Targeted Drug Delivery: A Backbone for Cancer Therapy

Kumbhar Swapnil*, Salunkhe Vijay and Magdum Chandrakant

Department of Quality Assurance., Rajarambapu College of pharmacy, Kasegaon, Maharashtra,

India.

*Corresponding Author E-mail: mr.swapnilkumbhar@gmail.com.

ABSTRACT:

Cancer is a life threatening disease which has affected globally the health of the living beings, most of the forms of cancer have reached their altitude of mortality and hence some more advanced therapies are recommended for their proper irradication. Increased population, pollution, insufficient intake of dietary supplement, functional food and neutraceuticals can cause oxidative stress and hence generation of free radicals led to cancer. Several other factors as smoking, chewing tobacco, gutka, prolong treatment of synthetic drugs, contact with certain chemicals and habit of nicotine like drugs also contribute to cancer. Increased population of cancer can affect economical, clinical and social burden. Pipeline drugs are also in their approval stage showed a distinct ray of hope in the surveillance of the patients. Surgery is considered for advanced cases but peoples have leaned towards the Ayurveda because the science of Ayurveda has added a step to curative aspects to cancer. Practice of Yoga may improve quality-of-life measures in cancer patients. The positive effects of Yoga and Ayurveda can be soothing to survivors as well and help them to deal with post-cancer distress. Targeted drug delivery has made it possible to treat deep seated tumors in a consistent manner with least amount of side effects.

KEYWORDS: Cancer ,Chemotherapy, Ayurveda, Yoga, Targeted drug delivery.

INTRODUCTION:

Cancer is a serious disease and is one of the leading causes of death globally, according to the World Health Organization.^[1]About 1,638,910 new cancer cases are expected to be diagnosed in 2012. ^[2]In 2012, about 577,190 Americans are expected to die of cancer, more than 1,500 people a day. Cancer is the second most common cause of death in the US In 2012, cancers with increasing incidence rates are expected to account for approximately 135,000 new cancer cases among men and 110,000 cases among women. Increasing incidence of esophageal adenocarcinoma and cancers of the pancreas and liver is particularly concerning because of their poor survival, highlighting the need for early detection and treatment options for these highly fatal cancers. Lung cancer rates were higher in urban areas and stomach cancer rates were higher in rural areas. Rates of tobacco-related cancer deaths were higher in urban than in rural men.^[3]

In women, cervical cancers were the leading fatal cancers in both rural and urban areas, with somewhat higher rates in rural areas. Rates of female breast cancer mortality were similar in rural and urban areas. Stomach cancer rates were higher in rural than in urban areas of India. For both sexes, death rates from infection-related cancers were higher in rural than in urban areas. The total economic impact of premature death and disability from cancer world wild are in billions. Generally lower socioeconomic status increases exposure to cancer risk factor such as higher rates of smoking, heavy drinking, obesity, physical inactivity and exposure to environmental carcinogens. Cancer is the major class of death among all diseases depending on its types, severity, phase and situation different types of treatment are possible. Herbal Remedies are mostly preferred where surgery is impossible and to avoid side effects of chemotherapy .Mostly ruler peoples are suffered by this ghost and if such diseases not cure properly ,then it is very risky to Indian government and family members to challenge to economical, social and clinical aspects. This risk will be reducing if targeted drug delivery approaches have been in use.

Different types of Cancer

There are more than 200 different types of cancer. There are over 60 different organs in the body where a cancer can develop. There are too many types of cancer to list them that are shown in Table no.1 ^[4-10]

Table no.1

Adrenal Cancer	Gastrointestinal CarcinoidTumors	Lymphoma of the Skin	Salivary Gland Cancer
Anal Cancer	Gastrointestinal Stromal Tumor (GIST)	Malignant Mesothelioma	Sarcoma - Adult Soft Tissue Cancer
Aplastic Anemia	Gestational Trophoblastic	Myelodysplastic Syndrome	Skin Cancer
Bile Duct Cancer	Hodgkig Disease	Nasal Cavity and Paranasal Sinus Cancer	Skin Cancer-Basal and Squamous Cell
Bladder Cancer	Kaposi Sarcoma	Nasopharyngeal Cancer	Skin Cancer - Melanoma
Bone Cancer	Kidney Cancer	Neuroblastoma	Small intestine Cancer
Brain Cancer	Laryngeal and Hypopharyngeal Cancer	Non-Hodgkin Lymphoma	Stomach cancer
Breast Cancer	Leukemia - Acute Lymphocytic (ALL) in Adults	Non-Hodgkin Lymphoma In Children	Testicular Cancer
Cancer of Unknown Primary	Leukemia - Acute Myeloid (AML)	Oral Cavity and Oropharyngeal Cancer	Thymus Cancer
Castleman Disease	Leukemia - Chronic Lymphocytic (CLL)	Osteosarcoma	Thyroid cancer
Cervical Cancer	Leukemia -Chronic Myeloid (CML)	Ovarian cancer	Uterine Sarcoma
Colon/Rectum Cancer	Leukemia -Chronic Myelomonocytic (CMML)	Pancreatic Cancer	Vaginal Cancer
Endometrial Cancer	Leukemia in Children	Penile Cancer	Valver Cancer
Esophagus Cancer	Liver Cancer	Pituitary Tumors	Waldenstrom Macroglobulinemia
Ewing Family Of Tumors	Lung Cancer	Prostate Cancer	Wilms Tumor
Eye Cancer	Lung Cancer - Non-Small Cell	Retinoblastoma	Rhabdomyosarcoma

Cancer treatment

Chemotherapy.^[11]

Chemotherapy can be used to reduce the symptoms and pain associated with cancer as well as to slow the growth of cancerous tumors. In some circumstances chemotherapy may even kill spreading cancerous cells. Chemotherapy utilizes a powerful combination of drugs that are either taken by mouth or injected directly into the bloodstream. Common and typical examples of chemotherapeutic agents are illustrated in Table no.2 ^[12-21]

Table no.2

Drug	Used to treat	Drug	Used to treat
5-FU (5-fluorouracil)	Breast Cancer, Colon Cancer, Esophageal Cancer.	Camptosar (irinotecan)	Colon Cancer, Pancreatic Cancer,Stomach Cancer
Adriamycin (doxorubicin)	Bladder Cancer, Breast Cancer, Kidney (Renal Cell) Cancer.	Matulane (procarbazine)	Hodgkin's Lymphoma
Afinitor (everolimus)	Kidney (Renal Cell) Cancer	Meticorten (prednisone)	Hodgkin's Lymphoma,Non-Hodgkin's Lymphoma,Multiple Myeloma,Prostate Cancer
Alkeran (melphalan)	Multiple Myeloma	Navelbine (vinorelbine)	Non-Small Cell Lung Cancer,Ovarian Cancer
Ara-C	Hodgkin's Lymphoma	Nexavar (sorafenib)	Liver Cancer
Avastin (bevacizumab)	Colon Cancer,Kidney (Renal Cell) Cancer,Non-Small Cell Lung Cancer	Novantrone (mitoxantrone)	Non-Hodgkin's Lymphoma,Prostate Cancer
BiCNU (carmustine)	Brain Tumors	Oncovin (vincristine)	Small Cell Lung Cancer, Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, Multiple Myeloma
Cytoxan	Ovarian Cancer	Platinol (cisplatin)	Pancreatic Cancer, Prostate Cancer
Dacogen (decitabine)	Myelodysplastic Syndrome	Sutent (sunitinib)	Kidney Cancer
Decadron (dexamethasone)	Non-Hodgkin's Lymphoma,Multiple Myeloma	Tarceva (erlotinib)	Non-Small Cell Lung Cancer
Ellence (epirubicin)	Breast Cancer,Stomach Cancer	Taxotere (docetaxel)	Breast Cancer, Non-Small Cell Lung Cancer, Ovarian Cancer, Pancreatic Cancer, Prostate Cancer, Stomach Cancer, Head and Neck Cancer
Eloxatin (oxaliplatin)	Colon Cancer, Pancreatic Cancer,Stomach Cancer	Temodar (temozolomide)	Brain Tumors, Kidney (Renal Cell) Cancer
Erbitux (cetuximab)	Colon Cancer, Non-Small Cell Lung Cancer,Head and Neck Cancer.	Thalomid (thalidomide)	Multiple Myeloma
Ethyol (amifostine)	Head and Neck Cancer	Toposar (etoposide)	Non-Small Cell Lung Cancer.
Fludara (fludarabine)	Non-Hodgkin's Lymphoma	Torisel(temsirolimus)	Bladder Cancer, Breast Cancer
Gemzar (gemcitabine)	Bladder Cancer, Kidney Cancer.	TYKERB (lapatinib)	Breast Cancer
Gleevec (imatinib mesylate)	Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia	Vectibix (panitumumab)	Colon Cancer
Herceptin(trastuzumab)	Breast Cancer	Velban (vinblastine)	Bladder Cancer,Hodgkin's Lymphoma
Hycamtin (topotecan)	Small Cell Lung Cancer	Velcade (bortezomib)	Multiple Myeloma
Ifex (ifosfamide)	Testicular Cancer,Hodgkin's Lymphoma.	Xeloda (capecitabine)	Colon, Breast Cancer

Pipeline

First-in-class drugs are defined by their novel mechanism of action (action of killing tumor cells) as well as their novel molecular structure.^[22] As such they are capable of killing tumor cells that are surviving treatment by other classes of anti-cancer agents. Each Niiki Pharma drug is first-in-class. Each has a different mechanism of tumor cell killing. In preclinical models, each is active against tumor cells that are resistant to current standard anti-cancer drugs.

Niiki Pharma has an extensive international patent portfolio including over 60 issued and pending patents and patent applications.NKP-1339 is tumor targeting because it have mimics iron and binds to transferrin, the body’s natural iron carrying system.^[23] Cancer cells have a greater need for iron compared to normal cells due to their rapid growth rate. Hence, the uptake of NKP-1339 in tumor cells is enhanced. Intracellular activation NKP-1339 is usually inert and is activated by a redox reaction once inside the tumor cell. NKP-1339 therefore uses transferrin as a "Trojan Horse" to enter into the tumor cells, where it is activated.Novel intracellular targets the activated NKP-1339 produces radical intermediates that target several cytosolic proteins. One of the key intracellular targets is believed to be GRP78.

NKP-1339 Undergoing Phase I trial in United States is ongoing.

NKP-2235KP-2235 is an oral first-in-class targeted molecule.^[24] NKP-2235 kills tumor cells by hitting several novel targets in tumor cells.FDA IND was approved in March 2011^[25]. Single agent dose escalation Phase clinical trial will begin shortly.

KP-3752 is a first-in-class targeted molecule with a novel anti-tumor activity profile.^[26] It is currently in pre-clinical studies.

Surgery:-

Surgery is the oldest form of cancer treatment.^[27] It also plays a key role in diagnosing cancer and finding out how far it has spread (a process is called staging). Advances in surgical techniques have allowed surgeons to operate on a growing number of patients and have good outcomes. When a surgeon has to cut into the body to operate, it’s called invasive surgery. Today, operations that involve less cutting and damage to nearby organs and tissues (less invasive surgery) often can be done to remove tumors while saving as much normal tissue and function as possible.

Surgery offers the greatest chance for cure for many types of cancer, especially those that have not spread to other parts of the body. Most people with cancer will have some type of surgery.Surgery can be done for many reasons. Some types of surgery are very minor and may be called procedures, while others are much bigger operations. The more common types of cancer surgeries are listed here.

Preventive (prophylactic) surgery ^[28]

Preventive surgery is done to remove body tissue that is likely to become cancer, even though there are no signs of cancer at the time of the surgery. For example, pre-cancerous polyps may be removed from the colon. Sometimes preventive surgery is used to remove an entire organ when a person has an inherited condition that puts them at a much higher risk for having cancer some day.

Diagnostic surgery ^[29]

This type of surgery is used to take out a piece of tissue (biopsy) to find out if cancer is present or what type of cancer it is. The diagnosis of cancer is made by looking at the cells under a microscope. There are many ways to get a sample of cells from an area that looks like it may be cancer. These are described in more detail in the section called “Surgery to diagnose and stage cancer.”

Curative surgery ^[30]

Curative surgery is done when cancer is found in only one area, and it’s likely that all of the cancer can be removed. In this case, curative surgery can be the main treatment. It may be used alone or along with chemotherapy or radiation therapy, which can be given before or after the operation.

Debunking (cytoreductive) surgery ^[31]

Debunking surgery is done to remove some, but not all, of the cancer. It is done when removing the entire cancerous tumor would cause too much damage to an organ or nearby tissues. In these cases, the doctor may take out as much of the tumor as possible and then try to treat what’s left with radiation or chemotherapy. Debunking surgery is commonly used for advanced cancer of the ovary and some lymphomas.

Palliative surgery ^[32]

This type of surgery is used to treat problems caused by advanced cancer. It is not done to cure the cancer. Palliative surgery can also be used to correct a problem that’s causing discomfort or disability. Surgery can be used to remove the blockage. Palliative surgery may also be used to treat pain when the pain is hard to control by other means.

Supportive surgery ^[33]

Supportive surgery is done to help with other types of treatment. For example, a vascular access device such as a Port-A-Cath^® or Infusaport^® can be surgically placed into a large vein. The port can then be used to give treatments and draw blood, instead of putting needles in the arms.

Restorative (reconstructive) surgery ^[34]

This type of surgery is used to improve the way a person looks after major cancer surgery, or to restore the function of an organ or body part after surgery. Examples include breast reconstruction after mastectomy or the use of tissue flaps, bone grafts, or prosthetic (metal or plastic) materials after surgery for head and neck cancers.

Ayurveda

Ayurvedic concept of cancer ^[35]

Charaka and Sushruta samhitas, two well-known Ayurvedic classics, describe cancer as inflammatory or non-inflammatory swelling and mention them as either Granthi (minor neoplasm) or Arbuda (major neoplasm). Ayurvedic literature defines three body-control systems, viz., the nervous system (Vata or air), the venous system (Pitta or fire), and the arterial system (Kapha or water) which mutually coordinate to perform the normal function of the body. In benign neoplasm (Vataja, Pittaja or Kaphaja) one or two of the three bodily systems are out of control and is not too harmful because the body is still trying to coordinate among these systems. Malignant tumours (Tridosaja) are very harmful because all the three major bodily systems lose mutual coordination and thus cannot prevent tissue damage, resulting in a deadly morbid condition.

Principles of ayurvedic treatment ^[36]

The therapeutic approach of Ayurveda has been divided into four categories as Prakritisthapani chikitsa (health maintenance), Roganashani chikitsa (disease cure), Rasayana chikitsa (restoration of normal function) and Naishthiki chikitsa (spiritual approach) .Finding the cause of an illness is the basic goal of Ayurvedic therapy. It classifies disease development into six stages that include aggravation, accumulation, overflow, relocation, build-up in a new location, and manifestation into a recognizable disease. Ayurvedic physicians can diagnose an illness at even initial stages of body imbalance and their therapeutic approach maintains a balance by supplying deficient substances as well as reducing the excessive ones. Surgery is considered only for advanced cases.

Novel approaches to treat –cancer ^[37]

Yoga and meditation ^[38]

Practice of Yoga may improve quality-of-life measures in cancer patients.^[39] It is unclear what aspect(s) may be beneficial or what populations should be targeted.

Other studies show improvements in how participants cope with symptoms from more physical conditions, like cancer. Learning breathing and relaxation techniques help patients manage pain, depression, anxiety, insomnia, and fatigue. The patients reported that their overall quality of life significantly improved in addition to mood, distress, sleep quality, and severity of cancer symptoms. Yoga can also help improve flexibility in cancer patients, which may allow the patients to gain confidence doing basic tasks. In a study performed by Susan DiStasio, women with breast cancer stated that they experienced lower pain on the day they practiced yoga, and men with prostate cancer said their stress decreased through yoga. The positive effects of yoga can be soothing to survivors as well and help them to deal with post-cancer distress.

Hyperthermia ^[40]

Hyperthermia means a body temperature that is higher than normal. High body temperatures are often caused by illnesses, such as fever or heat stroke. But hyperthermia can also refer to heat treatment – the carefully controlled use of heat for medical purposes. When cells in the body are exposed to higher than normal temperatures, changes take place inside the cells. These changes can make the cells more likely to be affected by radiation therapy or chemotherapy. Very high temperatures can kill cancer cells outright, but they also can injure or kill normal cells and tissues. The idea of using heat to treat cancer has been around for some time, but early attempts had mixed results. For instance, it was hard to maintain the right temperature in the right area while limiting the effects on other parts of the body. But today, newer tools allow better control and more precise delivery of heat, and hyperthermia is being studied for use against many types of cancer.

Next generation PDT / cancer treatment for the 21st century ^[41]

Next Generation PDT (NGPDT) has developed a uniquely effective Photodynamic Therapy (PDT) for the treatment of cancer. By building on proven and existing medical research for PDT cancer treatments, Next Generation PDT treats a wide variety of cancers non-invasively and with greater effect. NGPDT achieves these results through the development of a new generation photosensitizer which can selectively accumulate and identify the cancer tumor tissue.

Adenovirus-Based Gene Therapy; a Promising Novel Cancer Therapy ^[42]

Recent scientific research has established gene therapy as a new and promising approach to traditional therapies in order to combat severe forms of cancer. The mechanism behind gene delivery is to “correct” and rebuild broken down and infected tissue within the body. Essentially, DNA is used as a "pharmaceutical agent," as it supplements and alters genes within cells. it is also commonly co-administered with other anti-tumoral drugs.

Targeted drug delivery ^[43]

Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. Because scientists often call these molecules “molecular targets,” targeted cancer therapies are sometimes called “molecularly targeted drugs,” “molecularly targeted therapies,” or other similar names.^[44] By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies are more effective than other types of treatment, including chemotherapy and radiotherapy, and less harmful to normal cells Targeted cancer therapies interfere with cancer cell division (proliferation) and spread in different ways.^[45] Many of these therapies focus on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, cell responses to specific external stimuli, and even cell death. By blocking signals that tell cancer cells to grow and divide uncontrollably, targeted cancer therapies can help stop cancer progression and may induce cancer cell death through a process known as apoptosis. Other targeted therapies can cause cancer cell death directly, by specifically inducing apoptosis, or indirectly, by stimulating the immune system to recognize and destroy cancer cells and/or by delivering toxic substances directly to the cancer cells.^[46] The development of targeted therapies, therefore, requires the identification of good targets that is, targets that are known to play a key role in cancer cell growth and survival.

The development of targeted therapies ^[47]

Once a target has been identified, a therapy must be developed. Most targeted therapies are either small-molecule drugs or monoclonal antibodies. Small-molecule drugs are typically able to diffuse into cells and can act on targets that are found inside the cell. Most monoclonal antibodies cannot penetrate the cell’s plasma membrane and are directed against targets that are outside cells or on the cell surface.

The first target for targeted cancer therapy ^[48]

The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone estrogen, which many breast cancers require for growth. When estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation Aromatase inhibitors (AIs) are another class of targeted drugs that interfere with estrogen’s ability to promote the growth of ER-positive breast cancers.^[49] The enzyme aromatase is necessary to produce estrogen in the body. Blocking the activity of aromatase lowers estrogen levels and inhibits the growth of cancers that need estrogen to grow.

Some other targeted therapies:-

The development of monoclonal antibodies (mAbs), which act via antibody-dependent cell-mediated cytotoxicity (ADCC), represented a significant advance in cancer immunotherapy. FDA-approved targeted therapies. ^[50] Mostly used marketed Monoclonal antibodies are illustrated in Table no-3^[51-55]

Table no.3

Drug	Mechanism of action	Use
Nilotinib (Tasigna®)	The drug is another small-molecule tyrosine kinase inhibitor.	Treat some patients with CML.
Trastuzumab (Herceptin®)	The therapy is a monoclonal antibody that binds to the human epidermal growth factor receptor 2 (HER-2). HER-2, a receptor with tyrosine kinase activity, is expressed at high levels in some breast cancers.	Breast cancer, gastric or gastroesophageal junction adenocarcinoma.
Gefitinib (Iressa®)	Gefitinib inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), which is overproduced by many types of cancer cells.	Non-small cell lung cancer
Erlotinib (Tarceva®)	Small-molecule drug inhibits the tyrosine kinase activity of EGFR.	Metastatic non-small cell lung cancer and pancreatic cancer.
Cetuximab (Erbitux®)	The therapy binds to the external portion of EGFR, thereby preventing the receptor from being activated by growth signals, which may inhibit signal transduction and lead to antiproliferative effects.	Squamous cell carcinoma of the head and neck or colorectal cancer.
Panitumumab	Monoclonal antibody attaches to EGFR and prevents it from sending growth signals.	Metastatic colon cancer.
Temsirolimus (Torisel®)	This small-molecule drug is a specific inhibitor of a serine/threonine kinase called mTOR that is activated in tumor cells and stimulates their growth and proliferation.	Advanced renal cell carcinoma.
Everolimus (Afinitor®)	This small-molecule drug binds to a protein called immunophilin FK binding protein-12, forming a complex that in turn binds to and inhibits the mTOR kinase.	Advanced kidney cancer
Vandetanib (Zactima™)	This small-molecule drug binds to and blocks the activity of tyrosine kinase enzymes	Metastatic medullary thyroid cancer.

CONCLUSION:

Generally Conventional drugs are used on many types of cancers rather than targeted delivery because they have wide range of therapeutic approach, however due to its ultimate side effects they have been superseded by novel drug delivery. Chemotherapy includes use of wide range of synthetic drugs at periodic intervals which increase the danger of severity of high dosage regimen. Surgery is applicable only at such stage of cancer where tumor is restricted to a localized site. It is painful and does not assure full eradication of tumor. Ayurveda and Herbal anticancer therapy includes recommendations for lifestyle and use of specific foods and herbs which are very helpful not only in preventing the progression of the disease but also make the patients feel better and comfortable overcoming the symptoms. Cancer therapy in Ayurveda—learning from the past, examining the present and advancing to the future. Yoga treatments have been found to be useful in improving Quality of life of the cancer patients. Currently some pipeline drugs are undergoing USFDA approval for their novel mechanism of action to decrease the rate of Proliferation of tumor cells. Now a days, a pain free technique is also used in cancer treatment which involves use of photodiodes and destroying cancer cells have been discussed in this review Targeted cancer therapies highlights doctors a better way to tailor cancer treatment, especially when a target is present in some but not all tumors of a particular type, as is the case for HER-2. Eventually, treatments may be individualized based on the unique set of molecular targets produced by the patient’s tumor. Targeted drug delivery also hold the promise of being more selective for cancer cells than normal cells, thus harming fewer normal cells, reducing side effects, and improving life.

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Received on 11.12.2012 Accepted on 22.02.2013

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