Pegylation improves the pharmacokinetics and bioavailability of small-molecule drugs hydrolyzable by esterases: a study of phospho-Ibuprofen.

Esterase hydrolysis of drugs can accelerate their elimination, thereby limiting their efficacy. Polyethylene glycol (PEG) covalently attached to drugs (pegylation) is known to improve the efficiency of many drugs. Using as a test agent the novel phospho-ibuprofen (PI), we examined whether pegylation of PI could abrogate its hydrolytic degradation by esterases; PI, known to inhibit colon cancer growth, has a carboxylic ester hydrolyzable by carboxylesterases (CES).

Research and development in drug innovation: reflections from the 2013 bioeconomy conference in China, lessons learned and future perspectives.

The enormous progress biotechnology, bioinformatics and nanotechnology made in recent years provides opportunities and scientific framework for development of biomedicine and constitutes a paradigm shift in pharmaceutical R&D and drug innovation. By analyzing the data and related information at R&D level over the past decades, developmental tendency and R&D patterns were summarized. We found that a growing number of biologics in the pipeline of pharma companies with successful products already in the market though, small molecular entities have primarily dominated drug innovation.

Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice.

New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine.

Nanodelivery strategies in cancer chemotherapy: biological rationale and pharmaceutical perspectives.

Nanotechnology is revolutionizing our approach to drug delivery, a key determinant of drug efficacy. Here, we present cancer drug delivery strategies that exploit nanotechnology, providing first an overview of tumor biology aspects that critically affect the design of drug delivery carriers, namely the enhanced permeability and retention effect, the lower tumor extracellular pH and tumor-specific antigens. In general, nanoscience-based approaches have circumvented limitations in the delivery of cancer therapeutics, related to their poor aqueous solubility and toxicity issues with conventional vehicles and resulted in improved pharmacokinetics and biodistribution.

Topical phospho-sulindac (OXT-328) is effective in the treatment of non-melanoma skin cancer.

Phospho-sulindac (P-S, OXT-328), a novel sulindac derivative, has shown superior anticancer efficacy and safety compared to sulindac. In this study, we investigated the efficacy of topical P-S hydrogel in the treatment of non-melanoma skin cancer in preclinical models. P-S is a potent inhibitor of A431 epidermoid carcinoma in vitro and achieves this effect by inhibiting cell proliferation and inducing apoptosis.

In vitro and in vivo metabolic studies of phospho-aspirin (MDC-22).

Purpose: To investigate the metabolism of phospho-aspirin (PA, MDC-22), a novel anti-cancer and anti-inflammatory agent.

Methods: The metabolism of PA was studied in the liver and intestinal microsomes from mouse, rat and human.

Results: PA is rapidly deacetylated to phospho-salicylic acid (PSA), which undergoes regioselective oxidation to generate 3-OH-PSA and 5-OH-PSA.

Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety.

Background And Purpose: Phospho-ibuprofen (MDC-917) and phospho-sulindac (OXT-328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs).

Experimental Approach: The CYP/FMO-catalysed metabolism of phospho-ibuprofen and phospho-sulindac was studied by using in silico prediction modelling and a direct experimental approach.

Carboxylesterases 1 and 2 hydrolyze phospho-nonsteroidal anti-inflammatory drugs: relevance to their pharmacological activity.

Phospho-nonsteroidal anti-inflammatory drugs (phospho-NSAIDs) are novel NSAID derivatives with improved anticancer activity and reduced side effects in preclinical models. Here, we studied the metabolism of phospho-NSAIDs by carboxylesterases and assessed the impact of carboxylesterases on the anticancer activity of phospho-NSAIDs in vitro and in vivo. The expression of human liver carboxylesterase (CES1) and intestinal carboxylesterase (CES2) in human embryonic kidney 293 cells resulted in the rapid intracellular hydrolysis of phospho-NSAIDs.

Sterically stabilized liposomes incorporating the novel anticancer agent phospho-ibuprofen (MDC-917): preparation, characterization, and in vitro/in vivo evaluation.

Purpose: To incorporate phospho-ibuprofen (P-I), a lipophilic, water insoluble novel anti-cancer agent, into pegylated liposomes and upon formulation optimization to evaluate its antitumor activity in vitro and in vivo.

Methods: P-I loaded liposomes were prepared using the thin-film hydration method, and characterized for size, zeta potential, drug content and drug release. We examined their physical stability by particle size changes; their lyophilization ability in the presence of cryoprotectants; and their antitumor activity in vitro in human cancer cell lines and in vivo in a xenograft murine model.

Protonated nanostructured aluminosilicate (NSAS) reduces plasma cholesterol concentrations and atherosclerotic lesions in Apolipoprotein E deficient mice fed a high cholesterol and high fat diet.

The aim of this work was to assess the effect of chronic administration of protonated nanostructured aluminosilicate (NSAS) on the plasma cholesterol levels and development of atherosclerotic lesions in Apolipoprotein (ApoE) deficient mice fed a high cholesterol and high fat diet. Apolipoprotein E (ApoE) deficient mice were divided into the following treatment groups: protonated NSAS 1.4% (w/w), untreated control and 2% (w/w) stigmastanol mixed with high-cholesterol/high-fat diet.

Inhibition of intestinal absorption of cholesterol by surface-modified nanostructured aluminosilicate compounds.

The aim of this work was to assess the ability of aqueous suspensions of surface-modified nanostructured aluminosilicate (NSAS) compounds to reduce the intestinal absorption of cholesterol in a rat model. The rats were divided into 10 treatment groups which included several NSAS compounds at various doses, ezetimibe at 10 mg/kg, stigmastanol at 50 mg/kg, and normal saline. All compounds and controls were independently administered by oral gavage and then a mixture of [(3)H]cholesterol and cold cholesterol in 10% Intralipid(R) was immediately administered orally to the animals.

Advances in lipid nanodispersions for parenteral drug delivery and targeting.

Parenteral formulations, particularly intravascular ones, offer a unique opportunity for direct access to the bloodstream and rapid onset of drug action as well as targeting to specific organ and tissue sites. Triglyceride emulsions, liposomes and micellar solutions have been traditionally used to accomplish these tasks and there are several products on the market using these lipid formulations. The broader application of these lipid systems in parenteral drug delivery, however, particularly with new chemical entities, has been limited due primarily to the following reasons: a) only a small number of parenteral lipid excipients are approved, b) there is increasing number of drugs that are partially or not soluble in conventional oils and other lipid solvents, and c) the ongoing requirement for site-specific targeting and controlled drug release.

Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies.

The intestinal efflux pump, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of drugs which are substrates for this membrane transporter. In addition to anticancer and anti-HIV drugs, NCEs for other disease indications are P-gp substrates and there is considerable interest in inhibiting P-gp and thus increasing the bioavailability of these molecules. In this review article, an overview of P-gp and its role in drug transport and absorption will be presented first and then formulation strategies to effectively inhibit P-gp will be discussed and compared.

Advances in the use of tocols as drug delivery vehicles.

There has been increasing interest in recent years in the drug delivery applications of tocols and their derivatives. Their biocompatibility and potential to deliver both poorly soluble and water-soluble drugs make tocols attractive as drug delivery vehicles. This review article will focus primarily on topical, oral, and parenteral drug administration using tocols, although other routes of delivery such as pulmonary and nasal will also be discussed.

Tocol emulsions for drug solubilization and parenteral delivery.

Tocols represent a family of tocopherols, tocotrienols, and their derivatives, and are fundamentally derived from the simplest tocopherol, 6-hydroxy-2-methyl-2-phytylchroman, which is referred to as "tocol". The most common tocol is D-alpha-tocopherol, also known as vitamin E. Tocols can be excellent solvents for water insoluble drugs and are compatible with other cosolvents, oils and surfactants.