Current Drug Metabolism - Volume 10, Issue 8, 2009

Nanotechnology-based drugs, newly emerging pharmaceutics, are characterized by the physical sizes of the drugs engineering by various nano-materials such as nanoparticles [1, 2]. These nano-sized drugs can be designed to target specific tissues and organs by chemically and/or biologically tailoring the surfaces of particles or biomaterials [3, 4]. This issue covers four papers reviewing the strategy of nano-sized anti-cancer drugs to overcome the clinical unmet needs. C. J. Hu and L. Zhang summarize the mechanism of chemoresistance acquired by patients during chemotherapy. Furthermore, the smart biomaterials designed to overcome the drug resistance and to alleviate adverse side effects in patients. The majority of these biomaterials are the biomedical polymers that are commonly used as the excipients to formulate the potent anti-cancer drugs. N. Cuong and M. F. Hsieh describe preclinical and clinical improvements in the therapeutic efficacy of cancers using polyethylene glycol and polyamidoamine as low-toxic polymeric excipients. Likewise, W.T. Li reminds us that nanotechnology-based approach can also be applied to enhance the efficacy of photodynamic therapy of cancers. A comprehensive table of clinically-available photo sensitizers is provided in this review article for reader’s reference. In an article by Gigi N. C. Chiu and her colleagues, novel anti-cancer cocktails with rationally designed multi-targeting functions are displayed. The literatures reviewed cover a full range of agents including cytotoxic drugs, chemosensitizers, inhibitors of Pglycoprotien (multidrug resistance protein) and molecular targeted agents. Aside from cancer therapy, C. M. Huang and co-works give readers a specific insight into the biochemistry of the methicillin-resistant bacterial infection in which nanotechnology-based strategy is emerging to combat. The research advances of the drug and/or gene targeting relies heavily on the trafficking of agents in the sub-cellular level. Y. Y. Huang and his colleagues introduce the polymeric materials selected as gene carrier. Because of the charged nature of genes, the materials posses charges in order to encapsulate with genes. Therefore, the toxicity and metabolism are addressed in this article. This issue not only encompasses polymeric excipients to effectively fabricate pharmaceutics into nanoparticles, the reviews in the engineered inorganic nanoparticles and Chinese Herbs are covered to broaden the scientific scope of the current issue. R. A. Sperling and coworkers highlight the impact of inorganic nanoparticles on immune system, in particular the surface properties. S. Huang and W. H. Chang report the formulation of Chinese Herb with improved the therapeutic efficacy. We hope you enjoy reading the articles in this issue. Thanks to the reviewers of this issues for improving the quality of the articles.

This review focuses on the application of drug-loaded nanoparticles (NPs), also called therapeutic NPs, to combat cancer chemoresistance. Many cancer patients have encouraging response to first line chemotherapies but end up with cancer progression or cancer recurrence that requires further treatment. Response to subsequent chemotherapies with various agents usually drops significantly due to formidable cancer chemoresistance. A number of mechanisms have been postulated to account for cancer chemoresistance or poor response to chemotherapy. The best studied mechanism of resistance is mediated through the alteration in the drug efflux proteins responsible for the removal of many commonly used anticancer drugs. Therapeutic NPs have emerged as an innovative and promising alternative of the conventional small molecule chemotherapies to combat cancer drug resistance and have shown enhanced therapeutic efficacy and reduced adverse side effects as compared to their small molecule counterparts. Here the possible mechanisms of therapeutic NPs to combat cancer chemoresistance are reviewed, including prolonging drug systemic circulation lifetime, targeted drug delivery, stimuli-responsive drug release, endocytic uptake of drugs and co-delivering chemo-sensitizing agents. We also call attention to the current challenges and needs of developing therapeutic NPs to combat cancer drug resistance.

The efficacy of drug delivery systems using nanoparticles to enhance the pharmacokinetic properties of drugs has been confirmed in both preclinical trials and clinical settings. A nanosized drug system has improved efficacy, reduced side effects and clearance, increased cellular uptake and prolonged time in circulation. This article will focus recent studies of the pharmacokinetic behavior of such systems as poly(ethylene glycol) and polyamidoamine. Their derivatives are also analyzed. Additionally, some diseases with very good responsiveness are aslo reported.

Photodynamic therapy (PDT) combines photosensitizer, visible light and oxygen, which has the characteristics of high selectivity, minimal invasiveness, low side effect, and allowing repetitive application. The photophysics and mechanisms leading to cell death mediated by PDT have been studied extensively, and PDT has been approved as the modality for superficial tumors and non-cancerous diseases worldwide. For non-dermatogoical applications, the photosensitizers are delivered systemically. Selective therapeutic effect against tumor tissues can be provided by the nature of drugs and tumor physiology. Improved targeting photosensitizer helps preventing damage to the surrounding healthy tissue and lowering dose of drugs and light. The use of nanotechnology in photosensitizer delivery is an attractive approach because nanomaterials may satisfy the need for enhancing PDT efficacy. Recent advances in the use of nanotechnology for PDT application include formulation of biodegradable and non-degradable nanoparticles as passive carriers for photosensitizing agents as well as synthesizing photosensitizer-specific target moiety conjugates for active targeting. This article focuses on passive and active targeting strategies involving nanotechnology to enhance PDT efficacy for cancers.

The use of drug cocktails has become a widely adopted strategy in clinical cancer therapy. Cytotoxic drug cocktails are often administered based on maximum tolerated dose (MTD) of each agent, with the belief of achieving maximum cell kill through tolerable toxicity level. Yet, MTD administration may not have fully captured the therapeutic synergism that exists among the individual agents in the drug cocktail, as the response to a cocktail regimen, that is, whether the effect is synergistic or not, could be highly sensitive to the concentration ratios of the individual drugs at the site of action. It is important to realize that the inherently different pharmacokinetic profiles of the individual agents could have significant influence on the response to an anti-cancer drug cocktail by dictating the amount of the individual agents reaching the tumor site and therefore the concentration ratios. Furthermore, the individual agents may have unfavorable pharmacokinetic interactions that add to the difficulty in determining the therapeutic and/or toxicological effects of the drug cocktail. In this review, we will focus on how lipid-based nanoparticulate systems could address the above issues associated with anticancer drug cocktails. Specifically, we will highlight the use of liposome systems as the means to control and coordinate the delivery of various anti-cancer drug cocktails, encompassing conventional chemotherapeutics, chemosensitizing agents and molecularly targeted agents.

Staphylococcal infection can cause a wide range of diseases resulting either from staphylococcal bacteria invasion or through toxin production. The majority of infections caused by staphylococci are due to Staphylococcus aureus. Moreover, methicillin-resistant Staphylococcus aureus has recently been considered to be one of the major causes of hospital-acquired infections. The treatment of staphylococci infections is difficult because increased antibiotic resistant strains have become more common, increasing the risk of serious health penalty. Delivery of antibiotics via nanoparticles is a promising therapy, as a drug delivery mechanism, particularly for controlled release or depot delivery of drugs to decrease the number of doses required to achieve a clinical effect. This review emphasized the potential of nanoparticles in the targeted antibiotics for therapy of staphylococcal infections.

Gene delivery remains to be a very challenging field to efficiently transport the therapeutic gene and to modulate proteins with the desired function at the target site. The physiochemical and biological barriers are the major hurdles that need to be considered, particularly when administered systematically, in order to optimize the therapeutic efficacy. Numerous modifications have been extensively investigated aiming to provide protection from the plasma degradation, enhancement of transfection, target specificity, and most importantly, minimizing the side effects such as cellular toxicity and immune response. This article provides a review with respect to the in vitro and in vivo toxicity, as well as cellular and physiological interactions with the gene delivery system composed from viral vectors, cationic lipids and polymers. Recent progress and development are also addressed, with promising results that may be further adopted for clinical use.

The immune system is the responsible for body integrity and the prevention of external invasion. In principle, the immune system has not been evolutionarily trained to respond against inorganic engineered nanoparticles (NPs). However, how it will react against them will determine developments on the use of NPs as medical devices and their toxicological impact on human and environmental health. Initial observations show a broad range of results as a function of size, shape, concentration and surface state of NPs, and a variety of immune responses from absent to acute inflammation. In particular for the case of NP, the composition of the material, which strongly influences its physical properties, appears not to be the main determining factor for their behavior in biological environments as compared to surface state or size.

A number of new nanotechnology-based Chinese herb drugs have been developed that have efficient biopharmaceutical properties and desirable target characteristics. This offers several alternatives for medical applications. Nanoparticles of Chinese herb drugs possess many benefits, such as improving component solubility, enhancement of bioavailability, increasing absorbency of the organism, reducing medicinal herb doses, and achieving steady-state therapeutic levels of drugs over an extended period compared with traditional Chinese herb drug preparations. There are two basic techniques, ‘bottom up’ or ‘top down’, to prepare Chinese herb nanoparticles. Furthermore, specific surface modifications and new design strategies of Chinese herb drug nanoparticles are created to profit clinical applications. This review presents recent advances in nanotechnology-based Chinese herb drugs.

Chemical defensive system consisting of bio-sensoring, transmitting, and responsive elements has been evolved to protect multi-cellular organisms against environmental chemical insults (xenobiotics) and to maintain homeostasis of endogenous low molecular weight metabolites (endobiotics). Both genetic and epigenetic defects of the system in association with carcinogenesis and individual sensitivity to anti-tumor therapies have been intensely studied. Recently, several non-tumor human pathologies with evident environmental components such as rather rare functional syndromes (multiple chemical sensitivity, chronic fatigue, Persian Gulf, and fibromyalgia now collectively labeled as idiopathic environmental intolerances) and common diseases (vitiligo and systemic lupus erythematosus) have become subjects of the research on the impaired metabolism and detoxification of xenobiotics and endogenous toxins. Here, we collected and critically reviewed epidemiological, genetic, and biochemical data on the involvement and possible role of cytochrome P450 super family enzymes, glutathione-S-transferase isozymes, catechol-O-methyl-transferase, UDP-glucuronosyl transferases, and proteins detoxifying inorganic and organic peroxides (catalase, glutathione peroxidase, and peroxiredoxin) in the above pathologies. Genetic predisposition assessed mainly by single nucleotide polymorphism and gene expression analyses revealed correlations between defects in genes encoding xenobiotic-metabolizing and/or detoxifying enzymes and risk/severity of these syndromes/diseases. Proteome analysis identified abnormal expression of the enzymes. Their functions were affected epigenetically leading to metabolic impairment and, as a consequence, to the negative health outcomes shared by some of these pathologies. Data obtained so far suggest that distinct components of the chemical defensive system could be suitable molecular targets for future pathogenic therapies.

Drug metabolizing enzymes (DME) play a central role in the intestinal absorption/permeability, metabolism, elimination and detoxification of endogenous and exogenous compounds. DME include phase I and II metabolizing enzymes. The hydroxylation activity of phase I DME increases the hydrophilicity of the molecules. The electrophilicity of phase I DME-derived products is reduced via conjugation with endogenous ligands, such as glutathione and glucuronic acid, and facilitates their inactivation and excretion in the bile and/or the urine. The transport system is involved in the cellular input/output of molecules and drugs. Numerous endogenous and exogenous compounds, being the substrates of DME, regulate the expression of DME genes through the activation of a number of nuclear receptors. These nuclear receptors directly or indirectly target different regulatory sequences present in the promoter region of the DME genes. The review describes the activation process of nuclear receptors, as well as their interactions to elucidate the extended cross-talk between them in the regulation of DME.