Neuroinflammation — From Bench to Bedside (Ernst Schering Foundation Symposium Proceedings)

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In addition, these tools tend to be focused and generally do not include the full range of possible contributing factors. Some risk-assessment tools are gender specific and give 1-, 5-, or year stroke risk estimates. The Framingham Stroke Profile FSP uses a Cox proportional-hazards model with risk factors as covariates and points calculated according to the weight of the model coefficients. Point values can be calculated that correspond to a gender-specific year cumulative stroke risk. The FSP has been updated to account for the use of antihypertensive therapy and the risk of stroke and stroke or death among individuals with new-onset atrial fibrillation Table 5.

The FSP has been applied to ethnic minorities in the United Kingdom and found to vary across groups, but the suitability of the scale to predict outcomes has not been well tested. Modified Framingham Stroke Risk Profile. Alternative prediction models have been developed using other cohorts and utilizing different sets of stroke risk factors. It is clear that an ideal stroke risk—assessment tool that is generally applicable, simple, and widely accepted does not exist. Each available tool has its own limitations. The impact of newer risk factors for stroke, not collected in older studies, needs to be considered.

Research is needed to validate risk-assessment tools across age, gender, and racial-ethnic groups; evaluate whether any of the more recently identified risk factors add to the predictive accuracy of existing scales; and determine whether the use of these scales improves primary stroke prevention programs. The use of a risk-assessment tool such as the FSP should be considered as these tools can help identify individuals who could benefit from therapeutic interventions and who may not be treated on the basis of any 1 risk factor Class IIa, Level of Evidence B.

Although these factors are not modifiable, they identify those who are at highest risk of stroke and who may benefit from rigorous prevention or treatment of modifiable risk factors Table 2. The cumulative effects of aging on the cardiovascular system and the progressive nature of stroke risk factors over a prolonged period of time substantially increase stroke risk. The risk of stroke doubles for each successive decade after age 55 years. Stroke is more prevalent in men than in women.

Women accounted for Stroke mortality rates among adults in England and Wales are higher among persons who had lower birth weights. Regional differences in birth weight may partially underlie geographic differences in stroke-related mortality. However, the reason for this relationship remains uncertain, and statistical association does not prove causality. Racial and ethnic effects on disease risk can be difficult to consider separately.

African Americans 24,31 and some Hispanic Americans 32,33 have higher stroke incidence and mortality rates as compared with European Americans. Both paternal and maternal history of stroke have been associated with an increased stroke risk. Concordance rates for stroke are markedly higher in monozygotic than in dizygotic twins, 43 with a nearly 5-fold increase in stroke prevalence among monozygotic as compared with dizygotic twins. Genetic influences on stroke risk can be considered on the basis of individual risk factors, the genetics of common stroke types, and uncommon or rare familial stroke types.

The DeCode genetics group Iceland has reported genetic linkage of phosphodiesterase 4D chromosome 5q12 and 5-lipoxygenase activating protein chromosome 13q to common forms of ischemic stroke. Several rare genetic disorders have been associated with stroke. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL is characterized by subcortical infarcts, dementia, and migraine headaches. Marfan syndrome due to mutations in the fibrillin gene and neurofibromatosis types I and II are associated with an increased risk of ischemic stroke.

Gene-transfer therapy has been attempted to correct the genetic defect. Enzyme replacement therapy also appears to improve cerebral vessel function. It should be recognized that treatments are available for some of the factors that have a genetic predisposition or cause such as Fabry disease , and as described in the sections that follow.

Referral for genetic counseling may be considered for patients with rare genetic causes of stroke Class IIb, Level of Evidence C. There remain insufficient data to recommend genetic screening for the prevention of a first stroke. There are several well-documented risk factors for first ischemic stroke with clear data showing a reduction in stroke risk with treatment. An important risk factor for a first stroke that is not adequately reflected in the organizational scheme used in this guideline is the presence of atherosclerotic vascular disease in another vascular bed.

The risk factors for first stroke and the risk factors for cardiovascular disease overlap. The impact of management of these common risk factors is reviewed in the context of their specific impact on stroke throughout this statement but should also be considered in the context of global reduction of vascular disease. Persons with evidence of noncerebrovascular atherosclerotic vascular disease coronary heart disease, cardiac failure, or symptomatic peripheral arterial disease are at increased risk for a first stroke.

Treatments used in the management of these other conditions eg, platelet antiaggregants and as recommended in other sections of this guideline can reduce the risk of stroke Class and Level of Evidence as indicated in the relevant sections. Hypertension Table 3 affects at least 65 million persons in the United States and is a major risk factor for both cerebral infarction and intracerebral hemorrhage. There has been compelling evidence for more than 30 years that the control of high blood pressure contributes to the prevention of stroke as well as to the prevention or reduction of other target-organ damage, including congestive heart failure and renal failure.

It remains unsettled whether specific classes of antihypertensive agents offer special protection against stroke in addition to their blood pressure—lowering effects in other settings. Despite the efficacy of antihypertensive therapy and the ease of diagnosis and monitoring, a significant proportion of the population has undiagnosed or inadequately treated hypertension.

Treatment recommendations are based on this revised classification scheme Table 6. TABLE 6. The benefit of hypertension treatment for primary prevention of stroke is clear. Choice of a specific regimen must be individualized, but reduction in blood pressure is generally more important than the specific agent used to achieve this goal. Hypertension remains undertreated in the community, and programs to improve treatment compliance need to be developed and supported. Regular screening for hypertension at least every 2 years in most adults and more frequently in minority populations and the elderly and appropriate management Class I, Level of Evidence A , including dietary changes, lifestyle modification, and pharmacological therapy as summarized in JNC 7, 76 are recommended Table 6.

Virtually every multivariable assessment of stroke risk factors eg, Framingham, 15 Cardiovascular Health Study, 94 and the Honolulu Heart Study 95 has identified cigarette smoking as a potent risk factor for ischemic stroke Table 3 , associated with an approximate doubling of ischemic stroke risk after adjustment for other risk factors. In addition, smoking has been clearly associated with a 2- to 4-fold increased risk for hemorrhagic stroke. Cigarette smoking may also potentiate the effects of other stroke risk factors. For example, a synergistic effect exists between the use of OCs and smoking on the risk of cerebral infarction.

With nonsmoking, non—OC-using women used as the reference group, the odds of cerebral infarction were 1. With nonsmoking, non—OC-using women used as the reference group, the odds of hemorrhagic stroke were 1. There is growing acceptance that exposure to environmental tobacco smoke passive cigarette smoke is a risk factor for heart disease.

Smoking likely contributes to increased stroke risk through both acute effects on the risk of thrombus generation in narrowed arteries and chronic effects related to an increased burden of atherosclerosis. Although the most effective preventive measures are to never smoke and to minimize exposure to environmental tobacco smoke, risk is reduced with smoking cessation.

Smoking cessation is associated with a rapid reduction in the risk of stroke and other cardiovascular events to a level that approaches but does not reach that of those who never smoked. Sustained smoking cessation is difficult to achieve. However, effective behavioral and pharmacological treatments for nicotine dependence now exist. Cigarette smoking is clearly associated with the risk of stroke. Epidemiological studies show a reduction in risk with smoking cessation over time.

Although effective programs to facilitate smoking cessation exist, data showing that participation in these programs leads to a reduction in stroke are lacking. Abstention from cigarette smoking and for current smokers smoking cessation are recommended Table 7 Class I, Level of Evidence B. Data from cohort and epidemiological studies are consistent and overwhelming. Avoidance of environmental tobacco smoke for stroke prevention should also be considered Class IIa, Level of Evidence C. The use of counseling, nicotine replacement, and oral smoking-cessation medications has been found to be effective for smokers and should be considered Class IIa, Level of Evidence B.

TABLE 7. Other Guideline Recommendations. Persons with type 2 diabetes have both an increased susceptibility to atherosclerosis and an increased prevalence of atherogenic risk factors, notably hypertension, obesity, and abnormal blood lipids. Case-control studies of stroke patients and prospective epidemiological studies have confirmed an independent effect of diabetes on ischemic stroke, with an increased RR in persons with diabetes ranging from 1. Stroke risk can be reduced in patients with diabetes. A small randomized trial of multifactorial intensive interventions in patients with type 2 diabetes and microalbuminuria targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria with interventions including behavioral risk factor modification and the use of a statin, ACEI, ARB, or an antiplatelet drug as appropriate.

First events included 3 nonfatal strokes, 4 nonfatal MIs, and 3 cardiovascular deaths in the 80 patients in the intensive arm versus 11 nonfatal strokes, 8 nonfatal MIs, and 1 cardiovascular death in the 80 patients in the control arm.

The combination of hyperglycemia and hypertension has long been believed to increase the frequency of diabetic complications, including stroke. Several trials have compared the effect on stroke and other cardiovascular outcomes of tight control of blood glucose and blood pressure in type 2 diabetic patients versus less stringent management. Diabetic complications overt nephropathy, dialysis, or need for laser therapy were also reduced. The 2 regimens were compared among the subgroup of persons who also had diabetes in a prespecified analysis.

A comprehensive program that includes tight control of hypertension with ACEI or ARB treatment reduces the risk of stroke in persons with diabetes. Glycemic control reduces microvascular complications, but evidence showing a reduction in stroke risk with tight glycemic control is lacking. Adequately powered studies show that treatment of diabetic patients with a statin decreases their risk of a first stroke.

Treatment of adults with diabetes, especially those with additional risk factors, with a statin to lower the risk of a first stroke is recommended Class I, Level of Evidence A Table 7. With or without atrial fibrillation, all patients with mechanical heart valves require anticoagulation, with the target level of anticoagulation varying according to the type and position of the valve and the presence of other risk factors Class I. Atrial fibrillation alone is associated with a 3- to 4-fold increased risk of stroke after adjustment for other vascular risk factors Table 3.

The prevalence of atrial fibrillation increases with age. Importantly, rhythm control does not appear to reduce stroke rates, and as discussed below, antithrombotic therapies remain the mainstay for stroke prevention. Randomized clinical trials have firmly established the value of antithrombotic therapies for reducing the risk of stroke in patients with atrial fibrillation Table 3. The absolute risk of stroke varies fold among atrial fibrillation patients, according to age and associated vascular diseases. Several stroke risk—stratification schemes have been developed and validated.

The CHADS 2 score was derived from independent predictors of stroke risk in patients with nonvalvular atrial fibrillation Table 8. The threshold of absolute stroke risk warranting anticoagulation is importantly influenced by the estimated bleeding risk if anticoagulated, patient preferences, and access to high-quality anticoagulation monitoring.

Risk stratification is the first step in the decision process Table 8. Several studies have found that only about half of patients with atrial fibrillation who are candidates for anticoagulation receive warfarin. Therefore, age per se is not a contraindication to the anticoagulation of high-risk atrial fibrillation patients. The optimal target international normalized ratio INR for primary prevention of stroke in patients with nonvalvular atrial fibrillation appears to be 2.

The importance of treatment of hypertension is discussed in a previous section. It is unclear whether sustained control of hypertension in atrial fibrillation patients reduces cardiogenic embolism. However, intracerebral bleeding, the most devastating complication of anticoagulation in the elderly, is exquisitely sensitive to blood pressure control.

Atrial fibrillation is an important, treatable stroke risk factor. It should be noted that guideline statements from different groups may vary in their recommendations about risk stratification. Long-term anticoagulation importantly reduces stroke risk in those at higher risk and without contraindications to this treatment.

The development of safer, easier-to-use oral anticoagulants might improve the risk-benefit ratio. Controversy remains about the optimal target level of anticoagulation in those at risk of increased bleeding. Anticoagulation of patients with atrial fibrillation who have valvular heart disease particularly those with mechanical heart valves is recommended Class I, Level of Evidence A. Antithrombotic therapy warfarin or aspirin is recommended to prevent stroke in patients with nonvalvular atrial fibrillation according to assessment of their absolute stroke risk, estimated bleeding risk, patient preferences, and access to high-quality anticoagulation monitoring Table 8 Class I, Level of Evidence A.

Warfarin INR 2. Other types of cardiac disease that can contribute to the risk of thromboembolic stroke include dilated cardiomyopathy, valvular heart disease eg, mitral valve prolapse, endocarditis, prosthetic cardiac valves , and intracardiac congenital defects eg, patent foramen ovale [PFO], atrial septal defect, atrial septal aneurysm. In addition, MI is associated with the development of atrial fibrillation and is a source of cardiogenic emboli.

Primary Prevention of Ischemic Stroke | Stroke

Acute coronary syndromes are infrequently associated with stroke in the acute setting, occurring in 0. Although a detailed review of the management of cardiac conditions is beyond the scope of this guideline, several points will be highlighted. The incidence of stroke is inversely proportional to cardiac ejection fraction. A history of prior neurological events, increasing age, diabetes, and atrial fibrillation have been identified as risk factors for early and delayed stroke after cardiac surgery.

In addition to atrial fibrillation, a variety of cardiac conditions have been associated with an increased risk of stroke. Data on the relative benefits and risks of specific prophylactic interventions are beyond the scope of this document. These include the management of patients with valvular heart disease, unstable angina, chronic stable angina, and acute MI.

Epidemiological studies initially found no consistent association between cholesterol levels and overall stroke rates but were likely confounded by the inclusion of hemorrhagic as well as ischemic stroke. Only a few studies have analyzed the relationship between LDL cholesterol the major component of total cholesterol and ischemic stroke.

No consistent association has been found, although the total number of subjects at risk in these studies is limited. The relationship between HDL cholesterol and ischemic stroke is best determined from prospective studies because tissue inflammation and caloric deficit can reduce HDL levels after stroke.

Triglyceride levels vary considerably, making elevated levels difficult to evaluate as a risk factor for stroke. Elevated triglycerides are a component of the metabolic syndrome. Trends toward higher triglyceride levels in patients who subsequently experience ischemic stroke have been reported. Carotid intima-media thickness, measured by B-mode ultrasound, is an atherosclerotic disease marker. Lipoprotein levels have been correlated with carotid intima-media thickness. HMG-CoA reductase inhibitors statins have received regulatory approval for the prevention of ischemic stroke in patients with CAD; the approval was based on consistent benefits in large randomized trials using these agents.

However, confidence intervals in this study were wide, so a beneficial effect on stroke cannot be excluded. Nonstatin lipid-modifying therapies may also offer stroke protection, although the supporting data are less certain. Plasma lipids and lipoproteins total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and lipoprotein[a] affect the risk of ischemic stroke, but the exact relationships are still being clarified.

In general, increasing levels of total cholesterol are associated with higher rates of ischemic stroke. Low HDL is a risk factor for ischemic stroke in men, but more data are needed to determine its effect in women. Lipid-modifying medications can substantially reduce the risk of stroke in patients with coronary heart disease. National Cholesterol Education Program III guidelines for the management of patients who have not had a cerebrovascular event and who have elevated total cholesterol or elevated non—HDL cholesterol in the presence of hypertriglyceridemia are endorsed Table 9.

The use of lipid-lowering therapy in diabetic patients is specifically addressed in that section of this guideline. TABLE 9. However, at least 1 cohort study found similar rates of ipsilateral stroke over 10 years 9. Several studies have attempted to identify subgroups of patients with asymptomatic carotid artery stenosis who may be at particularly elevated stroke risk.

The Toronto Asymptomatic Cervical Bruit Study followed a cohort of patients for a mean of 23 months. A total of 8 patients 1. The North American Symptomatic Carotid Endarterectomy Trial investigators retrospectively reviewed their data on the risk of stroke in the territory of an asymptomatic carotid artery stenosis contralateral to the side of a symptomatic vessel. The average annual risk of ipsilateral stroke increased from 3. However, it should be noted that most of these studies were carried out before the widespread use of HMG-CoA reductase inhibitors ie, statins , which may be associated with a stabilization or reduction in carotid atherosclerotic disease, —,— and the rigor of adherence to other preventive strategies as reviewed in this guideline is not known.

As with asymptomatic carotid bruit, an asymptomatic stenosis of the carotid artery is an important indicator of concomitant ischemic cardiac disease. There have been 2 underpowered and 3 larger published randomized controlled trials designed to assess the benefit of carotid endarterectomy in patients with asymptomatic carotid artery stenosis. There were no major strokes or deaths in either group. Of the larger trials, the VA Cooperative Study of carotid endarterectomy for patients with asymptomatic carotid artery stenosis included men followed up for a mean of 48 months.

Combined perioperative and angiographic risk was 4. Although the rate of fatal and nonfatal stroke was reduced in the surgical group 4. However, the study was not powered to detect differences in outcome subgroups. There was a 1. The study was halted after a median follow-up of 2. The benefit began to accrue after 1 to 2 years. As with the VA Trial, the study was not powered to detect differences among patient subgroups.

Despite the differences in point estimates, a definite difference between men and women cannot be concluded because of the wide confidence intervals and the post hoc nature of analysis. Although a large population-based study did not find a significant overall difference in endarterectomy complication rates in women as compared with men, asymptomatic patients were not analyzed separately.

There was a 3. The overall 5-year risk of any stroke or perioperative death was For fatal or disabling strokes, the respective rates were 6. Although not significantly different, women benefited somewhat less than men after successful endarterectomy 4. Therefore, it remains uncertain whether there is a benefit in women.

Data presented in the ACST publication also permit calculation of the comparative rates of any stroke or death and of any major stroke or death. Similar to ACAS, the overall rate of any stroke or death was For any major stroke or death, the respective ACST rates were These sobering data must be taken into account when the procedure is considered. It should be noted that the benefit of endarterectomy in the setting of asymptomatic carotid artery stenosis is highly dependent on surgical risk, with the benefit being obviated by periprocedural complication rates in excess of the 2.

Even after community-wide performance measurement and feedback, the overall risk for stroke or death after endarterectomy performed for asymptomatic stenosis in 10 US states was 3. It is also important to recognize that surgery is only one of several potential treatments that can be used to reduce the risk of stroke in patients with asymptomatic carotid artery stenosis. Medical therapy was different at the time ACAS was performed as compared with current practice.

Although highly selected patients may benefit, screening of general populations for asymptomatic carotid stenosis is unlikely to be cost-effective. Carotid angioplasty with stenting has been available for several years, but clinical studies showing that it is equivalent or superior to carotid endarterectomy have been limited.

Because these rates include MI including those defined by cardiac enzyme elevations in the absence of electrocardiographic changes , the results are not directly comparable to ACAS or ACST. However, even in the stenting arm, the cumulative 1-year end point rate of 9. There was no evidence in any subgroup that carotid stenting was superior to endarterectomy for the prevention of stroke as an end point.

Because the study did not include medically treated controls, we cannot be certain how these asymptomatic, high—surgical-risk patients would have fared without either procedure. Although limited by post hoc and nonprespecified analyses, it is clear that careful patient selection is critical, with substantially less benefit or no benefit if all-cause mortality is considered as a part of the end points. The advent of carotid angioplasty—stenting offers another potential intervention. Given the low likelihood of ipsilateral stroke among patients with asymptomatic stenosis, complication rates will need to be in a similar range, and careful patient selection is imperative.

It is recommended that patients with asymptomatic carotid artery stenosis be screened for other treatable causes of stroke and that intensive therapy of all identified stroke risk factors be pursued Class I, Level of Evidence C. The use of aspirin is recommended unless contraindicated because aspirin was used in all of the cited trials as an antiplatelet drug except in the surgical arm of 1 study, in which there was a higher rate of MI in those who were not given aspirin Class I, Level of Evidence B.

Patient selection should be guided by an assessment of comorbid conditions and life expectancy, as well as other individual factors, should be balanced by an understanding of the overall impact of the procedure if all-cause mortality is considered as one of the end points, and should include a thorough discussion of the risks and benefits of the procedure with an understanding of patient preferences. Carotid angioplasty—stenting might be a reasonable alternative to endarterectomy in asymptomatic patients at high risk for the surgical procedure Class IIb, Level of Evidence B ; however, given the reported periprocedural and overall 1-year event rates, it remains uncertain whether this group of patients should have either procedure.

Other systemic effects include impaired growth and possible cognitive developmental retardation. Stroke prevention is most important for patients with homozygous SCD disease because most of the strokes associated with SCD occur in these patients. Transcranial Doppler ultrasound TCD has made identification of those at highest risk of stroke possible, allowing rational decisions about treatment for primary stroke prevention. The frequency of screening needed to detect most cases at risk has not been determined.

Unless exchange methods in which blood is removed from the patient with each transfusion are used, long-term transfusion is associated with iron toxicity that must be treated with chelation. This trial STOP II tested whether chronic transfusions for primary stroke prevention could be safely discontinued after at least 30 months range 30 to 91 months in children who had not had an overt stroke and who had reversion to low-risk TCD velocity with chronic transfusion therapy. The study was stopped after 79 of a planned sample of children were randomized when an interim analysis showed poorer outcomes in those who had transfusion therapy discontinued.

No systematic data are available on prevention of stroke in adults with SCD. Improvements in care have increased life expectancy in SCD, and it may be anticipated that stroke prophylaxis in older SCD patients will pose an increasing challenge in the future. TCD can be used to identify children with SCD who are at high risk of stroke and who may benefit from transfusion therapy. The optimal screening interval has not been established.

As reviewed above, treatment criteria using peak systolic velocities have now been published. Alternative methods of maintenance therapy that are safer than transfusion need to be developed in view of the data indicating the need for ongoing active treatment despite TCD normalization. Predictive methods other than TCD eg, magnetic resonance—based techniques should be systematically compared with, and combined with, TCD to further refine the estimation of stroke risk in individuals. Preventive therapies other than transfusion need to be tested.

Data on risk and prevention options in adults with SCD are sorely inadequate, and a stroke prevention strategy for adults needs to be developed. It is recommended that transfusion therapy be considered for those at elevated stroke risk Class I, Level of Evidence B. Although the optimal screening interval has not been established, it is reasonable that younger children and those with TCD velocities in the conditional range should be rescreened more frequently to detect development of high-risk TCD indications for intervention Class IIa, Level of Evidence B.

Adults with SCD should be evaluated for known stroke risk factors and managed according to the general guidelines in this statement Class I, Level of Evidence A. Although laboratory and observational studies of postmenopausal hormone therapy have suggested a beneficial effect for the prevention of cardiovascular disease and a reduction of stroke severity, randomized trials suggest harm. Previously, these guidelines surmised that the impact of postmenopausal hormone replacement therapy on stroke risk appeared to be neutral, but because of a lack of controlled studies, definitive conclusions could not be reached.

Within the first 6 months, the risk of stroke was higher among those randomized to estradiol RR 2. In addition, those who had a recurrent stroke and were randomized to hormonal therapy were less likely to recover. The first results from the WHI were for women with an intact uterus in whom a combination therapy conjugated equine estrogen and medroxyprogesterone was used as the active treatment.

The trial was stopped because of an increase in vascular events that included an absolute increase of 8 strokes per 10 person-years. A parallel trial included women with a previous hysterectomy who were treated with conjugated equine estrogen. Selective estrogen receptor molecules lack the steroidal structure of estrogen but have a tertiary structure that permits binding to estrogen receptors.

An increased risk of stroke is associated with the tested forms of hormone therapy. Two trials focused on women without a prior history of stroke and are directly relevant to primary stroke prevention. Prospective randomized data for other forms of hormone therapy are lacking. It is recommended that postmenopausal hormone therapy estrogen with or without a progestin not be used for primary prevention of stroke Class III, Level of Evidence A.

There are not sufficient data to provide recommendations about the use of other forms of therapy such as selective estrogen receptor modulators. In observational studies, several aspects of diet are associated with stroke risk. As reviewed by Bazzano et al and as corroborated by more recent publications, — a generally consistent body of evidence from prospective studies has documented that increased fruit and vegetable consumption is associated with a reduced risk of stroke in a dose-response fashion.

Median intake in the highest quintile was In ecological and some prospective studies, , a higher level of sodium intake is associated with an increased risk of stroke. A higher level of potassium intake is also associated with a reduced risk of stroke in prospective studies. The potential effects of sodium and potassium on stroke risk appear to be at least partially mediated through blood pressure.

In clinical trials, particularly dose-response studies, the relationship between sodium intake and blood pressure is direct and progressive without an apparent threshold. Other dietary factors may affect the risk of stroke, but the evidence is insufficient to make specific recommendations. In Asian countries, a low intake of animal protein, saturated fat, and cholesterol has been associated with an increased risk of stroke, but such relationships have been less apparent in Western countries.

Randomized controlled trials that are focused on diet and specifically target stroke do not exist. According to epidemiological studies, it is likely that diets rich in fruits and vegetables and with reduced sodium and increased potassium intake would reduce stroke risk. A reduced intake of sodium and increased intake of potassium are recommended to lower blood pressure Class I, Level of Evidence A , which may thereby reduce the risk of stroke.

The DASH diet, which emphasizes fruit, vegetables, and low-fat dairy products and is reduced in saturated and total fat, also lowers blood pressure and is recommended Class I, Level of Evidence A. A diet that is rich in fruits and vegetables may lower the risk of stroke and may be considered Table 7 Class IIb, Level of Evidence C. Regular physical activity has well-established benefits for reducing the risk of premature death and cardiovascular disease. The beneficial effects of physical activity have also been documented for stroke.

Dose-response studies comparing the effects of vigorous and lower levels of physical activity are limited. Additional protection was observed with increasing duration of exercise; however, the prevalence of such activities in the elderly was quite low. Other biological mechanisms have also been associated with physical activity, including reductions in plasma fibrinogen and platelet activity and elevations in plasma tissue plasminogen activator activity and HDL concentrations.

Currently available data support the benefits of physical activity Table 7. Physical activity is a modifiable behavior that requires greater emphasis in stroke prevention campaigns Table 4. A sedentary lifestyle is associated with an increased risk of stroke. Clinical trials documenting a reduction in the risk of a first stroke with regular exercise have not been done; however, exercise has beneficial effects on several other important stroke risk factors and is associated with a reduction in stroke risk in epidemiological studies.

Increased physical activity is recommended because it is associated with a reduction in the risk of stroke Class I, Level of Evidence B. The traditional classification of weight status is defined by body mass index BMI: weight [in kilograms] divided by the square of height [in meters]. Persons with a BMI of 25 to Being overweight is particularly common among black and Hispanic children. A growing body of evidence from large-scale prospective studies has documented that increased weight is associated with an increased risk of stroke in a dose-response fashion.

This apparent reduction in the strength of the association between BMI and stroke risk may be misleading because overweight is hypothesized to cause stroke via these other factors. To date, no clinical trial has tested the effects of weight reduction on reducing stroke risk. However, numerous trials have examined the effects of weight reduction on blood pressure in both nonhypertensive and hypertensive individuals. In a meta-analysis that aggregated results across 25 trials, mean systolic and diastolic blood pressure reductions from an average weight loss of 5.

A growing body of evidence shows that increased weight is associated with an increased risk of stroke in a dose-response fashion. Although no clinical trial has tested the effects of weight reduction on stroke outcomes, weight reduction is associated with a lowering in blood pressure see section on hypertension and may thereby contribute to a reduced stroke risk. Randomized trials of weight reduction for reducing stroke risk should be conducted. Epidemiological studies indicate that increased body weight and abdominal fat are directly associated with stroke risk. Weight reduction is recommended because it lowers blood pressure Class I, Level of Evidence A and may thereby reduce the risk of stroke.

Obesity, discussed separately in the previous section, is an important component of the metabolic syndrome and is associated with major health risk factors such as diabetes, hypertension, and hypercholesterolemia , poor health status, and lower life expectancy. They also stimulate inflammation by releasing cytokines and may play a role in the pathophysiology of dyslipidemia, hypertension, impaired thrombolysis, and renal damage. A variety of studies support or refute a relationship between glucose intolerance and stroke risk. The metabolic syndrome is highly prevalent in the United States Table 4.

The metabolic syndrome is a substantial predictor of coronary heart disease, cardiovascular disease which includes coronary heart disease and stroke , and all-cause mortality. Individual components of the metabolic syndrome have been associated with an increased risk of ischemic stroke and should be treated as appropriate. The specific risk of stroke in persons with the metabolic syndrome is uncertain, as is the impact of treatment of the combined syndrome.

Management of individual components of the metabolic syndrome, including lifestyle measures and pharmacotherapy as recommended in the National Cholesterol Education Program ATP III and the JNC 7, 76 as reviewed in other sections of this guideline, are endorsed. Lifestyle management should include exercise, appropriate weight loss, and proper diet. Pharmacotherapy may include medications for blood pressure lowering, lipid lowering, glycemic control, treatment of microalbuminuria or proteinuria, and antiplatelet therapy eg, aspirin according to the individual circumstance and risk.

It is not known whether agents that ameliorate aspects of the insulin resistance syndrome are useful for reducing stroke risk. Alcohol abuse can lead to multiple medical complications, including stroke. Strong evidence indicates that alcoholism and heavy drinking are risk factors for all stroke subtypes Table 4. The amount and possibly type of alcohol consumed influence risk. In the Copenhagen City Heart Study, consumption of 3 to 5 glasses of wine per day, but not beer or spirits, was associated with a reduced risk of stroke-related mortality.

In retrospective cohort studies, light-to-moderate consumption of alcohol in the form of wine has been associated with a reduced risk of stroke, whereas risk is increased with heavier consumption. Prospective trials are lacking. It is well established that alcohol can induce dependence and that alcoholism is a major public health problem. For a variety of health benefits, reduction of alcohol consumption in heavy drinkers through established screening and counseling methods as outlined in the US Preventive Services Task Force Update is endorsed Table 7. Drug addiction is often a chronic relapsing disorder associated with a number of societal and health-related problems.

An increase in the risk of both ischemic and hemorrhagic stroke has been reported. Several drugs of abuse have been associated with stroke Table 4. However, there is a paucity of data on the independent risk of stroke associated with drugs of abuse and no controlled trials demonstrating a reduction in risk with abstinence. Successful identification and management of drug abuse can be challenging.

When a patient is identified as having a drug addiction problem, referral for appropriate counseling may be considered Table 7 Class IIb, Level of Evidence C. The reported risks appear lower than for ischemic stroke, , except among older women in whom the risk of hemorrhagic stroke is greatest. One exception is cerebral venous thrombosis, for which there are data to suggest an association, especially among women with congenital thrombophilias such as factor V Leiden or a prothrombin gene mutation.

Some groups of women appear to be at higher risk for stroke associated with OC use. The absolute increase in stroke risk with low-dose OCs, if one exists, is small. The risk of stroke associated with OC use is low Table 4. Certain women, particularly those who have had a prior thrombotic event, may be at higher risk. Estimates are primarily based on epidemiological studies.

Epidemiological studies suggest that habitual snoring is a risk factor for ischemic stroke and is independent of confounding factors such as hypertension, ischemic heart disease, obesity, and age Table 4. Data on stroke was not reported separately. It will also shed light on the mechanisms of cell-specific interactions. Anchoring to specific cells is a key step in targeting.

It is controlled by ligand affinity and configuration surface density, interactive freedom, etc. Equally important are target features: surface density, clustering and accessibility of binding sites, phenotypic characteristics, and the microenvironment of target cells perfusion, pH, protease activity, etc. Carrier interactions with target determinants govern the specificity, selectivity, efficacy, fate, and safety of the DDS. A target determinant should ideally meet the following criteria: i it anchors a carrier to endothelium in the area of interest; ii it provides desirable subcellular addressing; and iii it is not adversely affected by carrier binding in the context of disease treatment.

Selective proteomics of the endothelial plasmalemma 64, and in vivo phage display 73 are advantageous for finding new targets, as they identify binding sites accessible from circulation in normal and pathological vasculature. Table 1. Catalytic activity is increased by chloride.

TM CD Ubiquitous, specific for endothelial cells Cell surface, single pass type I membrane protein Receptor for thrombin, participates in the generation of activated protein C. TM level reflects a balance between those opposite forces. The utility for vascular targeting depends on relative levels in endothelial vs other cells accessible to blood. For example, ICAM-1 is expressed by fibroblasts, epithelial, and muscle cells at levels comparable with those in endothelium. Nevertheless, these extravascular cells are not accessible to circulating macromolecules and carriers and hence do not compete with endothelial targeting.

In contrast, cytokine and transporter receptors are abundantly expressed on cells in blood, RES, lymphoid tissues, hepatocytes, and other compartments accessible to circulating DDS and, therefore provide very modest if any endothelial delivery. Constitutive determinants e. Some, including APP and ACE, 27, 28 disappear from the endothelium in pathological conditions, which inhibits targeting.

With respect to localization in the vascular system, endothelial surface molecules fulfill the continuum ranging from pan-endothelial to domain-specific determinants i. Pan-endothelial targets e. The level of expression and surface density of many pan-endothelial determinants vary between organs and types of vessels. For example, ACE and thrombomodulin are expressed in the pulmonary capillaries at several fold higher level than in other organs, and antibodies to these molecules anti-ACE and anti-TM preferentially accumulate in the lungs.

For example, inducible molecules APN and TEM-1 are upregulated in endothelium involved in angiogenesis in tumors and inflammation, , whereas adhesion molecules VCAM-1 and selectins are expressed predominantly in sites of inflammation. Determinants differ with respect to preferential localization in domains in the endothelial plasmalemma. The endothelium is normally accessible to blood cells, lipoproteins, and other particles circulating in the bloodstream. Accessibility limitations are more stringent for carriers relying on multivalent binding and are proportional to the size of carriers.

Epitopes located more proximally to the plasmalemma within the same target molecule are less suitable for harboring carriers than distal epitopes. Of note, shedding of endothelial glycocalyx induced by pathological mediators is implicated in enhanced accessibility of ICAM-1 to targeted carriers and activated leukocytes. Functions of target determinants are important in the context of drug delivery.

Molecules involved in transport from the bloodstream seem attractive to deliver drugs in the corresponding addresses. On the other hand, interference with functions of target molecules must be considered in the context of pathological condition s to be treated. Conversely, inhibition of angiotensin II production by ACE may be beneficial in management of hypertension and inflammation. The issue of adverse inhibition of the target is illustrated by thrombomodulin, an endothelial surface glycoprotein that has been studied for targeting of diverse cargoes to the pulmonary endothelium in mice and rats.

Ligand-coated carriers may inflict more potent effects than ligands alone. With the exception of targeting anticancer agents to tumor endothelium, endothelial drug delivery should not damage or disturb target cells. A more general aspect of this issue that should be considered is that biocompatibility of a single component does not guarantee safety of the nanocarrier. Systemic effects, such as activation of complement, coagulation or platelets, and toxicity toward the clearing tissues liver, kidney, lungs, etc.

Endothelial cell adhesion molecules CAMs represent arguably one of the most well-studied and versatile groups of endothelial determinants in the context of targeting nanocarriers. Further, targeting to these molecules achieves localization of drugs to diverse endothelial compartments. Vascular Cell Adhesion Molecule-1 VCAM-1 , P-selectin, and E-selectin are exposed on the surface of activated endothelial cells and facilitate the rolling phase of the vascular adhesion of leukocytes. Carriers conjugated with antibodies to these molecules bind to activated endothelium.

PECAM is stably expressed at a level of 0. CAMs are involved in adhesion and trafficking of leukocytes and in vascular signaling. These antibodies and antibody-carrying carriers and drug conjugates bind to endothelial cells and accumulate in vascularized organs after intravascular injection. Many groups have devised nanocarriers targeted to CAMs by conjugated antibodies. Some of these recombinant proteins have been clinically tested as anti-inflammatory agents and showed generally acceptable safety.

This type of ligand offers the advantages of a reduced risk of immune reactions and utility in diverse animal species. Targeting is controlled by carrier avidity, defined by ligand affinity, density, and freedom to interact with target. Reviewing the extensive literature on rheological control of interactions of ligand-coated particles with the vessel wall, pertinent to both adhesion of leukocytes and carrier targeting, is beyond the scope of this paper.

The majority of these studies involved particles of micrometer size and surfaces coated with immobilized molecules or endothelial cells in vitro. For example, several studies have indicated that binding is inversely correlated with shear stress. It was proposed that carriers either larger or smaller than this size may have an advantage anchoring on the endothelium.

Binding increased with an increase in diameter from 0. Carriers experience the hydrodynamic dragging force of blood proportional to their size; hence, the larger the DDS is the more target molecules need to be engaged to anchor DDS on the cell. In some studies carriers were perfused in the presence of blood components.

Due to the interaction of particle and cell, smaller particles are physically pushed by RBCs via volume exclusion. Likewise, an increase in particle dispersion coefficient is attributed to the increased rotation and tumbling of RBCs under increasing shear. These two contributions, increased particle dispersion and volume exclusion, act together to increase the carrier gradient along the cell-free-layer at the vessel walls. In smaller vessels, similar simulations show that carrier accumulation is enhanced further, likely due to the larger role volume exclusion plays since RBCs may be forced to physically contact the vessel wall.

Studies with targeted DDS in vivo have shown that while endothelial localization may increase with size into the micrometer range, targeting specificity tends to have a maximum in the hundreds of nanometers range. A study comparing vascular targeting through measurements of pulmonary uptake of anti-ICAM coated polystyrene spheres with sizes of 0. Carrier enlargement aggravates accessibility issues. At a nanometer scale, it has been shown that elongated carriers bind to endothelium more effectively than spherical ones Figure 7 A.

This was further investigated by coating nanorods and spheres with anti-transferrin-receptor monoclonal antibody. Rods exhibited almost an order of magnitude fold enhancement in attachment to brain endothelium. In a computational model comparing spheres and nanorods, the binding probability of a nanorod under a shear rate of 8 s —1 was found to be 3 times higher than that of its spherical counterpart. Flow-induced interactions play an important role in binding of nanoparticles to endothelium.

Several devices have been synthesized and mathematical models have been developed to investigate and explain these phenomena. These interesting mathematical predictions are supported by in vitro flow studies designed to mimic in vivo flow. Notably, discoid particles have been shown to marginate to the wall under flow better than their spherical counterparts. Carrier plasticity is likely to contribute significantly to targeting despite the lack of studies directly confirming this. While circulating in the fluid stream, rigid and flexible carriers may retain similar morphologies.

However, the latter carriers may flatten on the surface of the target Figure 7 B , thereby reducing the drag force of perfusion that leads to detachment. The same phenomenon will enhance binding via spreading over and engaging a higher number of binding sites. Additionally, lateral movement of ligand molecules in the flexible carriers favors congruency of ligand molecules interaction with multiple binding sites and their clusters. In addition, as noted in section Nanocarrier Behavior in the Circulation , flexible particles circulate for a longer time and have a better chance of achieving target than rigid particles.

Further, rigid particles have shown to be greater than 5-fold more likely to be internalized by immune cells when compared directly to their flexible counterparts in vitro. The transformational shift of DDS binding, which usually boosts targeting, is from a monovalent or bivalent ligand to a multivalent carrier. For example, computational analysis revealed that at least three ICAM antibodies coupled to a spherical carrier with diameter nm should engage simultaneously in binding to an endothelial cell in order to anchor the carrier.

Furthermore, in some cases, ligands with higher affinity yield inferior targeting. One scenario where this is the case is when high-affinity nanoparticles fail to penetrate into the target due to their retention at the surface of the target mass, such as tumors or thrombi. Unlike free ligands, ligand—drug or drug—carrier conjugates require congruency with target molecules for multivalent binding, which does not necessarily correspond to the maximal ligand density.

In some cases, as illustrated in Figure 8 , an excessive ligand density may inhibit the binding of NCs to target cells. Beyond a certain threshold, further elevation of ligand density resulted in a significant decrease in tumor localization. Defining the optimal surface density of a ligand, which may vary depending on the features of a carrier, ligand, target, and application, is a daunting and important task. Several factors could contribute to the outcome including carrier and ligand properties size, orientation, density, etc.

Quantitative parameters of ligand affinity and surface density on a carrier have to be determined empirically because surface density and clustering of target determinants in vivo remain to be characterized. Varying ligand surface density also may help enhance targeting selectivity. Specifically, in the application of imaging and detection of disease, off-target uptake should be minimized to enhance the signal-to-noise ratio of the target tissue.

This point was validated in a study on molecular imaging of pulmonary inflammation by isotope-labeled anti-ICAM nanocarriers. Admittedly, ICAM-1 is not an ideal target for this goal, since it is expressed at a relatively high basal level among the normal endothelium, while its level roughly doubles in inflamed counterpart. Damaged vascular wall exposes specific markers including normally hidden intracellular endothelial molecules e. These compounds activate coagulation and platelets to form a hemostatic plug preventing bleeding.

To compensate for deficiency of natural hemostatic mechanisms in patients with bleeding disorders, development of synthetic hemostats has been investigated. These synthetic hemostats must be specific and not induce clotting at off-target endothelial sites. Carrier design parameters become increasingly important if carriers are to perform such specific interactions in terms of circulation and endothelial interaction considering the exposure of multiple binding sites at injured vasculature and the dynamic nature of blood flow. To address the former, a number of spherical carriers have been proposed presenting either fibrinogen or fibrinogen-derived peptides, , which bind to markers exclusively present on activated platelets at the wound site.

In case of the latter, the size, shape, and flexibility must be finely tuned in order to perform on-demand hemostasis at a vascular injury site which is undergoing dramatic changes in blood flow and loss. Extensive efforts have focused on mimicking the size, shape, and flexibility of RBCs to better navigate carriers in the vasculature. Likewise, platelet mimetics are receiving much attention. Recently, Doshi et al. This enhanced effect was attributed to a combination of features as similar spherical particles were unable to perform as well.

Indeed, it has yet to be shown whether or not these synthetic cells will be able to marginate in blood flow or perform hemostasis as well as real platelets. Yet engineering of the shape and flexibility of carriers that has been demonstrated by synthetic RBCs, synthetic platelets, and filomicelles 90, is required to perform complicated functions that spherical particles may not be able to address.

Selective targeting to pathological endothelium is an important task. One intriguing idea explored by several laboratories is the strategy of combining on the surface of the carrier affinity ligands that bind to different determinants. This has the potential to boost the selectivity and efficacy of drug delivery.

Figure 10 illustrates this principle: one ligand binding to an inducible determinant provides the selectivity of recognition of altered cells, while the second ligand binding to a pan-endothelial determinant supports the anchoring. The idea, in essence, comes from the biology of leukocyte vascular homing and infiltration of the endothelium at sites of inflammation.

In addition to typical limitations associated with cell cultures and immobilized antigens, expression of binding data in relative scale further convolutes interpreting results of these studies. However, a dual targeting strategy employing spherical — nm carriers carrying antibodies to both ICAM and transferrin receptors has recently been tested in vivo and showed promising results: each of the ligands apparently promoted targeting to the vascular area of its destination, i.

Dual targeted NCs demonstrated approximately a 6-fold higher binding relative to single targeted NCs. Here microbubbles were targeted to ICAM-1 and selectins and demonstrated that dually targeted bubbles had significantly better adhesion strength to activated endothelial cells relative to single target bubbles. Monomolecular ligands interact with target determinants either in bivalent e.

Bivalent binding of an antibody to glycoprotein s on the cell surface offers higher affinity yet requires more freedom and congruency of carrier-target interaction. Ligands binding to distinct epitopes on the same target molecule may influence each other, for example, inhibiting binding to adjacent epitopes.

The competitive inhibition of binding to overlapping epitopes has been described for antibodies to ACE. Recently, it has been found, however, that distinct monoclonal antibodies directed to adjacent epitopes in the distal domain of the extracellular moiety of PECAM, stimulate binding of each other, both in cell culture and in vivo.

In theory, it may find utility in targeting strategies. With this strategy, a therapeutic effect was realized with increased activity of a scFv targeted to PECAM on endothelial cells. It will be interesting to see if this strategy of enhanced targeting can be applied to NC platforms for drug delivery and imaging of disease. The assessment of carrier fate within the target tissue of live animals is such a challenging endeavor that PK-related issues pale in comparison. No method affords accurate data of binding per cell at a given location in vivo.

The best data sets are provided by combining isotope tracing demonstrating uptake in an organ and microscopy imaging cellular distribution. Such a level of rigor is needed to characterize new, targeted DDS. Otherwise, studies may look enigmatic, such as vascular pulmonary targeting by an antibody to surfactant protein SP-A, the alveolar component inaccessible for liposomes in blood which is difficult to comprehend except as an artifact of passive retention in the pulmonary capillaries. Even at the current limited level of understanding of target biology and processes to intervene, many targeting paradigms are incredibly simplistic.

Yet, data on their distribution in the vascular lumen throughout blood vessels and in the endothelial cell plasmalemma are fragmentary, at best. Immunostaining, in situ hybridization, Western-blotting, and PCR do not distinguish surface and intracellular proteins. Systematic information on normal and pathological distribution of any of the endothelial target molecules in the in the vasculature is still missing. An immunochemistry-based atlas of the vascular distribution of ACE, the target of a widely used inhibitor therapy, is arguably the best attempt so far, but ACE organization in the endothelial plasmalemma in the vessels is still enigmatic.

In vitro experiments and computational studies complement expensive in vivo studies but must be interpreted carefully. In the context of targeting, issues of cell culture include i degeneration of the cell phenotype; ii conditions irrelevant to in vivo high dose, incubation without washing, prolonged exposure ; and iii lack of a proper cell environment for example, tissue components, flow, blood.

In particular, endothelial cells grown in cell culture are known to lose phenotypic features—caveolae, glycocalyx, ACE and other marker proteins, basal level of ICAM-1, etc. For example, studies of dual ligand targeting using densely co-immobilized target molecules hardly represent the in vivo situation accurately, especially in the case that one of the targets is scarce in the vasculature.

Most likely, this strategy may only be useful for a few determinants as both must coexist in close proximity to each other in order to permit simultaneous anchoring of both ligands. Intracellular delivery and addressing to proper cellular compartments are needed for the desirable effects of many drugs, especially biotherapeutics.

Anchoring on selected surface determinants offers mechanisms to boost the uptake and control the rate and pathway of internalization, subsequent trafficking, and fate of nanocarriers. The conventional wisdom is that anchoring of a drug or carrier to a molecule involved in uptake of its natural ligand s provides the intracellular delivery. Targeting nanocarriers to endothelial cells provides ample examples illustrating this principle but also examples of less intuitive and somewhat paradoxical pathways for intracellular drug delivery.

The endothelium exerts active fluid phase uptake via vesicular micro- and macropinocytosis pathways. Uptake of ligands that bind to internalizing receptors is more effective, specific, and controlled than passive fluid phase uptake. Like other cells, endothelial cells internalize ligands by phagocytosis and receptor-mediated endocytosis via caveoli 39, , and clathrin-coated and uncoated vesicles, as well as noncanonical pathways see below.

Endocytic, phagocytic, and pinocytic pathways have selectivity to certain ligands and pharmacological or genetic methods of inhibition to a degree and deliver cargoes to distinct destinations. Diverse cell types and phenotypes internalize and traffic carriers differently. For example, phagocytes internalize ligands of Fc-receptors, whereas nonphagocytic cells internalize transferrin via its receptor into cellular vesicles. Caveolar- and clathrin-mediated endocytosis are conventionally viewed as the predominant endothelial vesicular pathways.

Another conventional notion is that anchoring to a receptor leads to carrier uptake via the pathway naturally serving this molecule. Ligands binding to distinct epitopes of anchoring molecules may enter cells differently. Selection of ligands facilitating cellular uptake is an important and so far mostly empirical task.

Ligand modification affects internalization; obviously, loss of affinity cancels specific uptake mechanism. Modifications of antibodies that change their charge or enable hydrophobic interactions with phospholipids in cellular membranes stimulate their internalization. This concern is relevant to use of relatively promiscuous secondary interactions, such as those mediated by charge or hydrophobic interactions. It has been recognized for a long time that conversion of monovalent or bivalent ligands into multivalent carriers that can engage numerous copies of the receptors enhances internalization.

Generally, this high carrier avidity is viewed as favorable for intracellular delivery. However, excessive avidity may be detrimental for the subsequent dissociation of the carrier from the receptors during intracellular trafficking. This intriguing scenario has been illustrated in a study of transferrin-mediated transcytosis across the blood—brain barrier.

However, coating a nanocarrier with internalizable molecules does not necessarily result in internalization. For example, the uptake of a large, micrometer-size carrier may exceed cellular endocytic capacity; formation of such a large vacuole would require prohibitively extensive mobilization of cell membrane and cytoskeleton. Further, coupling ligands to carriers impedes their interaction with receptors and epitopes localized in invaginations and domains of the plasmalemma inaccessible to the particles of such size.

For example, conjugation of ligands of caveolar epitopes to carriers larger than the diameter of the neck of caveoli 70 nm abolishes endothelial targeting and transfer. Co-internalized ICAM dissociates from the anti-ICAM coated carriers in the endosomes and recycles to the cell surface, while the carriers traffic further to lysosomes. A body of evidence accumulated in vitro and in animal models indicates that PECAM and ICAM represent highly unusual endothelial targets providing either surface anchoring or internalization with the choice controlled by the parameters of the DDS design, i.

This feature permits targeting of drugs that either need to be retained on the cell surface such as monovalent antithrombotic fusion proteins or delivered inside the cell. Carrier size, shape, and plasticity modulate cellular uptake and trafficking. Depending on cell type, their functional states, and selection of anchoring molecules, the effects and mechanisms of the modulation vary.

Size-mediated restriction of accessibility to the binding site or the endocytic entry e. Our current understanding of the geometrical control of targeted DDS uptake is empirical and fragmentary. For example, in one prototype study, ICAM-targeted disks entered endothelial cells more slowly than spherical carriers of a similar size, whereas the pace of traffic through the vesicular compartments was controlled by size: smaller particles arrived at the lysosomes faster, regardless of their shape.

Larger particles either spheres or rods were more likely to localize in this region as compared to smaller particles. In the same study, rods were far less likely to accumulate in perinuclear regions as compared to spheres of the same volume. In extreme cases, high aspect ratio carriers aspect ratio close to 10, i.

For instance, in the HeLa cancer cell line, higher aspect ratio particles exhibited higher internalization rates than those exhibited by spherical carriers. Binding to distinct epitopes on the same anchoring molecule may lead to different outcomes. The functional status of target cells and their microenvironment modulate endocytosis. Thus, activated endothelium internalizes ICAM-targeted nanocarriers faster than the quiescent endothelium does both in vitro and in vivo.

The majority of publications on cellular uptake and trafficking of nanocarriers have employed static cell lines. A few studies have attempted to define the role of flow in endothelial uptake of nanoparticles using flow chambers and microfluidics; most dealt with nontargeted particles. Experiments in flow chambers revealed that prolonged exposure to flow leads to partial, yet significant, inhibition of endocytosis of nanocarriers targeted to ICAM and PECAM.

The rheological regulation of intracellular delivery represents an intriguing area of bioengineering and biomedicine. Very recently, a novel mode of biological modulation of internalization of targeted nanocarriers has been described.

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It is mediated by activation of the enzyme s metabolizing sphingomyelin in the plasmalemma and induced by binding of nanocarriers to ICAM-1 in endothelial and other cell types. Adhesion of carriers to endothelium may favor their transport across the cells via diverse mechanisms.

For example, elevation of the local concentration of a carrier in close proximity to the vessel wall may facilitate its passive entrance into transcellular and pericellular pathways, on the condition that binding is reversible and the gradient direction supports extravasation. However, anchoring to some endothelial molecules provides more specific and effective mechanisms. Some ligands of receptors involved in endocytosis via clathrin-coated pits, such as transferrin receptor, and caveoli, such as APP, are capable of crossing the endothelial barrier. In this context, it is intriguing to explore endothelial transport opportunities offered by CAM-mediated endocytosis, which can allow entrance of objects up to several micrometers.

All the issues discussed above in this rubric are pertinent here, including optimization of carrier labeling and tracing. First, carriers with lower ligand density retain better stealth features Figure 4. Second, the majority of TfR-mediated uptake occurs in liver; inhibition of hepatic uptake via reducing TfR avidity may also result in elevated blood level Figure In vitro models do allow quantitative assessment of internalization , , and probing cellular pathways by pharmacological and genetic inhibitors.

Lack of systemic and microenvironmental factors is a common shortcoming of cell culture studies. Prolonged incubations of serum-starved static cells with high doses of particles and use of acidic or proteolytic elution are prone to false-positive results. Even meticulously performed, common microscopy-based methods are not truly quantitative, while more precise methods are low-throughput. In our opinion, successful endothelial nanomedicine requires both adequate understanding of biomedical factors pertinent the medical objectives and optimal nanocarrier design.

The latter includes quantitative real-time tracing of both carrier and cargo, high-resolution localization in tissues, balanced combination of stealth and targeting features e. Carrier elongated geometry and plasticity allowing flow alignment and lateral diffusivity of ligands are likely to improve circulation, targeting and subcellular delivery.

Targeting these new DDS to the determinants optimally serving given biomedical context will yield the winning combination. Endothelial targeting is developing at a vigorous pace. Since first reports two decades ago, hundreds of studies have elaborated the strategy, which is on the verge of translation into the clinical domain. This objective represents a set of paramount challenges.

Animal studies only partially reflect therapy of patients with unique individual profiles. Mice provide high-throughput models including mutants lacking or expressing genes of interest, but interspecies differences are difficult to overestimate. Clinical relevance is inversely proportional to species availability. Many industrial and healthcare counterparts hesitate to embrace complex and costly DDS. Undoubtedly, well-defined targeted DDS will find additional utility as tools for probing of physiological pathways in animals.

And, of course, the targeted endothelial nanomedicine formulations enabling novel therapeutic mechanisms and qualitatively improving the outcome of dangerous human maladies will eventually be translated into the clinical domain. The authors declare no competing financial interest. American Chemical Society. A review. In its strictest definition from the National Nanotechnol. Initiative, nanotechnol. Despite this size restriction, nanotechnol.

Herein, we focus on the application of nanotechnol. Nature London , , Suppl. Macmillan Magazines. A review with 91 refs. When a pharmaceutical agent is encapsulated within, or attached to, a polymer or lipid, drug safety and efficacy can be greatly improved and new therapies are possible.

This has provided the impetus for active study on the design of degradable materials, intelligent delivery systems and approaches for delivery through different portals in the body. Wood, Kris C. Before gene therapy can be used in clin. As a step toward the development of a modular, multifunctional gene delivery system to overcome these diverse barriers, the authors have developed a family of linear-dendritic "hybrid" polymers which contain functionalities for tissue targeting, minimization of nonspecific interactions, endosomal buffering, and DNA binding.

Here, the authors demonstrate the rapid three-step, room-temp. The synthetic approach described here may be useful for the rapid synthesis and optimization of polymer gene delivery systems bearing a range of diverse functional domains, and the specific GRPtargeted systems developed in this study may potentially have clin.

Here, the translation from concept to clinic for the first exptl. The 4 component formulation is self-assembled into nanoparticles in the pharmacy and administered i. The designed features of this exptl. Lee, Justin B. The androgen receptor AR plays a crit. In vitro screening studies using a panel of cationic lipids showed that LNPs contg. LNP to be taken up into cells and to release the siRNA into the cell cytoplasm following endocytotic uptake.

Interactions of Liposomes with Mammalian Cells Annu. Liposomes—Methodology and Applications Front. Frontiers of Biology , 48 Lysosomes Appl. Canadian journal of physiology and pharmacology , 56 5 , ISSN: A review with 95 refs. Royal Society of Chemistry. Polymeric nanoparticles-based therapeutics show great promise in the treatment of a wide range of diseases, due to the flexibility in which their structures can be modified, with intricate definition over their compns.

Advances in polymn. In addn. Furthermore, they can be equipped with smart components to allow their delivery beyond certain biol. This tutorial review highlights the importance of well-defined chemistries, with detailed ties to specific biol. Nanotheranostics represents the next generation of medicine, fusing nanotechnol. By integrating therapeutic and imaging agents into one nanoparticle, this new treatment strategy has the potential not only to detect and diagnose disease but also to treat and monitor the therapeutic response.

This capability could have a profound impact in both the research setting as well as in a clin. In the research setting, such a capability will allow research scientists to rapidly assess the performance of new therapeutics in an effort to iterate their designs for increased therapeutic index and efficacy. In the clin. If not, patients can be more quickly removed from the clin.

To be effective, these theranostic agents must be highly site specific. Optimally, they will carry relevant cargo, demonstrate controlled release of that cargo, and include imaging probes with a high signal-to-noise ratio. There are many biol. These barriers include, but are not limited to, the walls of blood vessels, the phys. The rapid clearance of circulating particles during systemic delivery is a major challenge; current research seeks to define key design parameters that govern the performance of nanocarriers, such as size, surface chem.

The effect of particle size and surface chem. Recently it has been documented that shape and elasticity can have a profound effect on the behavior of delivery vehicles. Thus, having the ability to independently control shape, size, matrix, surface chem. In this Account, we describe the use of particle replication in nonwetting templates PRINT to fabricate shape- and size-specific microparticles and nanoparticles.

A particular strength of the PRINT method is that it affords precise control over shape, size, surface chem. We have demonstrated the loading of PRINT particles with chemotherapeutics, magnetic resonance contrast agents, and fluorophores. The surface properties of the PRINT particles can be easily modified with "stealth" poly ethylene glycol chains to increase blood circulation time, with targeting moieties for targeted delivery or with radiolabels for nuclear imaging.

These particles have tremendous potential for applications in nanomedicine and diagnostics. Informa Healthcare. Phospholipid micelles have proven to be the versatile pharmaceutical nanocarrier of choice for the delivery of poorly sol. Phospholipid micelles are typically expected to increase the accumulation of the loaded drugs in tumor tissues by taking advantage of the enhanced permeability and retention effect and by ligand-mediated active targeting.

Furthermore, by tailoring the compn. This review highlights the important advancements in the authors' lab.

Drug Delivery Rev. Venkataraman, Shrinivas; Hedrick, James L. Elsevier B. Amphiphilic polymeric nanostructures have long been well-recognized as an excellent candidate for drug delivery applications. With the recent advances in the "top-down" and "bottom-up" approaches, development of well-defined polymeric nanostructures of different shapes has been possible. Such a possibility of tailoring the shape of the nanostructures has allowed for the fabrication of model systems with chem.

With these model nanostructures, evaluation of the importance of particle shape in the context of biodistribution, cellular uptake and toxicity has become a major thrust area. Since most of the current polymeric delivery systems are based upon spherical nanostructures, understanding the implications of other shapes will allow for the development of next generation drug delivery vehicles. Herein we will review different approaches to fabricate polymeric nanostructures of various shapes, provide a comprehensive summary on the current understandings of the influence of nanostructures with different shapes on important biol.

PEGylated dendrimers are attractive for biol. The rapid and efficient synthesis of a robust and biodegradable PEGylated dendrimer based on a polyester-polyamide hybrid core is described. The architecture is designed to avoid destructive side reactions during dendrimer prepn.

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Therefore, a dendrimer functionalized with doxorubicin Dox was prepd. Both the dendrimer and Doxil were evaluated in parallel using equimolar dosage in the treatment of C26 murine colon carcinoma, leading to statistically equiv. The attractive features of this dendritic drug carrier are its simple synthesis, biodegradability, and versatility for application to a variety of drug payloads with high drug loadings. Percec, Virgil; Wilson, Daniela A. American Association for the Advancement of Science. Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biol.

Yet the precise mol. Libraries of amphiphilic Janus dendrimers, prepd. Dendrimersomes marry the stability and mech. This modular synthesis strategy provides access to systematic tuning of mol. Elsevier Ltd. The site-specific expression of selectins P- and E-selectin on endothelial cells of blood vessels during inflammation provides an opportunity for the targeted delivery of anti-inflammatory drugs to sites of chronic inflammation. It is well documented that the selectins mediate the initial interaction rolling of leukocytes in an inflamed vessel by binding to carbohydrate-presenting counter-receptors displayed on leukocytes.

Previous work in our lab. Specifically, we showed that drug-loaded poly lactic-co-glycolic-acid PLGA microspheres coated with biotinylated-Sialyl LewisX sLeX , a carbohydrate that serves as a ligand to selectins, mimic the adhesive behavior of leukocytes on selectins in flow chambers, displaying slow rolling under flow, suggesting that these drug-loaded particles can potentially target inflammatory sites in vivo. Since the effectiveness of this delivery system might depend on the degrdn. We show that degrading sLeX microspheres maintain the ability to recognize selectin surfaces under flow for at least 2 wk and that the ability to sustain recognition depends upon the extent at which microspheres are loaded.

We also show that microsphere rolling velocity increases as microsphere degrade and that this increase is due to a combination of increase in av. Control expts. Discher, Bohdana M. Science Washington, D. Vesicles were made from amphiphilic diblock copolymers and characterized by micromanipulation. The av. Both the membrane bending and area expansion moduli of electroformed polymersomes polymer-based liposomes fell within the range of lipid membrane measurements, but the giant polymersomes proved to be almost an order of magnitude tougher and sustained far greater areal strain before rupture.

The polymersome membrane was also at least 10 times less permeable to water than common phospholipid bilayers. The results suggest a new class of synthetic thin-shelled capsules based on block copolymer chem. Drug delivery, magnetic resonance and fluorescence imaging, magnetic manipulation, and cell targeting are simultaneously possible using a multifunctional mesoporous silica nanoparticle.

Superparamagnetic iron oxide nanocrystals were encapsulated inside mesostructured silica spheres that were labeled with fluorescent dye mols. The highly versatile multifunctional nanoparticles could potentially be used for simultaneous imaging and therapeutic applications. This Nano Focus article reviews recent developments in nanofabrication based on invited talks given at the "Chem. Methods of Nanofabrication" symposium, which was organized by the authors and presented at the th ACS National Meeting and Exhibition as one of seven symposia within the meeting theme, "Nanoscience: Challenges for the Future".

The three-day symposium included 25 experts from academia, national labs. We highlight several of the key results discussed and future directions and challenges in this rapidly changing field. Recent developments in drug delivery have been directed towards the development of self sustained systems that would be able to recognize various biomarkers and respond to their high concns. While such systems are diagnostic in nature, their use as therapeutic delivery systems is being expanded most through work done in academic institutions and small biotech companies.

Here, we examine the basis of such recognitive delivery systems and we identify their main mechanisms and transducing action, esp. Selected exptl. For the past 40 years, liposomal and polymeric delivery vehicles have been studied as systems capable of modulating the cytotoxicity of small mol.

Although a no. In this article, we review the motivations for and approaches to polymer and liposomal delivery with regard to camptothecin and cisplatin delivery. Conflict of interest: Drs Kieler-Ferguson and Frechet declare no conflicts of interest. Dr Szoka is the founder of a liposome drug delivery company that is not working on any of the compds.

Polymer nanomaterials have sparked a considerable interest as vehicles used for diagnostic and therapeutic agents; research in nanomedicine has not only become a frontier movement but is also a revolutionizing drug delivery field. A common approach for building a drug delivery system is to incorporate the drug within the nanocarrier that results in increased soly.

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With this foundation, nanoparticles with stealth properties that can circumvent RES and other clearance and defense mechanisms are the most promising. However, recent developments indicate that select polymer nanomaterials can implement more than only inert carrier functions by being biol. One representative of such materials is Pluronic block copolymers that cause various functional alterations in cells. The key attribute for the biol. As a result, Pluronics cause drastic sensitization of multidrug resistance tumors to various anticancer agents, enhance drug transport across the blood brain and intestinal barriers, and causes transcriptional activation of gene expression both in vitro and in vivo.

Collectively, these studies suggest that Pluronics have a broad spectrum of biol. Bentham Science Publishers Ltd. The development of the vectorized delivery systems combining advantages of the colloidal carriers, with active targeting to the receptors sites suggests that nanoparticles have a considerable potential for treatment after biophase internalization and pharmacokinetics, as for example gene therapy.

Two major mechanisms can be distinguished for addressing the desired sites for drug release: i passive and ii active targeting. Examples of passive targeting were presented: organ targeting by the Enhanced Permeability and Retention EPR effect; targeting the mononuclear phagocytic system; organ targeting by chemoembolization or local organ administration;sterical stabilization of nanoparticles PEGylation. A strategy that could allow active targeting involves the surface functionalization of drug carriers with ligands that are selectively recognized by receptors on the surface of the cells of interest.

The source for biophase bioavailability can be the systemic bioavailability following common routes of administration generally for systemic delivery of medicines , or directly the site specific biophase bioavailability for the formulations capable of cellular or nuclear drug internalization where the drug release only will take place for nanoparticulate drug delivery systems, DDS.

Once the pharmaceutical nanosystem was internalized, begins the release of the active moiety by different mechanisms, as for example the escape from endosome, or biodegrdn. The presentation will discusses the pharmacokinetics of drugs after systemic administration but esp.

Other E. In this review, the author has discussed various issues of the cancer drug targeting primarily related to the EPR enhanced permeability and retention effect, which utilized nanomedicine or macromol. The content goes back to the development of the first polymer-protein conjugate anticancer agent SMANCS and development of the arterial infusion in Lipiodol formulation into the tumor feeding artery hepatic artery for hepatoma.

The brief account on the EPR effect and its definition, factors involved, heterogeneity, and various methods of augmentation of the EPR effect, which showed remarkably improved clin. Various obstacles involved in drug developments and commercialization are also discussed through the author's personal experience and recollections. Uliel, Livnat; Royal, Henry D. Society of Nuclear Medicine and Molecular Imaging. Endovascular mapping and conjoint 99mTc-macroaggregated albumin 99mTc-MAA hepatic perfusion imaging provide essential information before liver radioembolization with 90Y-loaded microspheres in patients with primary and secondary hepatic malignancies.

The aims of this integrated procedure are to det. This pictorial essay presents an integrated comprehensive review of the anat. The relevant anatomy of the liver, including the std. This knowledge will enable the reader to provide a more useful interpretation of this complex multidisciplinary procedure. The uniform design was used to optimize the technol. The exptl. The drug loading and loading efficiency were After i.

Muller, David W. American Heart Association. The study and treatment of pulmonary diseases may be greatly facilitated by in vivo expression of specific recombinant genes in the pulmonary vasculature and lung parenchyma. To evaluate the feasibility of gene transfer to the pulmonary vasculature, cationic liposomes and adenoviral vectors encoding a human placental alk.

Pulmonary tissue was harvested within 20 min or 5, 14, or 28 days later and was analyzed for gene transfer and expression. Five days after exposure to liposomes or adenoviral vectors, transfer of DNA and expression of mRNA were demonstrated in transfected lung tissue. Recombinant alk. Expression of hpAP protein was obsd. No major adverse effects of gene expression were detected by histol. Gene transfer to the lung by either vector was not assocd.

These studies demonstrate that after intravascular gene delivery to the lung, recombinant genes are expressed in the vasculature and alveoli. This approach may provide a useful model for the exptl. Huang, Ryan B. Vascular-targeted drug delivery systems could provide more efficient and effective pharmaceutical interventions for treating a variety of diseases including cardiovascular, pulmonary, inflammatory, and malignant disorders.

However, several factors must be taken into account when designing these systems. The diverse blood hemodynamics and rheol. An effective vascular-targeted drug delivery system must be able to navigate through the bloodstream while avoiding immune clearance, attach to the vascular wall, and release its therapeutic cargo at the intended location. This review will summarize and analyze current literature reporting on 1 nanocarrier fabrication methods and materials that allow for optimum therapeutic encapsulation, protection, and release; 2 localization and binding dynamics of nanocarriers as influenced by hemodynamics and blood rheol.

Delivery and penetration of chemotherapeutic drugs into tumors are limited by a no. Coupling of chemotherapeutic drugs with tumor vasculature-homing peptides or administration of drugs in combination with biol. Advances in bionanotechnology are poised to impact the field of cardiovascular diagnosis and therapy for decades to come. This review seeks to illustrate selected examples of newly developed diagnostic and therapeutic nanosystems that have been evaluated in experimental atherosclerosis, thrombosis, and vascular biology.

We review a variety of nanotechnologies that are capable of detecting early cardiovascular pathology, as well as associated imaging approaches and conjunctive strategies for site-targeted treatment with nanoparticle delivery systems. Noble, Charles O. Ashley Publications Ltd. The continued evolution of targeted liposomal therapeutics has resulted in new agents with remarkable antitumor efficacy and relatively mild toxicity profiles.

A careful selection of the ligand is necessary to reduce immunogenicity, retain extended circulation lifetimes, target tumor-specific cell surface epitopes, and induce internalization and subsequent release of the therapeutic substance from the liposome. Methods for assembling targeted liposomes, including a novel micellar insertion technol.

Targeting strategies with liposomes directed at solid tumors and vascular targets are discussed. The authors believe the development of ligand-targeted liposomes is now in the advanced stage and offers unique and important advantages among other targeted therapies. Folate-Targeted Therapies for Cancer J. This article discusses the use of folic acid as a ligand to target therapeutic cargos of many sizes, shapes, mechanisms of action to tumor cells both in vitro and in vivo.

American Scientific Publishers. Endothelium plays a vital role in various vascular functions, and its dysfunction is a key underlying process closely related to diverse array of diseases such as atherosclerosis and tumor. Therefore, early detection of endothelial dysfunction at the functional or mol. Recent advances in nanotechnol. To visualize the specific pathogenic process at the mol. Combining the functional imaging agents along with therapeutic drugs has great potential for effective early detection, accurate diagnosis, and treatment of disease. The current review will highlight the application of various nanoparticle-based imaging agents and their recent developments in diagnosing endothelium dysfunction with a special emphasis on atherosclerosis and cancer.

The endothelium is a target for therapeutic and diagnostic interventions in a plethora of human disease conditions including ischemia, inflammation, edema, oxidative stress, thrombosis and hemorrhage, and metabolic and oncol. Unfortunately, drugs have no affinity to the endothelium, thereby limiting the localization, timing, specificity, safety, and effectiveness of therapeutic interventions.

Drug delivery platforms such as protein conjugates, recombinant fusion constructs, targeted liposomes, and stealth polymer carriers have been designed to target drugs and imaging agents to these determinants. We review endothelial target determinants and drug delivery systems, describe parameters that control the binding of drug carriers to the endothelium, and provide examples of the endothelial targeting of therapeutic enzymes designed for the treatment of acute vascular disorders including ischemia, oxidative stress, inflammation, and thrombosis.

The endothelium represents an important therapeutic target for containment of oxidative stress, thrombosis and inflammation involved in a plethora of acute and chronic conditions including cardiovascular and pulmonary diseases and diabetes. However, rapid blood clearance and lack of affinity to the endothelium compromise delivery to target and restrict medical utility of antioxidant enzymes e. The use of "stealth" PEG-liposomes prolongs circulation, whereas conjugation with antibodies to endothelial determinants permits targeting.

Constitutive endothelial cell adhesion mols. CAM antibodies and compds. Endothelial cells internalize nm diam. This permits size-controlled sub-cellular targeting of antioxidants into the endothelial interior and fibrinolytics to the endothelial surface. Conjugation of fibrinolytics to monovalent anti-ICAM permits targeting and prolonged retention on the endothelial surface. Therefore, CAM targeting of antioxidants and fibrinolytics might help to contain oxidative and thrombotic stresses, with benefits of blocking CAM. Avenues for improvement and translation of this concept into the clin.

Vascular endothelium plays strategic roles in many drug delivery paradigms, both as an important therapeutic target itself and as a barrier for reaching tissues beyond the vascular wall. Diverse means are being developed to improve vascular drug delivery including stealth liposomes and polymer carriers. Affinity carriers including antibodies or peptides that specifically bind to endothelial surface determinants, either constitutive or pathol.

There are several main endocytic pathways in EC, including clathrin- and caveoli-mediated endocytosis, phagocytosis and macropinocytosis these two are less characteristic of generic EC and the recently described Cell Adhesion Mol. CAM -mediated endocytosis. The latter may be of interest for intracellular drug delivery to EC involved in inflammation or thrombosis.

The metab. The latter route, characteristic of caveoli-mediated endocytosis, may serve for trans-endothelial drug delivery. Paracellular trafficking, which can be enhanced under pathol. Endothelial surface determinants involved in endocytosis, mechanisms of the latter and trafficking pathways, as well as specific characteristics of EC in different vascular areas, are discussed in detail in the context of modern paradigms of vascular drug delivery.

Targeting of therapeutic agents to mol. Drug targeting to cellular receptors involved in endocytic transport facilitates intracellular delivery, a requirement for a no. However, after several decades of exptl. The plethora of factors contributing to the relative efficacy of targeting makes the success of these approaches hardly predictable. Lack of fully specific targets, along with selection of targets with spatial and temporal expression well aligned to interventional requirements, pose difficulties to this process.