1. INTRODUCTION:

Cancer is one of the greatest threats to the mankind and is one of the major causes of deaths all over the world. It is most common in people between 40 to 60 years of age, but cases in younger population are also reported. It commonly originates in the tissues in which the cells are regularly replaced by mitosis. These tissues include skin, lining of digestive tract, reproductive organs, lungs and liver. Normally the cells of a given tissue divide at a certain fixed rate and in a controlled manner. For instance, the cells lining the gut are replaced completely every 36 hr; skin cells every few days; red blood corpuscles every few weeks. Sometimes mitosis occurs in these tissues at rates far above the normal and in an uncontrolled fashion. This result in an abnormal growth called tumor¹. Cancer is caused in all or almost all instances by mutation or by some abnormal activation of cellular genes that control cell growth and cell mitosis. Macromolecular transport pathways across tumor vessels occur via open gaps of trans-endothelial channels and inter-endothelial junctions².

Cancer may be defined as a malignant growth or enlargement of a tissue that occurs due to unlimited and uncontrolled mitotic divisions of certain cells and invades surroundings tissues. Cancer is a complex set of diseases. The study of cancer is called oncology. Each cancer is unique in the process of development, its probability of spreading and the symptoms one may occurrence³.

Cancer is a class of diseases characterized by uncontrolled cell growth. More than 100 types of cancer have been reported and each is classified by the nature of cell that is primarily affect. Cancer creates problems for the body when damaged cells divide uncontrollably and finally formed lump called tumors. Tumors that reside in one place and exhibit partial growth are normally considered to be benign.

More dangerous or malignant tumors form when following things occur:

 When cancerous cell travel all over the body by using blood or lymph systems. The process of destroying the healthy tissue is called invasion.

 Cell starts to divide and mature, by the process of angiogenesis they start make new blood vessels to feed itself.

 When a tumor effectively spreads to different part of the body and grows, it initiates destroying normal tissues, it is called to metastasize and this process is called metastasis⁴.

Major characteristics of cancer cells are:

 Self capability in expansion of signals.

 Inattentiveness to antigrowth signals.

 The capability of continuous angiogenesis.

 Improvement of unlimited replicative potential.

Tumor vasculature is diverse from the normal vasculature in the following respects.

 Permeability of the tumor vessels is less than that of normal vessels presumably due to availability of large pores.

 Hampered and altered expression of adhesion molecules by tumor vasculature endothelium.

 Turnover time of normal endothelium cells is estimated in the range of 1000 days or more, whereas tumor endothelium cells grow with a turnover time of only 4-5 days.

 These fast growing tissues need a lot of nourishment. The body responds to this need by creating small blood capillaries very quickly. Because they grow so rapidly, the capillaries that serve to develop the tumors are more porous than normal blood vessels⁵.

1.1 Causes of Cancer

Cancer is finally the result of uncontrolled cell grow. Normal cells have an organized path of growth, division, and death. Apoptosis is process of programmed cell death, and when this process breaks down, cancer begins to form. Cancer cells do not experience program death and in its place continue to mature and divide. Different cancers have different risk factors. Some of the potential catalysts of cancer are tobacco, certain diets, alcohol and exposure to ultraviolet radiation⁶.

1.2 Cancer Classification

Every cancer is unique in their process of grows and develops, its chances of spreading, the way it affects one`s body and the symptoms one may experience. All cancers, however, fall into one of four broad categories.

1) Carcinoma: Carcinoma is a malignant neoplasm of epithelial derived. This type of cancer begins in the tissues that line the body`s organs like colon, nose, penis, breasts, prostrate and urinary bladder. About 70% in all cancer are carcinomas.

2) Sarcoma: It is also a type of cancer that begins in bone, muscle, cartilage, fibrous tissue or fat. The common types of sarcomas are Ewing sarcoma and Kaposi`s sarcoma.

3) Leukemia: This type of cancer occurs in blood or blood-forming organs. When leukemia develops, the body produces a large number of abnormal blood cells.

4) Lymphoma: Lymphomas affect the lymphatic system.

There are over 20 types of lymphoma. Lymphomas are grouped together and are called non- Hodgkin`s lymphoma. This type of cancer can move to all part of the body, including the liver, bone marrow and spleen⁷.

Cancers are often referred to by terms that contain a prefix related to the cell type in which the cancer originated and a suffix. Common prefixes are included in (Table 1.1).

Table 1.1: Common prefix used with cancer cell type

PREFIXES

CELL TYPE

Adeno-

Chondro-

Erythro-

Hemangio-

Hepato-

Lipo-

Lympho-

Melano-

Myelo-

Myo-

Osteo-

Uro-

Retino-

Neuro-

Gland

Cartilage

Red blood cell

Blood vessels

Liver

Fat

White blood cell Pigment cell

Bone marrow

Muscle

Bone

Bladder

Eye

Brain

2. LUNG CANCER:

The lungs are the organs that help us to breath. They help to give oxygen to all the cells in the body. Lung cancer occurs when lungs cells become abnormal. Lung cancer cells move through the blood or lymph system to another area or organ in the body. This is called metastasis. Lung cancer is the most common non-skin cancer in the developed countries and the second most common overall worldwide.

Lung cancer causes more deaths every year in the United State in both males and females than any other type of cancer, with an average five-year survival rate of approximately 15%. Lung cancer is the most common causes of cancer-related deaths in men⁸.

The most common cause of the lung cancer is long-term exposure to tobacco smoke. The rate of lung cancer in nonsmokers, who account for as many as 15% of cases, is often recognized to a combination of genetic factors, gases, asbestos, and air pollution, including second hand smoke⁹.

2.1 Types of lung cancer

Lung cancers, also known as bronchogenic carcinomas, are classified into two types. This classification is based upon the microscopic emergence of the tumor cells. Lung cancer can grow and spread in different ways and may have different treatment options, so a distinction between these two types is important.

 Small cell lung carcinoma (SCLC)

 Non-small cell lung carcinoma (NSCLC)

2.1.1 Small cell lung carcinoma (SCLC)

These cancers are sometimes called oat cell carcinomas. SCLC comprises about 20% of lung cancers and is the most aggressive and rapidly growing of all lung cancers. SCLC is strongly related to cigarette smoking, with only 1% of these tumors occurring in nonsmokers. SCLC metastasize rapidly too many sites within the body and are most often discovered after they have spread extensively.

2.1.2 Non-small cell lung carcinoma (NSCLC)

NSCLC are the most common lung cancers, accounting for about 80% of all lung cancers. It can be divided into three types based on the type of cells found in the tumor¹⁰.

1) Adenocarcinomas are the most commonly seen type of NSCLC in the U.S. and comprise up to 50% of NSCLC. While adenocarcinomas are associated with smoking like other lung cancers, this type is observed as well in non smokers who develop lung cancer. Most adenocarcinomas occur in the peripheral or external areas of the lungs.

2) Large cell carcinomas sometimes referred to as undifferentiated carcinomas, are the least common type of NSCLC.

2.2 Sign and Symptoms of lung cancer

Symptoms that suggest lung cancer includes:

 Dyspnea (shortness of breath)

 Hemoptysis (coughing with blood)

 Chronic coughing or change in regular coughing pattern

 Chest pain or pain in the abdomen

 Cachexia (weight loss), fatigue and loss of appetite

 Dysphonia (horse voice)

 Clubbing of fingernails (uncommon)

 Dysphagia (difficulty swallowing)¹¹

Risk Factors:

 Smoke

 Breath in other people’s smoke

 Have contact with asbestos, radon gas or a lot of air pollution

 Have someone in family who had lung cancer

2.3 Stages of lung cancer

The stages of a cancer refer to the degree to which a cancer has spread in the body. Stages entail both assessment of a tumor's size as well as the presence or absence of metastases in the lymph nodes or in other organs and also important for determining how a particular cancer should be treated. Oncologist may use numerous tests to accurately know the stage of lung cancer like blood tests, X-rays, CT scans, bone scans, and MRI scans. Irregular blood tests may indicate the presence of metastases in bone or liver, and radiological procedures can entail the size of a cancer as well as possible spreading to other organs¹².

Stages of non small cell lung carcinoma in order of severity:

Stage I: The tumor is restricted to the lung.

Stages II: The tumor is restricted to the chest.

Stages III: Same as stage II with larger and more invasive tumors

Stage IV: Spread from the chest to other parts of the body.

2.4 Lung cancer treatment

Lung cancer treatment involves surgical chemotherapy, removal of the cancer and radiation therapy, as well as combinations of these treatments.

2.4.1 Surgery: Surgical removal of the tumor is generally performed for limited-stage (stage I or sometimes stage II) NSCLC and is the treatment of choice for cancer that has not spread beyond the lung. Surgical resection has been used in patient with limited stages diseases, either alone or with other therapies but it is not currently considered standard therapy¹³. It involves the following:

 Lobectomy (removal of one lobe).

 Pneumonectomy (removal of an entire lung).

 Lymphadenectomy (lymph nodes in the region of the lungs are also removed).

2.4.2 Radiation: Radiation therapy may be use for treatment of both NSCLC and SCLC. High-energy X-rays or other types of radiation are used to kill cancer cells in radiation therapy. Chin and co-workers showed the P-707 Preliminary analysis of local radiation therapy technique fornon-small cell lung cancer¹⁴.

2.4.3 Chemotherapy: Chemotherapy refers to the administration of drugs that stop the growth of cancer cells by killing them or preventing them. Chemotherapy may be given alone, as an adjuvant to surgical therapy, or in combination with radiotherapy. Both NSCLC and SCLC can be treated with chemotherapy.

The main problems currently associated with non targeted drug delivery system are: biodistribution of drugs throughout the body; the lack of drug specific affinity toward a pathological site; the necessity of a large total dose of a drug to achieve high local concentration; non-specific toxicity and other adverse effects due to high drug doses.

2.4.4 Targeted Drug Delivery

The delivery of the drug for achieving the sufficient concentration to the definite organ and to achieve the desirable therapeutic response is the main aim of the delivery of the drug by the drug targeting concept. The distribution of other tissue seems to be unnecessary, wasteful and a potential cause of toxicity. The concept of the designing specified delivery system to achieve selected drug targeting has been from the perception of Paul Ehrlich, who proposed the idea of magic ‘bullet’. He demonstrated targeted drug delivery as an event where, a drug-carrier complex, delivers drug(s) exclusively to the presented target cells in a specific manner. Drug delivery to cells, tissues or organs with "magic bullets" is now medically known as "active targeting". With the availability of suitable ligands, this approach takes advantage of relatively abundant expression of a particular receptor on the target cell relative to non-target cells. Targeted drug delivery implies for selective and effective localization of pharmacological active moiety at preselected target in therapeutic concentration, while restricting its entrance to the non target organ, which minimizing toxic effects and maximizing therapeutic index¹⁵.

2.4.5 Approaches to drug targeting

An ideal targeted drug delivery approach would not only increase therapeutic efficacy of drugs but also decrease the toxicity associated with drug to allow lower doses of the drug to be used in therapy. Arrays of methods of targeting are classified in following approaches¹⁶:

 First order targeting approach (delivery to a discrete organ)

 Second order targeting approach (targeting to a specific cell type within a tissue or organ)

 Third order targeting approach (delivery to a specific intracellular compartment in the cells).

Targeted drug delivery may be achieved by using carrier systems. The various approaches of vectoring the drug to the target site can be broadly classified as:

 Active targeting

 Passive targeting

 Inverse targeting

 Dual targeting

 Double targeting

 Combination targeting

1) Passive targeting: This relies on the natural distribution pattern of the drug carrier system that depends on the physicochemical or pharmacological factors. Drug or drug carrier systems can be passively targeted utilizing the pathophysiological and anatomical opportunities. Passive targeting involves long circulating macromolecular systems, based on the concept that circulating macromolecules accumulate passively in tumors, due to enhanced endothelial permeability and retention of macromolecule due to poor lymphatic drainage. Systems that target the systemic circulation are generally characterized as passive delivery system i.e. targeting occurs because of body’s natural response to the physicochemical characteristics of the drug or drug carrier system. The ability of some colloids to be taken up by the RES especially in liver and spleen has made them ideal vectors for passive hepatic targeting of drug to these compartments¹⁷. Zhang and co-workers that Paclitaxel-loaded Pluronic P123/F127 enhance the antitumor efficacy against non-small cell lung cancer based on passive tumor targeting and modulation of drug resistance¹⁸. Kutscher and co-workers show the enhanced passive pulmonary targeting and retention of PEGylated rigid microparticles in rats. Kutscher and co-workers explain the relationship between microparticle size and lung targeting efficiency, intra-lung distribution and retention time was systematically studied after intravenous administration of rigid fluorescent polystyrene MPs of various sizes¹⁹.

2) Active targeting approaches: This employs a deliberately modified drug, drug-carrier molecule capable of recognizing and interacting with a specific cell, tissue or organ. These ligand based systems for targeting minimize the chance of serum-protein binding and opsonization on their surface. These ligand based systems for targeting are advantageous over other systems because they are long-circulatory as they minimize the chance of serum protein binding and opsonization on their surface (Fig. 1.1). Active targeting is accomplished by attachment of specific molecules on the carrier’s surface, which enhance the binding and interactions with antigens or receptors expressed on specific cell populations. Byrne and co-workers showed the active targeting schemes for nanoparticle systems in cancer therapeutics²⁰.

3) Inverse targeting: It is essentially based on successful attempts to circumvent and avoid passive uptake of colloidal carriers by reticuloendothelium system (RES). This effectively leads to the reversion of bio distribution tend of the carriers and hence the process is referred to as inverse targeting. Inverse targeting can be achieve by suppress the function of RES by a pre-injection of a large amount of blank colloidal carriers or macromolecules²¹.

4) Dual targeting: This classical approach of the drug targeting consist of transporter molecules, which have their own intrinsic effect thus synergy the effect of loaded active drug. On the basis of this approach, drug conjugates can be prepared with fortified activity profile against the disease. Lauren and co-workers demonstrated that vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways characterize two clinically validated targets for non–small-cell lung cancer, and there is strong biologic rationale for therapeutic approaches targeting both pathways in NSCLC and other diseases. They reported that clinically using combinations of drugs that target the pathways separately, such as erlotinib and bevacizumab, or individual drugs that target both pathways. Randomized phase II studies in previously treated patients with NSCLC suggest that dual VEGF/EGFR inhibition might be more active than targeting either pathway alone and that the combination could also enhance the efficacy of chemotherapy21. In other study, Muller and co-workers explained that roles of miRNAs in carcinogenesis. They show that expression profiles of miRNAs are different in lung cancer vs. normal lung, although the significance of this aberrant expression is poorly understood. show that expression of miR-29s is inversely correlated to DNMT3A and -3B in lung cancer tissues, and that miR-29s directly target both DNMT3A and -3B. These findings support a role of miR-29s in epigenetic normalization of NSCLC, providing a rationale for the development of miRNA-based strategies for the treatment of lung cancer²².

5) Double targeting: It is a newly developed method for drug targeting. It is other than passive and active targeting for drug delivery systems. The combination is made between spatial control and temporal control of drug delivery.

6) Combination targeting: The term combination is used for the site-specific delivery of protein and peptides. Combination targeting systems consist of carriers, polymers and homing devices of molecular specificity that could provide a direct approach to target site.

2.4.6 Advantages of targeted drug delivery system

 Reduction of adverse side effects, because there are seldom peak drug blood levels above the drug therapeutic range and into the toxic range.

 Targeted drug delivery system provides a reduction in drug blood level fluctuation. It provides control in the rate of drug release in case of controlled drug delivery system i.e. the “peak and valleys” of drug in blood or serum level are eliminated.

 Reduction in dosing frequency.

 The duration of action can be extended for days or month²³.

3. CONCLUSIONS:

Cancer is one of the major causes of death in the all over the world. The treatment and management of lung cancer is difficult by the currently available medications, due to various limitations. Therefore, practical strategies are required to develop such systems which can facilitate the drug transport to the lung in sufficient concentration. This can be achieved by targeted drug delivery system. Targeted drug delivery provides considerable therapeutic benefits to patients in terms of both local and systemic treatment. More effective delivery of targeted drug delivery system has resulted in the development of novel methods to treat cancer. Targeted drug delivery system systems are able to target various portions of the cancer using specific targeting moieties and evade the problems associated with multi-drug resistance. There is a great deal that can be done to treat and possibly prevent cancer by treating it in as early a stage as possible. This will require better detection and targeting methods which many of the researchers will definitely follow and hopefully achieve.

4. ACKNOWLEDGEMENT:

The authors are thankful to Director, University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G.) for providing necessary facilities relating to present work and UGC-MRP 41-748/2012 (SR); CGCOST (CCOST/650/2011) for financial assistance for the studies.

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Received on 22.09.2013 Modified on 06.10.2013

Research J. Pharm. and Tech. 6(11): November 2013; Page 1302-1306