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1.  The combination of EPA+DHA and low-dose aspirin ingestion reduces platelet function acutely whereas each alone may not in healthy humans 
Aspirin’s effectiveness in reducing cardiovascular disease events is inadequate in some individuals, a phenomenon termed aspirin “resistance”. The hypothesis that combining low dose aspirin with eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) reduces platelet function in the acute setting has not been investigated.
Patients and methods
We conducted a clinical trial of EPA+DHA and aspirin ingestion in healthy adults. Fasting blood samples were drawn at baseline and 4 h after supplementation with EPA/DHA (3.4 g/d), aspirin (81 mg), and both. Platelet function was measured using the Platelet Function Analyzer-100 (PFA-100). Plasma lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), autotaxin, angiogenesis activators, and cytokines were measured.
Platelet function decreased with the combination of aspirin+EPA/DHA (p=0.03) but not with either alone (p>0.05). EPA-LPC increased (p=0.002).
Discussion and conclusions
Our results demonstrate that a potentially beneficial effect on platelet function occurred within 4 h after ingestion of low-dose aspirin and EPA+DHA in healthy adults.
PMCID: PMC3589139  PMID: 23017325
Omega-3 fatty acids; Eicosapentaenoic acid; Docosahexaenoic acid; Aspirin; Acetylsalicylic acid; Platelet function; Platelet function analyzer-100
2.  Regional consensus opinion for the management of Beta thalassemia major in the Arabian Gulf area 
Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The mutations that give rise to either alpha or beta thalassemia are numerous, resulting in a wide spectrum of clinical severity ranging from carrier state to life-threatening, inherited hemolytic anemia that requires regular blood transfusion. Beta thalassemia major constitutes a remarkable challenge to health care providers. The complications arising due to the anemia, transfusional iron overload, as well as other therapy-related complications add to the complexity of this condition. To produce this consensus opinion manuscript, a PubMed search was performed to gather evidence-based original articles, review articles, as well as published work reflecting the experience of physicians and scientists in the Arabian Gulf region in an effort to standardize the management protocol.
PMCID: PMC3848639  PMID: 24044606
Anemia; Chelation; Arabian Gulf; Iron chelation therapy; Iron overload; Thalassemia management; Transfusion
3.  Effects of Obesity and Sex on Antimicrobial Pharmacokinetics and Acute Kidney Injury: Validation of a Preclinical Model 
Obese patients may be at a greater risk for acute kidney injury (AKI) with the use of certain antimicrobial agents that are dosed by weight. Current preclinical models of AKI utilize the male rat within a narrow weight range that limits extrapolation of the generated results. We evaluated the pharmacokinetics and AKI potential of gentamicin in 14-week-old diet-induced obesity-prone (n = 40) and obesity-resistant (n = 40) rats of both sexes. Single daily doses of gentamicin (12.5, 18.75, or 25 mg/kg of body weight) or saline (control) were administered intraperitoneally for 14 doses. Blood samples were collected after doses 1, 7, and 14, assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and analyzed using a nonparametric population pharmacokinetic approach for gentamicin. Urine was collected after doses 1, 3, and 5 and assayed for kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) and normalized to creatinine (Cr) values. Histology was performed on all animals, and the degree of proximal tubular injury was graded. The mean (minimum, maximum) weight of the rats was 330 (136, 580) g. NGAL/Cr predicted AKI better than did KIM-1/Cr and was detectable in male rats after dose 1 and in obesity-prone female rats after dose 5. Proximal tubular injury by histology was significantly higher in male than in female rats. A significant relationship between the gentamicin area under the curve from zero to 24 hours (AUC0–24) estimates and the maximum NGAL/Cr ratio was observed. This preclinical model has the potential to aid with dose extrapolation for body size and improve assessment of the toxicology potential of antimicrobials in development.
PMCID: PMC3553709  PMID: 23147732
4.  Fibrin and Collagen Differentially but Synergistically Regulate Sprout Angiogenesis of Human Dermal Microvascular Endothelial Cells in 3-Dimensional Matrix 
Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors.
PMCID: PMC3657431  PMID: 23737792
5.  Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration 
Wet age-related macular degeneration (AMD) is the most common reason for vision loss in the United States. Many treatments, such as laser therapy and photodynamic therapies, have been used but their efficacy is limited. Emerging anti-vascular endothelial growth factor (VEGF) therapies are now considered the standard of care. Anti-VEGF agents inhibit angiogenesis in the eye by suppressing abnormal blood vessel growth, leading to vision improvement. Ranibizumab and bevacizumab are two examples of anti-VEGF drugs that have been approved; both showed promise based on the visual acuity scale. Aflibercept, another new therapy known to trap VEGF and inhibit multiple growth factors, is promising not only because it can be taken bimonthly based on year 1 of the VIEW trials, but it can also be extended, as demonstrated in year 2 of the VIEW trials. Based on a cost–effect analysis, aflibercept is comparable to other leading therapies. This is a review of relevant clinical trials that have proven the non-inferiority and safety of aflibercept compared to the standard of care and its unique role in the current management of wet AMD.
PMCID: PMC3595183  PMID: 23503202
aflibercept; VEGF; anti-VEGF; pegatanib; bevacizumab; ranibizumab; VIEW trials
6.  Adsorption of doxorubicin on poly (methyl methacrylate) -chitosan-heparin coated activated carbon beads 
Langmuir  2012;28(9):4396-4403.
Extracorporeal filter cartridges, filled with activated carbon bead (ACB) adsorbent, have been used for removal of overdosed cancer drugs from the blood. Coatings on adsorbent matrices, poly (methyl methacrylate) (PMMA)/activated carbon bead and PMMA/chitosan/heparin/ACB composites, were tested to improve their biocompatibility and blood compatibility. PMMA coating on ACBs was accomplished in a straightforward manner using a PMMA solution in ethyl acetate. One-step hybrid coating of ACBs with PMMA-anticoagulant heparin required the use of acetone and water co-solvents. Multi-layer coatings with three components, PMMA, chitosan, and heparin involved three steps: PMMA was first coated on ACBs; chitosan was then coated on the PMMA coated surface; and finally heparin was covalently attached to the chitosan coating. Surface morphologies were studied by scanning electron microscopy. X-ray photoelectron spectroscopy confirmed −SO3− group. Adsorption, of a chemotherapy drug (doxorubicin) from both water and PBS, by the coated ACBs was examined. The adsorption isotherm curves were fitted using the Freundlich model. The current adsorption system might find potential applications in the removal of high dose regional chemotherapy drugs while maintaining high efficiency, biocompatibility, and blood compatibility.
PMCID: PMC3309418  PMID: 22313019
doxorubicin; drug removal; carbon beads; adsorption; heparin coating; blood compatibility
7.  The Effects of EPA+DHA and Aspirin on Inflammatory Cytokines and Angiogenesis Factors 
In a recent study, we showed that the combination of aspirin plus the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) synergistically inhibited platelet function. As aspirin, EPA, and DHA have demonstrated anti-inflammatory properties, we hypothesized that the ingestion of EPA and DHA, with and without aspirin, would reduce plasma levels of inflammatory cytokines and angiogenesis factors more than aspirin alone and before aspirin was ingested.
Using multiplex technology, we investigated the effects of aspirin (single-dose 650 mg on day 1), EPA+DHA (3.4 g/d for days 2-29), and aspirin with EPA+DHA (day 30) on plasma levels of inflammatory cytokines and angiogenesis factors in healthy adults.
Aspirin alone had no effect on any factor versus baseline, but EPA+DHA, with and without aspirin, significantly reduced concentrations of 8 of 9 factors. Although EPA+DHA plus aspirin reduced concentrations of a subset of the factors compared to baseline, neither aspirin alone nor the combination significantly reduced the level of any analyte more robustly than EPA+DHA alone.
These data suggest that EPA+DHA has more pronounced down-regulatory effects on inflammation and angiogenesis than aspirin. The implications of these findings for the use of combined therapy for cardiovascular disease remain to be clarified.
PMCID: PMC3331709  PMID: 22530200
eicosapentaenoic acid; docosahexaenoic acid; lipid mediators; fatty acids; angiogenesis; hemostasis; platelet function; cytokines; aspirin
8.  Current primary open-angle glaucoma treatments and future directions 
Primary open-angle glaucoma (POAG) is a leading cause of blindness with no known cure. Management of the disease focuses on lowering intraocular pressure (IOP) with current classes of drugs like prostaglandin analogs, beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors. These treatments have not helped all patients. Some patients continue to experience deterioration in the optic nerve even though their IOPs are within the normal range. New views have surfaced about other pathophysiological processes (such as oxidative stress, vascular dysfunction, and retinal cell apoptosis) being involved in POAG progression, and adjunctive treatments with drugs like memantine, bis(7)-tacrine, nimodipine, and mirtogenol are advocated. This review examines the current and proposed treatments for POAG. Some of the proposed drugs (bis(7)-tacrine, nimodipine, vitamin E, and others) have shown good promise, mostly as monotherapy in various clinical trials. It is recommended that both the current and proposed drugs be put through further robust trials in concurrent administration and evaluated.
PMCID: PMC3484725  PMID: 23118520
bis(7)-tacrine; betaxolol; memantine; mirtogenol; POAG; timolol; travoprost
9.  Chemoenzymatic Synthesis of Homogeneous Ultralow Molecular Weight Heparins 
Science (New York, N.Y.)  2011;334(6055):498-501.
Ultralow molecular weight (ULMW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 daltons, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process. Here, we report 10- and 12-step chemoenzymatic syntheses of two structurally homogeneous ULMW heparins (MW = 1778.5 and 1816.5) in 45 and 37% overall yield, respectively, starting from a simple disaccharide. These ULMW heparins display excellent in vitro anticoagulant activity and comparable pharmacokinetic properties to Arixtra, as demonstrated in a rabbit model. The chemoenzymatic approach is scalable and shows promise for a more efficient route to synthesize this important class of medicinal agent.
PMCID: PMC3425363  PMID: 22034431
10.  Ultraperformance ion-pairing liquid chromatography with on-line electrospray ion trap mass spectrometry for heparin disaccharide analysis 
Analytical biochemistry  2011;415(1):59-66.
A high resolution method for the separation and analysis of disaccharides prepared from heparin and heparan sulfate (HS) using heparin lyases is described. Ultraperformance liquid chromatography in a reverse-phase, ion-pairing mode efficiently separates eight heparin/HS disaccharides. The disaccharides can then be detected and quantified using electrospray ionization mass spectrometry. This method is particularly useful in the analysis of small amounts of biological samples, including cells, tissues and biological fluids, as it provides high sensitivity without being subject to interference from proteins, peptides and other sample impurities.
PMCID: PMC3108029  PMID: 21530482
heparin; heparan sulfate; heparin lyase; disaccharide analysis; biological samples; ultraperformance liquid chromatography; mass spectrometry
11.  Control of the heparosan N-deacetylation leads to an improved bioengineered heparin 
The production of the anticoagulant drug heparin from non-animal sources has a number of advantages over the current commercial production of heparin. These advantages include better source material availability, improved quality control, and reduced concerns about animal virus or prion impurities. A bioengineered heparin would have to be chemically and biologically equivalent to be substituted for animal-sourced heparin as a pharmaceutical. In an effort to produce bioengineered heparin that more closely resembles pharmaceutical heparin, we have investigated a key step in the process involving the N-deacetylation of heparosan. The extent of N-deacetylation directly affects the N-acetyl/N-sulfo ratio in bioengineered heparin and also impacts its molecular weight. Previous studies have demonstrated that the presence and quantity of N-acetylglucosamine in the nascent glycosaminoglycan chain, serving as the substrate for the subsequent enzymatic modifications (C5 epimerization and O-sulfonation), can impact the action of these enzymes and, thus, the content and distribution of iduronic acid and O-sulfo groups. In this study, we control the N-deacetylation of heparosan to produce a bioengineered heparin with an N-acetyl/N-sulfo ratio and molecular weight that is similar to animal-sourced pharmaceutical heparin. The structural composition and anticoagulant activity of the resultant bioengineered heparin was extensively characterized and compared to pharmaceutical heparin obtained from porcine intestinal mucosa.
PMCID: PMC3124281  PMID: 21484210
Heparin; Heparosan; Porcine intestine; Deacetylation
12.  High Density Lipoprotein (HDL) Modulation Targets 
Drugs of the future  2010;35(1):33-39.
Given the strong genetic determinants of favorable HDL-C levels, the ability to procure the cardiovascular disease and longevity benefits associated with this mediator of the reverse cholesterol transport pathway through pharmaceutical intervention is challenging. Niacin is still the most robust HDL-C raising pharmaceutical agent on the market at its use leads to elevations up to 35%. Cholesteryl ester transfer protein (CETP) and endothelial lipase (EL) are two targets involved in the reverse cholesterol transport pathway that have become therapeutic targets of various investigations for raising HDL. However, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was stopped in December 2006 due to excess mortality in the group of patients treated with torcetrapib, a CETP inhibitor. Other CETP inhibitors being studied include anacetrapib and JTT-705. Other CEPT inhibitors including TA-8995, DRL-17822, JTT-302, and others are under investigation. Additionally a biologic target CETi-1, an investigational vaccine in phase II development designed to elicit antibodies that bind and inhibit the activity of CETP leading to blocking the ability of the protein to transfer cholesterol from HDL to LDL and thus causing HDL cholesterol levels to rise is under clinical investigation for sometime.
PMCID: PMC3381456  PMID: 22740724
High Density lipoprotein (HDL); Low Density lipoprotein (LDL); atherosclerosis; coronary heart disease (CHD); Cholesteryl ester transfer protein (CETP); Endothelial Lipase; Longevity; Stroke; Coronary artery Diseases (CAD); cardiovascular diseases (CVD); Inflammation; genetics; niacin; statins; fibrates
13.  Novel Therapeutic Targets for Preserving a Healthy Endothelium: Strategies for Reducing the Risk of Vascular and Cardiovascular Disease 
Cardiology Journal  2011;18(4):352-363.
The endothelium lies in a strategic anatomical position between the circulating blood and vascular smooth-muscle cells as a source of vasodilators such as nitric oxide, prostacyclin, and hyperpolarizing factor as well as heparin-like substances as well as other molecules with anti-proliferative properties. These effects of endothelial cells may explain why platelets and monocytes usually do not adhere at the blood vessel wall. However, under pathological conditions, endothelial dysfunction occurs and significantly contributes to the increase of platelet-vessel wall interaction, vasoconstriction, pro-inflammation, and proliferation. Under these conditions, endothelium-dependent vasodilation is reduced and endothelium-dependent constrictor responses are augmented. Upon vessel wall injury platelets rapidly adhere to the exposed sub-endothelial matrix which is mediated by several cellular receptors present on platelets or endothelial cells and various adhesive proteins. Subsequent platelet activation results in the recruitment of additional platelets and the generation of platelet aggregates forming a stable platelet plug. Therapeutic strategies aimed at improving or preserving endothelial function therefore may be promising in the prevention and treatment of coronary artery disease. Diagnostic modalities for assessment of endothelial function should allow for the early detection of vascular endothelial dysfunction before the manifestation of serious adverse vascular disorders.
PMCID: PMC3342824  PMID: 21769815
vascular; endothelial cell; cardiovascular disorders; coronary syndrome; vasoconstriction; vasodilation; inflammation; anti-inflammation; anti-platelet; pro-platelet; anticoagulant; pro-coagulant; Diagnosis of endothelial function
14.  Current status and future directions in the management of chronic hepatitis C 
Virology Journal  2012;9:57.
Hepatitis C virus (HCV) is endemic worldwide, and it causes cirrhosis and other complications that often lead to death; nevertheless, our knowledge of the disease and its mechanisms is limited. HCV is most common in underdeveloped nations, including many in Africa and Asia. The virus is usually transmitted by parenteral routes, but sexual, perinatal, and other types of transfer have been known to occur. Approximately 80% of individuals who contract hepatitis C develop a chronic infection, and very few are able to spontaneously clear the virus. Because hepatitis C is asymptomatic in the majority of patients, the presence of HCV RNA in the serum is the best diagnostic tool. Although serious complications from hepatitis C may not occur for 20 years, 1/5 of chronic patients eventually develop life - threatening cirrhosis. More research is needed on the different therapy options for the disease, and many factors, most importantly the genotype of the virus, must be taken into account before beginning any treatment. As there is no vaccine against HCV at present, the most effective and recommended therapy is pegylated-interferon-α-2a plus ribavirin. While interferon is marginally effective as a monotherapy, both adding the moiety and combining it with ribavirin have been shown to dramatically increase its potency. While there are numerous alternative and complementary medicines available for patients with hepatitis C, their efficacy is questionable. Currently, research is being done to investigate other possible treatments for hepatitis C, and progress is being made to develop a vaccine against HCV, despite the many challenges the virus presents. Until such a vaccination is available, prevention and control methods are important in containing and impeding the spread of the virus and mitigating its deleterious effects on the health of people and communities worldwide.
PMCID: PMC3325870  PMID: 22385500
Hepatitis C; Fibrosis; Cirrhosis; Hepatic carcinoma; Prevention; Treatment; Antiviral
15.  Impact of autoclave sterilization on the activity and structure of formulated heparin 
Journal of pharmaceutical sciences  2011;100(8):3396-3404.
The stability of a formulated heparin was examined during its sterilization by autoclaving. A new method to follow loss in heparin binding to the serine protease inhibitor, antithrombin III, and the serine protease, thrombin, and was developed using a surface plasmon resonance (SPR) competitive binding assay. This loss in binding affinity correlated well with loss in anti-factor IIa (thrombin) activity as well as anti-factor Xa activity as measured using conventional amidolytic assays. Autoclaving also resulted in a modest breakdown of the heparin backbone as confirmed by a slight reduction in number averaged and weight averaged molecular weight and an increase in polydispersity. While no clear changes were observed by nuclear magnetic resonance spectroscopy, disaccharide composition analysis using high-performance liquid chromatography-electrospray ionization mass spectrometry suggested loss of selected sulfo groups had taken place. It is this sufo group loss that probably accounts for a decrease in the binding of autoclaved heparin to antithrombin III and thrombin as well as the observed decrease in its amidolytic activity.
PMCID: PMC3163591  PMID: 21416466
heparin; surface plasmon resonance; antithrombin III; thrombin; interaction; stability; autoclaving
16.  Crosstalk between Integrin αvβ3 and Estrogen Receptor-α Is Involved in Thyroid Hormone-Induced Proliferation in Human Lung Carcinoma Cells 
PLoS ONE  2011;6(11):e27547.
A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK) 1/2 has been identified on integrin αvβ3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10−7 M), T4 significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3′-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Neutralizing antibody to integrin αvβ3 and an integrin-binding Arg-Gly-Asp (RGD) peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac) lacks thyroid hormone function but inhibits binding of T4 and T3 to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα)-positive lung cancer cells, thyroid hormone (T4>T3) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T4-induced, but not T3-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA) expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.
PMCID: PMC3222665  PMID: 22132110
17.  Nanoparticle Delivery of Natural Products in the Prevention and Treatment of Cancers: Current Status and Future Prospects 
Cancers  2011;3(4):4024-4045.
The advent of nanotechnology has had a revolutionary impact on many aspects of 21st century life. Nanotechnology has provided an opportunity to explore new avenues that conventional technologies have been unable to make an impact on for diagnosis, prevention, and therapy of different diseases, and of cancer in particular. Entities in nanometer sizes are excellent platforms to incorporate various drugs or active materials that can be delivered effectively to the desired action site without compromising the activity of the incorporated drug or material. In particular, nanotechnology entities can be used to deliver conventional natural products that have poor solubility or a short half life. Conventional natural products used with entities in nanometer sizes enable us to solve many of the inherent problems (stability, solubility, toxicity) associated with natural products, and also provide a platform for targeted delivery to tumor sites. We recently introduced the novel concept of using nanotechnology for enhancing the outcome of chemoprevention, which we called ‘nanochemoprevention’. This idea was subsequently exploited by several laboratories worldwide and has now become an advancing field in chemoprevention research. This review examines some of the applications of nanotechnology for cancer prevention and therapy using natural products.
PMCID: PMC3763408  PMID: 24213123
nanoparticles; cancer; chemoprevention; natural product; epigallocatechin-3-gallate; curcumin; resveratrol; taxol; camptothecin
18.  Nanotechnology-Based Detection and Targeted Therapy in Cancer: Nano-Bio Paradigms and Applications 
Cancers  2011;3(3):2888-2903.
The application of nanotechnology to biomedicine, particularly in cancer diagnosis and treatment, promises to have a profound impact on healthcare. The exploitation of the unique properties of nano-sized particles for cancer therapeutics is most popularly known as nanomedicine. The goals of this review are to discuss the current state of nanomedicine in the field of cancer detection and the subsequent application of nanotechnology to treatment. Current cancer detection methods rely on the patient contacting their provider when they feel ill, or relying on non-specific screening methods, which unfortunately often result in cancers being detected only after it is too late for effective treatment. Cancer treatment paradigms mainly rely on whole body treatment with chemotherapy agents, exposing the patient to medications that non-specifically kill rapidly dividing cells, leading to debilitating side effects. In addition, the use of toxic organic solvents/excipients can hamper the further effectiveness of the anticancer drug. Nanomedicine has the potential to increase the specificity of treatment of cancer cells while leaving healthy cells intact through the use of novel nanoparticles. This review discusses the use of nanoparticles such as quantum dots, nanoshells, nanocrystals, nanocells, and dendrimers for the detection and treatment of cancer. Future directions and perspectives of this cutting-edge technology are also discussed.
PMCID: PMC3759178  PMID: 24212938
nanomedicine; nanoparticles; dendrimer; PLGA; quantum dots; oncology; site-directed delivery; early detection; therapy
19.  Therapeutics formulated to target cancer stem cells: Is it in our future? 
With the political, social and financial drives for cancer research, many advances have been made in the treatment of many different cancer types. For example, given the increase in awareness, early detection, and treatment of breast and prostate cancers, we have seen substantial increases in survival rates. Unfortunately there are some realms of cancer that have not seen these substantial advancements, largely due to their rapid progression and the inability to specifically target therapy.
The hypothesis that cancers arise from a small population of cells, called cancer stem cells (CSCs), is gaining more popularity amongst researchers. There are, however, still many skeptics who bring into question the validity of this theory. Many skeptics believe that there is not a specific subset of cells that originate with these characteristics, but that they develop certain features over time making them more resistant to conventional therapy. It is theorized that many of the relapses occurring after remission are due to our inability to destroy the self-renewing CSCs. This central idea, that CSCs are biologically different from all other cancer cells, has directed research towards the development of therapy to target CSCs directly. The major dilemma in targeting therapy in myeloproliferative disorders, malignancies of the central nervous system or malignancies in general, is the inability to target CSCs as opposed to normal stem cells. However, with the recent advances in the identifications of unique molecular signatures for CSCs along with ongoing clinical trials targeting CSCs, it is possible to use targeted nanotechnology-based strategies in the management of different types of cancers.
PMCID: PMC3073868  PMID: 21439058
Cancer Stem Cell; Cancer Stem Cell Like; Molecular Signature; Cell Surface Markers; Microenvironment; Targeted Therapy; Chemoresistance; Cancer Recurrence; Signaling Pathways
20.  Pharmacodynamic Modeling of Anti-Cancer Activity of Tetraiodothyroacetic Acid in a Perfused Cell Culture System 
PLoS Computational Biology  2011;7(2):e1001073.
Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations.
Author Summary
Clinical treatment protocols for specific solid cancers have favorable response rates of 20%–25%. Cancer cells frequently become resistant to treatment. Therefore, novel anti-cancer drugs and combination regimens need to be developed. Conducting enough clinical trials to evaluate combinations of anti-cancer agents in several regimens to optimize treatment is not feasible. We showed that tetrac inhibits the growth of various cancer cell lines. Our newly developed in vitro system allowed studying the effects of tetrac over time in various human cancer cell lines. Our mathematical model could distinguish two effects of tetrac and may be used to predict effects of other than the studied dosage regimens. Human breast cancer cells were more sensitive to the effect on success of replication than the effect on growth rate, whereas the maximum possible effect was larger for the latter effect. Nanoparticulate tetrac, which does not enter into cells, had a larger effect than unmodified tetrac. The combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab showed approximately additive effects. Our in vitro perfusion system together with mathematical modeling may be useful for dose-finding, translation from in vitro to animal and human studies, and studying effects of other chemotherapeutic agents or their combinations.
PMCID: PMC3033367  PMID: 21304935
21.  Molecular Basis for Certain Neuroprotective Effects of Thyroid Hormone 
The pathophysiology of brain damage that is common to ischemia–reperfusion injury and brain trauma include disodered neuronal and glial cell energetics, intracellular acidosis, calcium toxicity, extracellular excitotoxic glutamate accumulation, and dysfunction of the cytoskeleton and endoplasmic reticulum. The principal thyroid hormones, 3,5,3′-triiodo-l-thyronine (T3) and l-thyroxine (T4), have non-genomic and genomic actions that are relevant to repair of certain features of the pathophysiology of brain damage. The hormone can non-genomically repair intracellular H+ accumulation by stimulation of the Na+/H+ exchanger and can support desirably low [Ca2+]i.c. by activation of plasma membrane Ca2+–ATPase. Thyroid hormone non-genomically stimulates astrocyte glutamate uptake, an action that protects both glial cells and neurons. The hormone supports the integrity of the microfilament cytoskeleton by its effect on actin. Several proteins linked to thyroid hormone action are also neuroprotective. For example, the hormone stimulates expression of the seladin-1 gene whose gene product is anti-apoptotic and is potentially protective in the setting of neurodegeneration. Transthyretin (TTR) is a serum transport protein for T4 that is important to blood–brain barrier transfer of the hormone and TTR also has been found to be neuroprotective in the setting of ischemia. Finally, the interesting thyronamine derivatives of T4 have been shown to protect against ischemic brain damage through their ability to induce hypothermia in the intact organism. Thus, thyroid hormone or hormone derivatives have experimental promise as neuroprotective agents.
PMCID: PMC3193027  PMID: 22016721
thyroid hormone; thyronamines; sodium-proton exchanger; calcium ATPase; seladin-1; transthyretin; ischemia–reperfusion injury
22.  Biosensors: the new wave in cancer diagnosis 
The earlier cancer can be detected, the better the chance of a cure. Currently, many cancers are diagnosed only after they have metastasized throughout the body. Effective, accurate methods of cancer detection and clinical diagnosis are urgently needed. Biosensors are devices that are designed to detect a specific biological analyte by essentially converting a biological entity (ie, protein, DNA, RNA) into an electrical signal that can be detected and analyzed. The use of biosensors in cancer detection and monitoring holds vast potential. Biosensors can be designed to detect emerging cancer biomarkers and to determine drug effectiveness at various target sites. Biosensor technology has the potential to provide fast and accurate detection, reliable imaging of cancer cells, and monitoring of angiogenesis and cancer metastasis, and the ability to determine the effectiveness of anticancer chemotherapy agents. This review will briefly summarize the current obstacles to early detection of cancer and the expanding use of biosensors as a diagnostic tool, as well as some future applications of biosensor technology.
PMCID: PMC3781701  PMID: 24198482
biosensor; oncogene; nanotechnology; biotechnology; cancer detection; diagnosis; point-of-care
23.  Bevasiranib for the Treatment of Wet, Age-Related Macular Degeneration 
Age- related Macular Degeneration (AMD) is the leading cause of severe visual impairment in people 65 years and older in industrialized nations. Exudative, or “wet”, AMD is a late form of AMD (as distinguished from atrophic, so-called dry, AMD) and is responsible for over 60% of all cases of blindness due to AMD. It is widely accepted that vascular endothelial growth factor (VEGF) is a key component in the pathogenesis of choroidal neo-vascularization (CNV), which is a precursor to wet AMD. The current gold-standard for treating wet AMD is the monoclonal antibody fragment ranibizumab (trade name Lucentis), which targets VEGF. Other agents used to treat wet AMD include pegaptanib (Macugen), bevacizumab (Avastin; off-label use), and several other experimental agents. The advent of small interfering RNA (siRNA) has presented a whole new approach to inhibiting VEGF. This article reviews the status of a novel siRNA-based therapeutic, bevasiranib, for the treatment of wet AMD. Bevasiranib is believed to work by down regulating VEGF production in the retina. Studies in human cell-lines and animal models have shown that VEGF siRNAs are effective in inhibiting VEGF production. Although there is a lack of sufficient published data on human studies supporting the use of bevasiranib for wet AMD, available data indicates that due to its unique mechanism of action, bevasiranib might hold some promise as a primary or adjunct treatment for wet AMD.
PMCID: PMC3661434  PMID: 23861616
age-related macular degeneration; vascular endothelial growth factor; bevasiranib
24.  Introducing Nanochemoprevention as a Novel Approach for Cancer Control: Proof of Principle with Green Tea Polyphenol Epigallocatechin-3-Gallate 
Cancer research  2009;69(5):1712-1716.
Chemoprevention, especially through the use of naturally occurring phytochemicals capable of impeding the process of one or more steps of carcinogenesis process, is a promising approach for cancer management. Despite promising results in preclinical settings, its applicability to humans has met with limited success largely due to inefficient systemic delivery and bioavailability of promising chemopreventive agents. Here, we introduce the concept of nanochemoprevention, which uses nanotechnology for enhancing the outcome of chemoprevention. We encapsulated green tea polyphenol epigallocatechin-3-gallate (EGCG) in polylactic acid–polyethylene glycol nanoparticles and observed that encapsulated EGCG retains its biological effectiveness with over 10-fold dose advantage for exerting its proapoptotic and angiogenesis inhibitory effects, critically important determinants of chemopreventive effects of EGCG in both in vitro and in vivo systems. Thus, this study could serve as a basis for the use of nanoparticle-mediated delivery to enhance bioavailability and limit any unwanted toxicity of chemopreventive agents, such as EGCG.
PMCID: PMC2950093  PMID: 19223530
25.  Pharmacogenetics in breast cancer: steps toward personalized medicine in breast cancer management 
There is wide individual variability in the pharmacokinetics, pharmacodynamics, and tolerance to anticancer drugs within the same ethnic group and even greater variability among different ethnicities. Pharmacogenomics (PG) has the potential to provide personalized therapy based on individual genetic variability in an effort to maximize efficacy and reduce adverse effects. The benefits of PG include improved therapeutic index, improved dose regimen, and selection of optimal types of drug for an individual or set of individuals. Advanced or metastatic breast cancer is typically treated with single or multiple combinations of chemotherapy regimens including anthracyclines, taxanes, antimetabolites, alkylating agents, platinum drugs, vinca alkaloids, and others. In this review, the PG of breast cancer therapeutics, including tamoxifen, which is the most widely used therapeutic for the treatment of hormone-dependent breast cancer, is reviewed. The pharmacological activity of tamoxifen depends on its conversion by cytochrome P450 2D6 (CYP2D6) to its abundant active metabolite, endoxifen. Patients with reduced CYP2D6 activity, as a result of either their genotype or induction by the coadministration of other drugs that inhibit CYP2D6 function, produce little endoxifen and hence derive limited therapeutic benefit from tamoxifen; the same can be said about the different classes of therapeutics in breast cancer. PG studies of breast cancer therapeutics should provide patients with breast cancer with optimal and personalized therapy.
PMCID: PMC3513214  PMID: 23226048
pharmacogenomics; genetic; pharmacokinetic; pharmacodynamic; personalized medicine; pharmacotherapy; anticancer drugs; efficacy; safety

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