The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for n drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.

http://www.protocol-online.org/forums/uploads/monthly_09_2010/post-8165-008503000%201284677034.ipb

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

Recent advances in nanoscience and nanotechnology radically changed the way we diagnose, treat, and prevent various diseases in all aspects of human life. Silver nanoparticles (AgNPs) are one of the most vital and fascinating nanomaterials among several metallic nanoparticles that are involved in biomedical applications. AgNPs play an important role in nanoscience and nanotechnology, particularly in nanomedicine. Although several noble metals have been used for various purposes, AgNPs have been focused on potential applications in cancer diagnosis and therapy. In this review, we discuss the synthesis of AgNPs using physical, chemical, and biological methods. We also discuss the properties of AgNPs and methods for their characterization. More importantly, we extensively discuss the multifunctional bio-applications of AgNPs; for example, as antibacterial, antifungal, antiviral, anti-inflammatory, anti-angiogenic, and anti-cancer agents, and the mechanism of the anti-cancer activity of AgNPs. In addition, we discuss therapeutic approaches and challenges for cancer therapy using AgNPs. Finally, we conclude by discussing the future perspective of AgNPs.

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Silver Nanoparticles: Synthesis, Characterization, Properties, Applications, and Therapeutic Approaches

Since their discovery in the 1960s, liposomes have been studied in depth, and they continue to constitute a field of intense research. Liposomes are valued for their biological and technological advantages, and are considered to be the most successful drug-carrier system known to date. Notable progress has been made, and several biomedical applications of liposomes are either in clinical trials, are about to be put on the market, or have already been approved for public use. In this review, we briefly analyze how the efficacy of liposomes depends on the nature of their components and their size, surface charge, and lipidic organization. Moreover, we discuss the influence of the physicochemical properties of liposomes on their interaction with cells, half-life, ability to enter tissues, and final fate in vivo. Finally, we describe some strategies developed to overcome limitations of the "first-generation" liposomes, and liposome-based drugs on the market and in clinical trials.

https://www.dovepress.com/getfile.php?fileID=23533

Liposomes as nanomedical devices

The purpose of this work is to review the published studies on the mechanisms of action and resistance of 5-fluorouracil. The review is divided into three main sections: mechanisms of anti-tumor action, studies of the resistance to the drug, and procedures for the identification of new genes involved in resistance with microarray techniques. The details of the induction and reversal of the drug resistance are also described.

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5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies

Biodistribution and delivery efficiency of unmodified tumor-derived exosomes.

Eddy Pasquier 1,5 , Joseph Ciccolini 2 , Manon Carre 3 , Sarah Giacometti 2 , Raphaelle Fanciullino 2 , Charlotte Pouchy 1,‡ , Marie-Pierre Montero 3 , Cindy Serdjebi 2 , Maria Kavallaris 1 and Nicolas Andre 3,4,5 1 Children’s Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia 2 Pharmacokinetics Unit, UMR-MD3, Aix-Marseille Univ, Marseille, France 3 INSERM UMR 911, Centre de Recherche en Oncologie biologique et en Oncopharmacologie, Aix-Marseille Univ, Marseille, France 4 Hematology & Pediatric Oncology Department, La Timone University Hospital of Marseille, France 5 Metronomics Global Health Initiative, Marseille, France ‡ Current Address: Universite Pierre et Marie Curie - Univ Paris 6, CNRS UMR 7211, INSERM U959, Paris, France Received: October 13, 2011; Accepted: October 14, 2011; Published: October 17, 2011; Keywords: breast cancer, angiogenesis, propranolol, beta-adrenergic receptor antagonist, chemotherapy, combination therapy Correspondence: Eddy Pasquier, PhD, email: // Nicolas Andre, MD, PhD, email: // // Abstract Recent clinical evidence revealed that the use of beta-blockers such as propranolol, prior to diagnosis or concurrently with chemotherapy, could increase relapse-free and overall survival in breast cancer patients. We therefore hypothesized that propranolol may be able to increase the efficacy of chemotherapy either through direct effects on cancer cells or via anti-angiogenic mechanisms. In vitro proliferation assay showed that propranolol (from 50-100 μM) induces dose-dependent anti-proliferative effects in a panel of 9 human cancer and “normal” cell lines. Matrigel assays revealed that propranolol displays potent anti-angiogenic properties at non-toxic concentrations (<50 μM) but exert no vascular-disrupting activity. Combining chemotherapeutic drugs, such as 5-fluorouracil (5-FU) or paclitaxel, with propranolol at the lowest effective concentration resulted in synergistic, additive or antagonistic effects on cell proliferation in vitro depending on the cell type and the dose of chemotherapy used. Interestingly, breast cancer and vascular endothelial cells were among the most responsive to these combinations. Furthermore, Matrigel assays indicated that low concentrations of propranolol (10 – 50 μM) potentiated the anti-angiogenic effects of 5-FU and paclitaxel. Using an orthotopic xenograft model of triple-negative breast cancer, based on s.c injection of luciferase-expressing MDA-MB-231 cells in the mammary fat pad of nude mice, we showed that propranolol, when used alone, induced only transient anti-tumor effects, if at all, and did not increase median survival. However, the combination of propranolol with chemotherapy resulted in more profound and sustained anti-tumor effects and significantly increased the survival benefits induced by chemotherapy alone (+19% and +79% in median survival for the combination as compared with 5-FU alone and paclitaxel alone, respectively; p<0.05). Collectively our results show that propranolol can potentiate the anti-angiogenic effects and anti-tumor efficacy of chemotherapy. The current study, together with retrospective clinical data, strongly suggests that the use of propranolol concurrently with chemotherapy may improve the outcome of breast cancer patients, thus providing a strong rationale for the evaluation of this drug combination in prospective clinical studies.

/pdf/propranolol-potentiates-the-anti-angiogenic-effects-and-anti-31vgqpnvmc.pdf

Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment

Anticancer drugs are essential agents in the global strategy developed to fight cancer. Still, narrow therapeutic indices, erratic pharmacokinetics profiles and lack of selectivity towards malignant tissues often hamper their efficacy at the bedside, when they not cause severe toxicities. In this respect, developing innovative drug delivery strategies that would selectively target malignant tissues is still an ongoing story, both in experimental and in clinical oncology. Delivery systems such as liposomes are usually required when an existing formulation is not satisfactory, because encapsulation is expected to provide higher therapeutic efficacy and safety. Such significant improvement in therapeutic efficacy and/or therapeutic indices has already been achieved in patients with some liposome-encapsulated drugs such as anthracyclines. It is now possible to develop a wide range of vectors varying in size, composition, and surface morphology suitable for a variety of therapeutic applications, including for targeting tumor tissues. Reformulation of anticancer drugs in liposomes remains a challenging opportunity to stretch the therapeutic indices of many cytotoxic drugs, through the optimization of their distribution in the body. Despite these promising and exciting perspectives in oncology, to date only few drugs (e.g., anthracyclines) have actually made their way as liposomes from the bench to the bedside. However, as target therapies have brought a new hope in the cancer war in the 2000's, developing now targeted delivery systems is more and more seen as the next step to further improve clinical outcome in cancer patients. This review covers the achievements, limits, and new expectancies of anticancer drugs as candidates for liposomal encapsulation.

Liposome-encapsulated anticancer drugs: still waiting for the magic bullet?

Improving the efficacy-toxicity balance of anticancer agents remains an ongoing challenge in oncology. Beside the ever-growing development of innovative drugs addressing newly discovered molecular targets, nanotechnologies provide today a promising and exciting strategy to achieve this goal. The idea of carrying active compounds to their respective targets so as to improve their efficacy while sparing healthy tissue and reducing side-effects is not new. However, this area of research is in constant rise, and benefits from the latest advances in the field of biopharmaceutics, medicinal chemistry and nanomedicine. In addition to anthracyclines already widely present as liposomal drugs on the shelves, a variety of anticancer drugs can be now encapsulated into different chemical of structures so as to enhance their specificity toward malignant cells, mainly through improved pharmacokinetics profiles. Indeed, the recent advances in chemistry allow now a wide variety of scaffolds to be used as drug-carriers, so as optimize the delivery of cytotoxics. Even more recently, conjugated-drugs such as nanoalbumin (Nab) conjugates have emerged as a new promising alternative to improve both anticancer drugs distribution in the body and efficacy/toxicity balance eventually. This review covers the achievements and current limits of nanoparticles in oncology, with a special focus on nab-paclitaxel as a paradigmatic drug for this new generation of conjugated entities.

Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs

Optimization of trans-Resveratrol bioavailability for human therapy

Developing innovative delivery strategies remains an ongoing task to improve both efficacy and safety of drug-based therapy. Nanomedicine is now a promising field of investigation, rising high expectancies for treating various diseases such as malignancies. Putting drugs into liposome is an old story that started in the late 1960s. Because of the near-total biocompatibility of their lipidic bilayer, liposomes are less concerned with the safety issue related to the possible long-term accumulation in the body of most nanoobjects currently developed in nanomedicine. Additionally, novel techniques and recent efforts to achieve better stability (e.g., through sheddable coating), combined with a higher selectivity towards target cells (e.g., by anchoring monoclonal antibodies or incorporating phage fusion protein), make new liposomal drugs an attractive and challenging opportunity to improve clinical outcome in a variety of disease. This review covers the physicochemistry of liposomes and the recent technical improvements in the preparation of liposome-encapsulated drugs in regard to the scientific and medical stakes.

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Raphaelle Fanciullino

Papers

Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment

Liposome-encapsulated anticancer drugs: still waiting for the magic bullet?

Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs

Optimization of trans-Resveratrol bioavailability for human therapy

Optimizing Druggability through Liposomal Formulations: New Approaches to an Old Concept