomedicine Symposium is planned for October 8th-10th, 2006 (www.nanodds.org). By gathering basic and clinical scientists with the common interest of using nanotechnology in the delivery of therapeutic and diagnostic agents this symposium series aims at narrowing the gap between research communities in academia, government and industry. This issue presents a collection of selected review articles by the speakers and attendees of the Second Nanomedicine and Drug Delivery Symposium held in Brooklyn, NY in August 2004. One promising class of nanomaterials for drug delivery are polymer micelles. They were first proposed in 80'-ies as nanocontainers for biological agents by H. Ringsdorf, A. Kabanov and K. Kataoka [3-5], and have now attracted great attention in the literature. Polymer micelles can incorporate drugs into the hydrophobic polymer core protected by a hydrophilic polymer corona. The corona enables long circulation times of the micelles in the body and prevents the affect of the drugs entrapped in the core on the non-target cells. By modifying the surface of the micelles with antibodies, the site specific delivery and release of the payload at the disease site has been achieved. Several polymer micelle systems are now evaluated in clinical trials. The article by S.R. Croy and G.S. Kwon [6] opens the current issue with a comprehensive overview of this rapidly developing field. The second article by C. Allen and colleagues focuses on the problems of drug loading within the micelles and drug release from the micelles [7]. The interactions between the drug and the micelle core are discussed in terms of their influence on the drug loading and release properties of the micelles. The balance between drug loading and micelle stability is highlighted as a critical factor in the optimization of micelle-drug formulations. The methods employed to prepare drug-loaded micelles and the drug release assays are reviewed. The in vivo performance of micelles as delivery systems is evaluated by comparing the pharmacokinetics of free drug and drug administered in micelle-based formulations. A different approach to drug loading and release was realized in a relatively new class of nanosized drug carriers called “nanogels”. First proposed in the end of the 90'-ies the nanogels represent cross-linked networks of water soluble polymers of nanoscale size. These networks are swollen and do not have a hydrophobic core in aqueous dispersions in the absence of the drug. However, the added drug can spontaneously bind to the polymer chains of the nanogels, for example, due to electrostatic interactions, and become entrapped in nanogel particles. This method allows for very high degrees of loading of drugs in nanogels. Nanogels are “ soft ” materials that change shape and volume as the chemical composition of the environment changes or upon interaction with the cell membranes. These properties can be used facilitate the release of the loaded drugs within the target cells. The work on nanogels and other colloidal microgels has been overviewed by S. Vinogradov [8]. The theme of colloidal gels is continued by Kazakov and Levon in the fourth article of this issue [9].........

Polymeric micelles are nanoscopic core/shell structures formed by amphiphilic block copolymers. Both the inherent and modifiable properties of polymeric micelles make them particularly well suited for drug delivery purposes. An emphasis of this review has been placed on both the description and characterization techniques of the physical properties of polymeric micelles. Relevant properties discussed include micellar association, morphology, size and stability. These properties and characterization techniques are included to provide context for the known advantages and applications of polymeric micelles for drug delivery. The advantages and applications discussed include solubilization of poorly soluble molecules, sustained release and size advantages, and protection of encapsulated substances from degradation and metabolism. The three most widely studied block copolymer classes are characterized by their hydrophobic blocks, and are poly(propylene oxide), poly(L-amino acid)s and poly(ester)s. These three classes of block copolymers are reviewed with multiple examples of current research in which formulation techniques with polymeric micelles have been applied to some of the most challenging molecules in the pharmaceutical industry. The polymeric micelles used for drug delivery in these examples have shown the abilities to attenuate toxicities, enhance delivery to desired biological sites and improve the therapeutic efficacy of active pharmaceutical ingredients.

Block copolymer micelles have become accepted as a viable strategy for drug formulation and delivery. Block copolymer micelles may serve as solubilizers and/or true drug carriers depending on their drug retention properties in vivo. Indeed the formulation of hydrophobic drugs in these micelle systems has been shown to provide up to a 30 000 fold increase in the water solubility of some compounds. In addition, the administration of drugs in copolymer micelles has been shown to reduce their toxicity and improve their therapeutic efficacy. The present review is focused on the drug loading and release properties of block copolymer micelles. Specifically, the properties of the drug, properties of the micelle core and the presence of interactions between the drug and the coreforming block are discussed in terms of their influence on the drug loading and release properties of the micelles. The various methods employed to prepare drug-loaded micelles are reviewed and the in vitro release assays used to predict the in vivo release characteristics of the formulations are discussed. The balance between drug loading and micelle stability is highlighted as a critical factor in the optimization of micelle-based formulations. The in vivo performance of micelles as delivery systems is evaluated by comparing the pharmacokinetics of free drug and drug administered in micelle-based formulations. Overall, the composition-property and property-performance relationships outlined in this review may aid in guiding the rational design of block copolymer micelles for drug delivery. In addition, suggestions for future research in this area are provided as a means to assist in furthering block copolymer micelles as one of the leading advanced drug delivery technologies for the systemic administration of drugs.

Colloidal microgels have recently received attention as environmentally responsive systems and now are increasingly used in applications as carriers for therapeutic drugs and diagnostic agents. Synthetic microgels consist of a crosslinked polymer network that provides a depot for loaded drugs, protection against environmental hazards and template for post-synthetic modification or vectorization of the drug carriers. The aim of this manuscript is to review recent attempts to develop new microgel formulations for oral drug delivery, to design metal-containing microgels for diagnostic and therapeutic applications, and to advance approaches including the systemic administration of microgels. Novel nanogel drug delivery systems developed in the authors' laboratory are discussed in details including aspects of their synthesis, vectorization and recent applications for encapsulation of low molecular weight drugs or formulation of biological macromolecules. The findings reviewed here are encouraging for further development of the nanogels as intelligent drug carriers with such features as targeted delivery and triggered drug release.

Nanoparticles have been extensively studied as drug delivery systems. In this review, we focus on a relatively new type of nanoparticles - lipobeads - a liposome-hydrogel assembly as a novel drug delivery system. An appropriate assemblage of spherical hydrogel particles and liposomes combines the properties of both classes of materials and may find a variety of biomedical applications. The bi-compartmental structure of lipobeads is a natural configuration. Thus, the technology of their preparation can be a key step of designing more stable and effective vaccines. Biocompatibility and stability, ability to deliver a broad range of bioactive molecules, environmental responsiveness of both inner nanogel core and external lipid bilayer, and individual specificity of both compartments make the liposome-nanogel design a versatile drug delivery system relevant for all known drug administration routes and suitable for different diseases with possibility of efficient targeting to different organs. New findings on reversible and irreversible aggregation of lipobeads can lead to novel combined drug delivery systems regarding lipobeads as multipurpose containers. The research on hydrogelliposome submicrometer structures has just begun and fundamental studies on interactions between hydrogels and liposomes are in demand.

Several nanoscale carriers (nanoparticles, liposomes, water-soluble polymers, micelles and dendrimers) have been developed for targeted delivery of cancer diagnostic and therapeutic agents. These carriers can selectively target cancer sites and carry large payloads, thereby improving cancer detection and therapy effectiveness. Further, the combination of newer nuclear imaging techniques providing high sensitivity and spatial resolution such as dual modality imaging with positron emission tomography/computed tomography (PET/CT) and use of nanoscale devices to carry diagnostic and therapeutic radionuclides with high target specificity can enable more accurate detection, staging and therapy planning of cancer. The successful clinical applications of radiolabeled monoclonal antibodies for cancer detection and therapy bode well for the future of nanoscale carrier systems in clinical oncology. Several radiolabeled multifunctional nanocarriers have been effective in detecting and treating cancer in animal models. Nonetheless, further preclinical, clinical and long-term toxicity studies will be required to translate this technology to the care of patients with cancer. The objective of this review is to present a brief but comprehensive overview of the various nuclear imaging techniques and the use of nanocarriers to deliver radionuclides for the diagnosis and therapy of cancer.

The fact that in vivo the extracellular matrix (ECM) or substratum with which cells interact often includes topography at the nanoscale underscores the importance of investigating cell-substrate interactions and performing cell culture at the submicron scale. An important and exciting direction of research in nanomedicine would be to gain an understanding and exploit the cellular response to nanostructures. Electrospinning is a simple and versatile technique that can produce a macroporous scaffold comprising randomly oriented or aligned nanofibers. It can also accommodate the incorporation of drug delivery function into the fibrous scaffold. Endowed with both topographical and biochemical signals such electrospun nanofibrous scaffolds may provide an optimal microenvironment for the seeded cells. This review covers the analysis and control of the electrospinning process, and describes the types of electrospun fibers fabricated for biomedical applications such as drug delivery and tissue engineering.

Dyslipidaemia is common in solid organ transplant recipients and its presence is associated with chronic rejection and accelerated atherosclerosis, leading to an increased prevalence of cardiovascular disease (CVD). CVD is a major cause of morbidity and mortality in transplant recipients. It is therefore of interest and clinical value to introduce agents that effectively and safely reduce the incidence of this outcome. In the present review we consider the potential benefits of statin administration in adults who have undergone solid organ (mainly renal, heart and liver) transplantation, as well as in paediatric transplant patients. We also briefly review the effects of combination therapy with ezetimibe and statins in this population. Overall, statins are efficient and safe drugs for the management of dyslipidaemias in transplant populations, and in most trials they had a beneficial effect on long-term survival rates, CVD events and rejection rates. The transplanted population is different from other patient groups, mostly due to concomitant immunosuppressive therapy. Statins, at an appropriate dosage, should be prescribed to dyslipidaemic transplanted patients but they should be closely monitored for adverse effects.

Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue. PDCs offer added advantages of reduced deleterious effects of anticancer drugs and augmentation of its formulation capability (e.g. Solubility). There are now at least eleven PDCs that have entered phase I/II/III clinical trial as anticancer drugs. PDCs once entered into the tumor tissue, taking advantage of EPR, are endocytosed into the cell either by simple or receptor mediated endocytosis. Various polymeric carriers have been used with hydrolyzable linker arm for conjugation with bioactive moiety. The hydrolyzable linkages of PDC are broken down by acid hydrolyses of lysosomes and releases the drug. High concentrations of the chemotherapeutic agent are maintained near the nucleus, the target site. Passive targeting by PDCs is due to the physiological event of EPR, which is becoming one of the major thrust areas for targeting solid tumors.