Pamam Dendrimers Drug Delivery Multinuclear Platinum Anticancer Drugs Biology Essay

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Introduction

Cancer is a major cause of death worldwide and it is responsible for 27% of all deaths in the UK in 2008 in which 30% consist of males and 25% for females.1 Therefore, many are developing newer anti-cancer drugs with improved efficacy and lesser side effects. Cancer is a disease where any part of the body can be affected and the most prevailing feature of cancer is the rapid growth of abnormal cells that grow and multiply uncontrollably, which then invade and spread to other organs.2 There are a number of risk factors for the development of cancer and ageing is one of the factor since the accumulation of risk will combined with the tendency of slow cellular repair mechanisms when a person grows older. 2 Other risk factors include tobacco use, low fruit and vegetable intake, alcohol use, being overweight or obese, and physical inactivity. More than 30% of cancer can be prevented by avoiding key risk factors, according to the international cancer collaborators study in 2005.2

Types of Cancer

There are over 200 different types of cancer but the main types of cancer leading to overall death each year are lung cancer (22%), colorectal (10%) which was the second most common cause of cancer death and breast cancer was the third most common cause of cancer death in all persons (8%), despite being rare in men.1 Lung cancer has two main types which are: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) where 1 in 5 lung cancer are small cell and the rest are non-small cell.3 There are three main types of non-small cell lung cancer which are squamous cell carcinoma, this being the most common type of lung cancer, followed by adenocarcinoma and large cell carcinoma.3 The biggest risk factor for lung cancer is smoking and treatment involves the use of drugs like cisplatin, carboplatin, paclitaxel etc.

The leading cause of cancer deaths in women is breast cancer which caused 12,047 deaths and accounted for 16% of all female cancer mortality in UK in the year 2008.1 The first symptom in 9 out of 10 breast cancers is a breast lump. Treatment may include a combination of surgery, radiotherapy, chemotherapy, drugs to block hormones or their effects on cancer cells, which are hormonal therapies, and a drug called Herceptin® (trastuzumab).3 Prostate cancers is the commonest type of cancer in men and it generally affects men over 50, and is rarely found in younger men.3 Prostate cancer caused 10,168 deaths in the UK in the year 2008 which is accounted for 12% of all male deaths from cancer.1 Treatment include Docetaxel-based therapy which improves survival in patients.5

Cell Process in Cancer

Cancer is a multifaceted disease which can be explained as a dysfunction of the cell cycle. One common feature of most of the tumours is that they harbour one or more genetic mutations which allow them to proliferate outside their normal growth boundaries.6 Cell replication occurs in a series of event call the cell cycle. This cycle consists of the S phase, where DNA replication happens, M phase where mitosis begins. The important key is that S phase must always follow M phase which means that DNA replication must not start till mitosis is completed.6 Then there's the two gaps in-between the S and M phase which are called G1 which follows on from mitosis and G2 where the cells prepares for entry into the mitosis. Lastly is the G0 state where cell may reversibly exit from G1 if there is lack of the right growth-promoting signals.6

Chemotherapy

Chemotherapy is an anti-cancer drug treatment that aims to destroy various stages of cancer cells.7, 8 It is a drug therapy that can kill or stop these cancer cells from dividing. There are over 50 different chemotherapy drugs in which some are given as capsules or tablets but often they are given by infusion into the vein. This works by the drug entering the bloodstream, travelling throughout the body to treat cancerous cells wherever they are. Sometimes only a single chemotherapy drug is used, but most of the time various combination drugs is used.3

Chemotherapy can be given in stages. It can be given before surgery where it is use to shrink a tumour so that the tumour would be easier to remove or it could be given after a surgery to make sure that any cancerous cells left in the body are killed so that the likelihood for the cancer to come back would be less. Furthermore, it is use to shrink tumour or slow the progress of the disease in patient with advanced cancer. This is also known as palliative chemotherapy.7 The type of chemotherapy that is given depends on factors such as the type of cancer, where the cancer started, what the cancer cells look like under a microscope, whether the cancer has spread to other parts of the body, and the patient's general health.7

Although the advantage of chemotherapy is that it kills cancerous cells, the disadvantage of it is that also kills or harms healthy cells, which causes side effects.4 Areas that are affected by chemotherapy where normal cells divide quickly are at the bone marrow, digestive system, hair, and skin.8 In the bone marrow, blood cells are usually the ones affected such as white blood cells that helps the body to fight infection, platelets which helps with the clotting of blood and red blood cells which carries oxygen to all the cells in the body. As a result, patients undergoing chemotherapy will have risk of developing infections, getting bruises or bleeding gums and have shortness of breath.8 As for the digestive system, it gives patients the sick and vomiting feeling and some chemotherapy drug might cause diarrhoea or constipation. Sometimes after undergoing chemotherapy, the hair might start to fall out depending on the drug and the dose and it usually starts within two or three weeks after the treatment. Lastly, the skin starts to feel dry and itchy or becomes sensitive to sunlight and from time to time, the nails will start to discolour or may split and not grow at the usual rate. 8

Discovery of Platinum Drug - Cisplatin

Cisplatin or cis-diamminedichloroplatinum(II) was discovered by Barnett Rosenberg in the 1970s and it made history as a successful anticancer drug.9 It all happen 40 years ago when Rosenberg had decided to examine whether electrical currents played a role in cellular division.10 At the time of examining the effect of electric fields on the growth of Escherichia coli (E. coli) cells, a biological activity of platinum compounds was discovered and this had led to the development of some of the widely used anticancer drugs of today.11 It was discovered that compounds that formed by reaction of platinum from the electrodes with ammonium chloride buffer had stopped cell division and induced filamentous growth in the bacteria.11 The discovery of cisplatin was reported and various testing was done which eventually led to more clinical research of other platinum based compounds.

Structure and Mechanism

The anti-cancer platinum exists in two complexes: the cis-isomer which is known as cisplatin and the trans-isomer which does not exhibit a comparably useful pharmacological effect. As for the cis-isomer, it is now a platinum-based chemotherapy drug used to treat various types of cancers. The structure of cisplatin consists of a platinum ion right in the middle of a flat square with two chloride ions which forms the leaving group and two amines which are known as the carrier ligands making up the corner.12 Cisplatin is activated intracellularly by the aquation of the two chloride leaving groups which binds to DNA covalently. It produces cross-links on DNA between two adjacent guanines or adenine and guanine by the coordination to N7 purine bases.12 This prevents replication and transcription. The formation of the major GG adduct gives the antitumor effect of cisplatin because the tumour response correlates with the level of GG adducts, the recognition and processing by DNA damage-response proteins induce signal transduction pathways which leads to apoptosis or necrosis.12

Fig. 1. The anti-cancer platinum complex (A) cisplatin and its inactive isomer (B) transplatin.

Fig. 2. Formation of cisplatin DNA adduct

Treatment with Cisplatin

Cisplatin has a major role in cancer chemotherapy, especially for testicular cancer, where the overall cure rate exceeds 90%, and is almost 100% for early-stage disease.13 Cisplatin and carboplatin have been use widespread for years to treat most cancer, including ovarian, cervical, head and neck, and non-small-cell lung cancer.11 However, the treatment is limited by side effects such as nephrotoxicity, emetogenesis and neurotoxicity. Nephrotoxicity and emetogenesis can be managed by hydration in conjunction with the use of diuretics, and serotonin-receptor antagonist.14 However neurotoxicity is still a significant dose-limiting toxic effect of cisplatin which results in peripheral neuropathy, tinnitus and high-frequency hearing loss.15

Resistance

A further downside of cisplatin is treatment resistance of tumours to the drug. Although some patients show high response rates to platinum drugs, most patients will develop resistance to these drugs during treatment.16 Resistance developed are known as acquired resistance or resistance which are intrinsic to cells. Several studies of cisplatin and carboplatin drug resistance have been dominated by observations made on cell lines, and imply that resistance may involve two broad mechanisms: insufficient amount of platinum to reach the targeted DNA; the failure of achieving cell death after platinum-DNA adduct formation.9

Through intensive efforts, a more clearer understanding of the mechanisms of cisplatin resistance had been obtained, and they are divided into four groups: (i) mechanisms that involves the reduction of platinum accumulation; (ii) mechanisms that involves inactivation of cisplatin intracellularly by coordination to thiol-containing biomolecules (glutathione and metallothioneins); (iii) mechanism that enhances the repair of DNA damage; and (iv) mechanisms that stops the induction of apoptosis.16 Even though these resistance mechanisms may act concurrently in cancer cells that are resistant to cisplatin, reducing platinum accumulation is important for preventing the reaction of cisplatin with DNA, and decreasing apoptosis is important after formation of cisplatin-DNA adduct to prevent the effects of cisplatin.

Picoplatin and Multinuclear platinum complex BRR 3464

To overcome the downside of cisplatin, platinum-based drugs development has move from carboplatin and oxaliplatin to the newest generation of drugs, such as picoplatin and multinuclear platinum complex BBR3464 (triplatin).

Picoplatin [cis-amminedichloro-2-methylpyridine platinum (II)] is a new generation platinum-based compound created to provide steric bulk around the platinum centre and overcome platinum resistance.9, 17 Studies confirmed that picoplatin has the ability to retain its activity in the presence of increasing levels of glutathione and metallothionein and the ability to overcome mechanisms that decreases the accumulation of cisplatin.17 Furthermore, evidence from phase I trial shows that picoplatin showed therapeutic effect when administered orally and in phase II studies, picoplatin showed clinical efficacy in non-small cell lung cancer, small cell lung cancer, ovarian cancer, prostate cancer and breast cancer, showing the potential that it can not only be broadly use in platinum-resistant cancers but also in platinum-sensitive cancers.18,19 Morever, it was found that picoplatin had low incidence of nephrotoxicity, neurotoxicity and ototoxicity despite having reversible thrombocytopenia and neutropenia observed.9,19

As for the multinuclear platinum complex BBR3464 (triplatin), it is a representative of a new class of anticancer drugs and is more potent than the mononuclear cisplatin [cis-diamminedichloroplatinum(II)].20 BBR3464 has two terminal trans-[PtCl(NH3)2] units that are linked by a tetra amine [trans-Pt(NH3)2{H2n(CH2)6NH2}2]2+ unit. The two platinum ends can be employed in a formation of covalent bond with DNA bases (Guanine).21 Therefore it has the ability to induce long-range delocalized intra- and interstrand cross-links DNA adducts which helps escape the classical mechanism of cisplatin resistance which relates to DNA damage recognition and repair. Furthermore, BBR3464 has the ability to modify DNA in a way which is different from cisplatin where BBR3464 can evoke different pathways of cellular response to DNA damage like for example, triggering the apoptic pathway.20 Currently, investigations are motivated by the fact that BBR3464 has the potential to treat lung and skin cancers which are difficult to treat.21 However there are toxicities associated with BBR3464 therapy in phase I studies where it was found to cause neutropenia and diarrhoea, which limits its therapeutic use.22

Enhanced Permeability and Retention (EPR) effect.

The enhanced permeability and retention (EPR) effect is a special phenomenon of macromolecules and lipids in solid tumours which relates to the anatomical and pathophysiological difference from normal tissues.23 It exploits the anatomical and pathophysiological abnormalities of tumour tissue and serves as a foundation for the development of macromolecular anticancer therapy.23, 24 The EPR effect has two components: first it alters biodistribution where it shows that there was higher concentration of nano-size drug accumulation in the tumour tissues compared to other organs. This effect is dependent on time and can be reproduced in tumours of different size. Secondly it increases the plasma half-life of the nano-size drugs as the size, molecular weight ranging from 20 - 800kD, exceeds the limit of renal excretion threshold which also limits the clearance. This helps in prolonging the therapeutic effect in addition to targeting.25

Factors affecting the enhanced permeability and retention effect are vascular endothelial growth factor, bradykinin and prostaglandins, and nitric oxide. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), plays an important role in tumour angiogenesis. It not only is a mitogen for endothelial cells but it also has a vital role in tumour growth and metastasis because of its induction of vascular permeability.24 As for bradykinin (BK) and prostaglandins (PGs), it has a vital role in enhancing permeability in inflammatory and tumour tissue and therefore in sustaining tumour growth. 24 There's also nitric oxide (NO) which is a well known mediator of vasodilatation, angiogenesis, hypotension, cell proliferation and extravasations. Nitric Oxide synthesizes from I-arginine by Nitric Oxide synthase (NOS) which induces vascular permeability in tumours. 24

EPR effect is the commonest characteristics that differentiate a tumour from normal tissue. For a better therapy, a combination of the choice of drug (which exploits the EPR effect) and targeting moieties (those that can guide drugs to or into the cells) will be best. 24

Dendrimer

Dendrimer was first discovered at the beginning of 1980's by Donald Tomalia and co-workers. The term originally comes from "dendrons" meaning a tree in Greek.26 Dendrimers are a family of nanosized, three-dimensional polymers characterized by a tree-like branching architecture with very low polydispersity and high functionality.27,28 Drug delivery can be achieved by linking a drug to the polymer through one of two approaches: Hydrophobic drugs can be joined within the hydrophobic dendrimer interior to make them water-soluble or drugs can be coupled onto the suface of the dendrimer covalently.29 There are several dendimer families namely PAMAM dendrimers (the dendrimer used in this research), biodegradable dendrimers, amino acid-based dendrimers, glycodendrimers, hydrophobis dendrimers and asymmetric dendrimers.27

Poly (amidoamine) (PAMAM) dendrimer was the first dendrimer family to be synthesized and commercialized. PAMAM dendrimers are mono-dispersed multi-branched polymers that contain an amine or diaminoalkane core which reacts thru Michael addition of metyl acrylate monomers to produce a branch that can be transformed to the smallest generation of PAMAM dendrimers with surface groups such as NH2, OH or COOH.27, 30

Dendrimers are use as a drug delivery vehicle of anticancer drugs because they are well-suited and because they have high water solubility, monodispersed size and uniform composition. Furthermore, the unique branching of the dendrimers and high number of functional groups present on the surface can be use to either encapsulate or directly conjugate tonnes of therapeutic molecules that will be brought to the cytoplasm of cancer cells.27

Background on Research

It is because platinum drugs are most widely used to treat cancer, there's much interest in wanting to improve the treatment with this complex. Patients are still experiencing side effects and toxicities associated with platinum therapy thus more new platinum drugs are being developed. With the introduction of picoplatin and BBR3464, the more potent agent, it is able bind more selectively and has fewer side effects.

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