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SUMMARY
Summary
Drug delivery to the cardiovascular system is different from delivery to other
systems because of the anatomy and physiology of the vascular system; it
supplies blood and nutrients to all organs of the body. Drugs can be
introduced into the vascular system for systemic effects or targeted to an
organ via the regional blood supply. In addition to the usual formulations of
drugs such as controlled release, devices are used as well. This report starts
with an introduction to molecular cardiology and discusses its relationship to
biotechnology and drug delivery systems.
Drug delivery to the cardiovascular system is approached at three levels: (1)
routes of drug delivery; (2) formulations; and finally (3) applications to
various diseases. Formulations for drug delivery to the cardiovascular system
range from controlled release preparations to delivery of proteins and
peptides. Cell and gene therapies, including antisense and RNA interference,
are described in full chapters as they are the most innovative methods of
delivery of therapeutics. Various methods of improving systemic administration
of drugs for cardiovascular disorders are described including use of
nanotechnology.
Cell-selective targeted drug delivery has emerged as one of the most
significant areas of biomedical engineering research, to optimize the
therapeutic efficacy of a drug by strictly localizing its pharmacological
activity to a pathophysiologically relevant tissue system. These concepts have
been applied to targeted drug delivery to the cardiovascular system. Devices
for drug delivery to the cardiovascular system are also described.
Role of drug delivery in various cardiovascular disorders such as myocardial
ischemia, hypertension and hypercholesterolemia is discussed. Cardioprotection
is also discussed. Some of the preparations and technologies are also
applicable to peripheral arterial diseases. Controlled release systems are
based on chronopharmacology, which deals with the effects of circadian
biological rhythms on drug actions.A full chapter is devoted to drug-eluting
stents as treatment for restenosis following stenting of coronary
arteries.Fifteen companies are involved in drug-eluting stents.
New cell-based therapeutic strategies are being developed in response to the
shortcomings of available treatments for heart disease. Potential repair by
cell grafting or mobilizing endogenous cells holds particular attraction in
heart disease, where the meager capacity for cardiomyocyte proliferation
likely contributes to the irreversibility of heart failure. Cell therapy
approaches include attempts to reinitiate cardiomyocyte proliferation in the
adult, conversion of fibroblasts to contractile myocytes, conversion of bone
marrow stem cells into cardiomyocytes, and transplantation of myocytes or
other cells into injured myocardium.
Advances in molecular pathophysiology of cardiovascular diseases have brought
gene therapy within the realm of possibility as a novel approach to treatment
of these diseases. It is hoped that gene therapy will be less expensive and
affordable because the techniques involved are simpler than those involved in
cardiac bypass surgery, heart transplantation and stent implantation. Gene
therapy would be a more physiologic approach to deliver vasoprotective
molecules to the site of vascular lesion. Gene therapy is not only a
sophisticated method of drug delivery; it may at time need drug delivery
devices such as catheters for transfer of genes to various parts of the
cardiovascular system.
The cardiovascular drug delivery markets are estimated for the years 2007 to
2017 on the basis of epidemiology and total markets for cardiovascular
therapeutics. The estimates take into consideration the anticipated advances
and availability of various technologies, particularly drug delivery devices
in the future. Markets for drug-eluting stents are calculated separately. Role
of drug delivery in developing cardiovascular markets is defined and unmet
needs in cardiovascular drug delivery technologies are identified.
Selected 87 companies that either develop technologies for drug delivery to
the cardiovascular system or products using these technologies are profiled
and 68 collaborations between companies are tabulated. The bibliography
includes 200 selected references from recent literature on this topic. The
report is supplemented with 27 tables and 6 figures
TABLE OF CONTENTS
0. Executive Summary 11
1. Cardiovascular Diseases 13
- Introduction 13
- History of cardiovascular drug delivery 13
- Overview of cardiovascular disease 14
- Coronary artery disease 14
- Angina pectoris 14
- Limitations of current therapies for myocardial ischemic disease 14
- Cardiomyopathies 14
- Cardiac arrhythmias 15
- Congestive heart failure 15
- Peripheral arterial disease 15
- Current management 16
- Atherosclerosis 16
- The endothelium as a target for cardiovascular therapeutics 16
- Molecular cardiology 17
- Cardiogenomics 17
- Cardioproteomics 17
- Personalized cardiology 18
- Pharmacogenomics of cardiovascular disorders 18
- Modifying the genetic risk for myocardial infarction 19
- Management of heart failure 19
- Management of hypertension 20
- Pharmacogenomics of diuretic drugs 20
- Pharmacogenomics of ACE inhibitors 20
- Management of hypertension by personalized approach 21
- Pharmacogenetics of lipid-lowering therapies 21
- Polymorphisms in genes involved in cholesterol metabolism 21
- Role of eNOS gene polymorphisms 22
- Important advances in cardiovascular therapeutics 22
- Drug delivery, biotechnology and the cardiovascular system 23
2. Methods for Drug Delivery to the Cardiovascular System 25
- Introduction 25
- Routes of drug delivery to the cardiovascular system 25
- Local administration of drugs to the cardiovascular system 25
- Intramyocardial drug delivery 25
- Drug delivery via coronary venous system 26
- Intrapericardial drug delivery 26
- Formulations for drug delivery to the cardiovascular system 26
- Sustained and controlled release 27
- Programming the release at a defined time 27
- Dosage formulation of calcium channel blockers 28
- Sustained and controlled release verapamil 28
- Methods of administration of proteins and peptides 28
- Delivery of peptides by subcutaneous injection 29
- Depot formulations and implants 29
- Poly(ethylene glycol) technology 29
- Microencapsulation for protein delivery 30
- Localized delivery of biomaterials for tissue engineering 30
- Oral delivery of proteins and peptides 30
- DDS to improve systemic delivery of cardiovascular drugs 31
- Nanotechnology-based drug delivery 32
- Targeted drug delivery to the cardiovascular system 33
- Immunotargeting of liposomes to activated vascular endothelial cells 34
- PEGylated biodegradable particles targeted to inflamed endothelium 34
- Devices for cardiovascular drug delivery 35
- Local drug delivery by catheters 35
- Microneedle for periarterial injection 36
- Nanotechnology-based devices for the cardiovascular system 37
- Liposomal nanodevices for targeted cardiovascular drug delivery 37
- Nanotechnology approach to the problem of "vulnerable plaque" 38
- Role of cardiovascular imaging in cardiovascular therapeutics 38
- Chronopharmacotherapy of cardiovascular diseases 39
- Drug delivery in the management of cardiovascular disease 40
- Drug delivery in the management of hypertension 40
- Transnasal drug delivery for hypertension 40
- Transdermal drug delivery for hypertension 41
- Oral extended and controlled release preparations for hypertension 41
- Long-acting hypertensives for 24 h blood pressure control 42
- Drug delivery to control early morning blood pressure peak 42
- Role of drug delivery in improving compliance with antihypertensive
therapy 43
- Drug delivery for congestive heart failure 43
- Oral human brain-type natriuretic peptide 43
- Nitric oxide-based therapies for congestive heart failure 43
- Automated drug delivery system for cardiac failure 44
- DDS in the management of ischemic heart disease 44
- Intravenous emulsified formulations of halogenated anesthetics 45
- Injectable peptide nanofibers for myocardial ischemia 45
- Delivery of angiogenesis-inducing agents for myocardial ischemia 45
- Drug delivery for cardioprotection 46
- Drug delivery for cardiac rhythm disorders 47
- Drug delivery in the treatment of angina pectoris 47
- Sustained and controlled-release nitrate for angina pectoris 48
- Transdermal nitrate therapy 48
- Controlled release calcium blockers for angina pectoris 49
- Drug delivery in the management of pulmonary hypertension 49
- Anticoagulation in cardiovascular disease 50
- Oral heparin 50
- Low molecular weight heparin-loaded polymeric nanoparticles 50
- Transdermal anticoagulants 51
- Thrombolysis for cardiovascular disorders 51
- Use of ultrasound to facilitate thrombolysis 51
- Delivery of alteplase through the AngioJet rheolytic catheter 51
- Drug delivery for peripheral arterial disease 52
- Delivery of thrombolytic agent to the clot through a catheter 52
- Immune modulation therapy for PAD 52
- NO-based therapies for peripheral arterial disease 53
- Drug delivery in the management of hypercholesterolemia 53
- Controlled/sustained release formulations of statins 53
- Combinations of statins with other drugs to increase efficacy 54
- Controlled release fenofibrate 55
- Extended release nicotinic acid 55
- Intravenous infusion of lipoprotein preparations to raise HDL 56
- Innovative approaches to hypercholesterolemia 56
- Single dose therapy for more than one cardiovascular disorder 57
3. Cell Therapy for Cardiovascular Disorders 59
- Introduction 59
- Inducing the proliferation of cardiomyocytes 59
- Role of stem cells in repair of the heart 59
- Cell-mediated immune modulation for chronic heart disease 59
- Cell therapy for atherosclerotic coronary artery disease 60
- Transplantation of myoblasts for myocardial infarction 60
- MyoCell"! (Bioheart) 61
- Transplantation of cardiac progenitor cells for revascularization of
myocardium 62
- Methods of delivery of cells to the heart 62
- Cellular cardiomyoplasty 62
- IGF-1 delivery by nanofibers to improve cell therapy for MI 62
- Intracoronary infusion of bone marrow-derived cells for AMI 63
- Non-invasive delivery of cells to the heart by MorphRguide catheter 63
- Transplantation of stem cells for myocardial infarction 63
- Transplantation of embryonic stem cells 63
- Transplantation of hematopoietic stem cells 64
- Transplantation of cord blood stem cells for myocardial infarction 64
- Intracoronary infusion of mobilized peripheral blood stem cells 64
- Human mesenchymal stem cells for cardiac regeneration 65
- Cytokine preconditioning of human fetal liver CD133+ SCs 65
- Transplantation of expanded adult SCs derived from the heart 66
- Transplantation of endothelial cells 66
- Transplantation of genetically modified cells 66
- Transplantation of cells secreting vascular endothelial growth factor 66
- Transplantation of genetically modified bone marrow stem cells 67
- Cell transplantation for congestive heart failure 67
- Myoblasts for treatment of congestive heart failure 67
- Injection of adult stem cells for congestive heart failure 67
- Role of cell therapy in cardiac arrhythmias 68
- Atrioventricular conduction block 68
- Ventricular tachycardia 69
- ESCs for correction of congenital heart defects 69
- Cardiac progenitors cells for treatment of heart disease in children 70
- Stem cell therapy for peripheral arterial disease 70
- Clinical trials of cell therapy in cardiovascular disease 71
- A critical evaluation of cell therapy for heart disease 73
- Publications of clinical trials of cell therapy for CVD 73
- Future directions for cell therapy of CVD 73
4. Gene Therapy for Cardiovascular Disorders 75
- Introduction 75
- Techniques of gene transfer to the cardiovascular system 76
- Direct plasmid injection into the myocardium 76
- Catheter-based systems for vector delivery 76
- Ultrasound microbubbles for cardiovascular gene delivery 77
- Vectors for cardiovascular gene therapy 77
- Adenoviral vectors for cardiovascular diseases 77
- Plasmid DNA-based delivery in cardiovascular disorders 78
- Intravenous rAAV vectors for targeted delivery to the heart 78
- Hypoxia-regulated gene therapy for myocardial ischemia 78
- Angiogenesis and gene therapy of ischemic disorders 79
- Therapeutic angiogenesis vs. vascular growth factor therapy 79
- Gene painting for delivery of targeted gene therapy to the heart 80
- Gene delivery to vascular endothelium 80
- Targeted plasmid DNA delivery to the cardiovascular system with
nanoparticles 80
- Gene delivery by vascular stents 81
- Gene therapy for genetic cardiovascular disorders 81
- Genetic disorders predisposing to atherosclerosis 81
- Familial hypercholesterolemia 82
- Apolipoprotein E deficiency 83
- Hypertension 84
- Genetic factors for myocardial infarction 84
- Acquired cardiovascular diseases 84
- Coronary artery disease with angina pectoris 85
- Ad5FGF-4 85
- Ischemic heart disease with myocardial infarction 85
- Myocardial repair with IGF-1 therapy 86
- Congestive heart failure 86
- Rationale of gene therapy in CHF 87
- Genetic manipulation of b
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