Kewal K. Jain

Advances in the field of nanooncology

Nanooncology, the application of nanobiotechnology to the management of cancer, is currently the most important chapter of nanomedicine. Nanobiotechnology has refined and extended the limits of molecular diagnosis of cancer, for example, through the use of gold nanoparticles and quantum dots. Nanobiotechnology has also improved the discovery of cancer biomarkers, one such example being the sensitive detection of multiple protein biomarkers by nanobiosensors. Magnetic nanoparticles can capture circulating tumor cells in the bloodstream followed by rapid photoacoustic detection. Nanoparticles enable targeted drug delivery in cancer that increases efficacy and decreases adverse effects through reducing the dosage of anticancer drugs administered. Nanoparticulate anticancer drugs can cross some of the biological barriers and achieve therapeutic concentrations in tumor and spare the surrounding normal tissues from toxic effects. Nanoparticle constructs facilitate the delivery of various forms of energy for noninvasive thermal destruction of surgically inaccessible malignant tumors. Nanoparticle-based optical imaging of tumors as well as contrast agents to enhance detection of tumors by magnetic resonance imaging can be combined with delivery of therapeutic agents for cancer. Monoclonal antibody nanoparticle complexes are under investigation for diagnosis as well as targeted delivery of cancer therapy. Nanoparticle-based chemotherapeutic agents are already on the market, and several are in clinical trials. Personalization of cancer therapies is based on a better understanding of the disease at the molecular level, which is facilitated by nanobiotechnology. Nanobiotechnology will facilitate the combination of diagnostics with therapeutics, which is an important feature of a personalized medicine approach to cancer.

The handbook of biomarkers

1. Introduction -Definitions -Historical aspects of biomarkers -Classification of biomarkers -Types of biomarkers -The ideal biomarker -Biomarkers and systems biology -Relation of biomarkers to other technologies and healthcare 2. Technologies for Discovery of Biomarkers -Introduction -Detection of biomarkers in tissues and body fluids -Disease biomarkers in breath -Genomic technologies -Epigenomic technologies -Proteomic technologies -Glycomic technologies -Metabolomic technologies -Lipidomics -Fluorescent indicators for biomarkers -Molecular imaging technologies -Nuclear magnetic resonance -Nanobiotechnology -Bioinformatics -Pitfalls in the discovery and development of biomarkers 3. Biomarkers and Molecular Diagnostics -Introduction -Molecular diagnostic technologies -Detection and expression profiling of miRNA 4. Biomarkers for Drug Discovery & Development -Introduction -Biomarker technologies for drug discovery -Biomarkers and drug safety -Applications of biomarkers for drug development 5. Role of Biomarkers in Healthcare -Introduction -Biomarkers of inflammation -Biomarkers of oxidative stress -Biomarkers in metabolic disorders -Biomarkers in immune disorders -Biomarkers of musculoskeletal disorders -Biomarkers of osteoporosis -Biomarkers of infectious diseases -Biomarkers of liver disease -Biomarkers of pancreatitis -Biomarkers of renal disease -Biomarkers of pulmonary diseases -Biomarkers in obstetrics and gynecology -Biomarkers for genetic disorders -Biomarkers of aging -Biomarkers of miscellaneous disorders -Biomarkers and nutrition -Biomarkers of gene-environmental interactions in human disease -Future role of biomarkers in healthcare -Applications of biomarkers beyond healthcare 6. Biomarkers of Cancer -Introduction -Types of cancer biomarkers -Molecular diagnostic techniques for cancer -Technologies for detection of cancer biomarkers -Applications of cancer biomarkers -Role of biomarkers in drug development in oncology -Biomarkers according to location/type of cancer -Role of the NCI in biomarkers of cancer -Future prospects for cancer biomarkers 7. Biomarkers of Disorders of the Nervous System -Introduction -Discovery of biomarkers for neurological disorders -Data mining for biomarkers of neurological disorders -Antibodies as biomarkers in disorders of the nervous system -Biomarkers of neural regeneration -Biomarkers of disruption of blood-brain barrier -Biomarkers of neurotoxicity -Biomarkers of neurodegenerative disorders -Biomarkers of multiple sclerosis -Biomarkers of stroke -Biomarkers of traumatic brain injury -Biomarkers of CNS infections -Biomarkers of epilepsy -Biomarkers of normal pressure hydrocephalus -Biomarkers of retinal disorders -Biomarkers for autism -Biomarkers of sleep disorders -Biomarkers of psychiatric disorders 8. Biomarkers of Cardiovascular Disorders -Introduction -Biomarkers of cardiovascular diseases -Methods for identification of cardiovascular biomarkers -Applications of biomarkers of cardiovascular disease -Role of biomarkers in the management of cardiovascular disease -Fut

Recent advances in nanooncology.

Nanobiotechnology is playing an important role in advances in oncology and currently nanooncology is the most important chapter of nanomedicine. Nanobiotechnologies have refined molecular diagnostics and enabled early detection of tumors and discovery of biomarkers of cancer. Various nanoparticles are the basis of diagnostic assays for cancer as well as contrast materials for MRI. Nanobiotechnology is facilitating the discovery and development of drugs for cancer. Several nanobiotechnologies, mostly based on nanoparticles, have been described to facilitate drug delivery in cancer, which is important for optimizing the effect of drugs and reducing toxic side effects. Nanoparticles for targeted drug delivery in cancer enable combination of diagnostics and therapeutics and act as adjuncts to hyperthermia and photodynamic therapy. Several applications of nanobiotechnology in cancer surgery include use of nanoparticles to visualize tumor during surgery as aid to proper removal, and nanorobotics for remotely controlled diagnostics combined with therapeutics. Selected new developments in nanooncology have been highlighted in this review and these point to an important role in development of personalized oncology.

Biomarkers of Cancer

Any measurable specific molecular alteration of a cancer cell either on DNA, RNA, protein, or metabolite level can be referred to as a cancer biomarker. The expression of a distinct gene can enable its identification in a tissue with none of the surrounding cells expressing the specific biomarker. In the past decade, molecular dissection of the cancer by means of mRNA expression profiling enabled detailed classification according to tumor subtypes. The traditional system of tumor node metastases (TNM) has been the main tool for identifying prognostic differences among patients and for guiding the treatment. The TNM system is based on the macroscopic and microscopic morphological examination of pathological samples. Despite the advantage of uniformity for international communications and studies, there are many limitations of this system as a first line method for prediction and prognosis of cancer. It is difficult to distinguish related disease subtypes, which have different clinical outcomes. Hence there is a need for more exact molecular biomarkers for use in clinical practice. In recent years the discovery of cancer biomarkers has become a major focus of cancer research. The widespread use of prostate-specific antigen (PSA) in prostate cancer screening has motivated researchers to identify suitable biomarkers for screening different types of cancer. Biomarkers are also useful for diagnosis, monitoring cancer progression, predicting recurrence and assessing efficacy of treatment (Jain 2014). The advent of targeted therapies such as imatinib (Novartis’ Gleevec), trastuzumab (Roche’s Herceptin) and rituximab (Roche’s Mabthera), where a causal relationship has been established between drug target and therapy, drives the need for biomarkers for selecting the patients for a given therapy as well as for predicting drug resistance.

Role of Biomarkers in Health Care

Study of biomarkers of various diseases will help to improve the management in three ways: 1. By providing a better understanding of the disease pathomechanism 2. By improving the diagnosis and determining the prognosis 3. By providing a basis for development of therapeutics and monitoring the effect of therapeutics on the disease

Biomarkers of Cardiovascular Disorders

Cardiovascular disease (CVD) has remained the leading cause of death worldwide despite the tremendous progress made in medical and surgical treatment for this disease. In the US, approximately 70 million persons have symptoms or findings (without symptoms) pertaining to coronary artery disease (CAD); of these patients, 10% have clinically confirmed disease. Not all of these patients have coronary artery disease, as some may have only angina pectoris but no demonstrable pathology in the coronary arteries. On the other hand, there are patients with coronary artery disease who may not have any investigations or require hospitalization. Sometimes it is postmortem finding in patients who die of other causes. The incidence is 1 million myocardial infarctions per year and 700,000 coronary-related deaths per year in the US. Nearly 8 million Americans alive today have suffered at least one heart attack and so are at greater risk for congestive heart failure (CHF) or another, potentially fatal, heart attack. Each year, of more than 1.2 million Americans who suffer heart attacks, about 400,000 develop CHF due to damage to the heart, and half of these die within 5 years. People who have had a heart attack have a sudden death rate that is 5–6 times greater than in the general population. Hypertension (HPN) affects about 70 million persons in the US with an overlap with those suffering from CAD.

Technologies for Discovery of Biomarkers

Biomarkers are present in all parts of the body including body fluids and tissues. Most of the clinical laboratory examinations are done on body fluids such as blood and urine. Biomarkers can be detected on imaging studies or examination of body tissues. Even exhaled breath contains biomarkers. A wide range of technologies is utilized for detection of biomarkers and a number of assays are already available.

Gene Therapy of Cancer

Gene therapy is defined as the transfer of defined genetic material to specific target cells of a patient for the ultimate purpose of preventing or altering a particular disease state (Jain 1998). It has three components: (1) identification of the gene that is mutated in a disease and obtaining a healthy copy of that gene, (2) carrier or delivery vehicle called vectors to deliver the healthy gene to a patient’s cells, and (3) additional DNA elements that turn on the healthy gene in the right cells and at the right levels. Gene therapy usually involves in situ production of therapeutic proteins but some approaches require suppression of gene expression to achieve therapeutic effects. Applications of gene therapy would be narrow if confined only to transfer of defined genetic material to specific target cells using vectors, which are usually viral but several nonviral vectors are used as well. Genes and DNA can be introduced without the use of vectors, and various techniques are being used to modify the function of genes in vivo without gene transfer, e.g., gene repair. Gene medicines may modify the effects of genes. If one includes cell therapy, particularly with the use of genetically modified cells, the scope of gene therapy becomes much broader. As a further extension, one can include genetically modified bacteria for delivery of therapeutic agents. Gene therapy can now be combined with antisense techniques and RNA interference (RNAi), further increasing the therapeutic scope. Details of gene therapy techniques are described in detail in a special report on this topic (Jain 2013). Cancer, the most important application of gene therapy currently, is the topic of this chapter.

Molecular Diagnosis of Cancer

Cancer is a multifactorial disease involving interaction of genetic, environmental, hormonal, and dietary risks. Genes play an important role. Oncogenomics (Chap. 2), sequencing (Chap. 3), oncoproteomics (Chap. 4), and biomarkers (Chap. 5) are relevant to molecular diagnosis of cancer. Basic molecular diagnostic technologies are described in detail in a special report on this topic (Jain 2013). Some of the technologies used for diagnosis of cancer are described in this chapter.

Role of Nanotechnology in Biological Therapies

Biological therapies are playing an increasing role in modern medicine. This term include recombinant human proteins, monoclonal antibodies (MAbs), vaccines, cell therapy, gene therapy, antisense, and RNA interference (RNAi). Some technologies for cell and gene therapy are in themselves sophisticated methods of therapeutic delivery, whereas others require special methods of delivery. The role of nanobiotechnology in delivery of biologicals will be discussed in this chapter. MAbs are considered along with drug delivery for cancer in Chap. 7.