03 Apr 2018
Better understanding of the biology of cancer cells has led to the development of biologic agents that mimic some of the natural signals that the body uses to control cell growth. Clinical trials have shown that this cancer treatment, called biological response modifier (BRM) therapy, biologic therapy, biotherapy, or immunotherapy, is effective for several cancers. Some of these biologic agents, which occur naturally in the body, can now be made in the lab. Examples are interferons, interleukins, and other cytokines. These agents imitate or influence the natural immune response of the body. By altering the cancer cell growth or by acting indirectly to help healthy cells control the cancer.
One of the most exciting applications of biologic therapy has come from identifying certain tumor targets, called antigens, and aiming an antibody at these targets. This method was first used to find tumors and diagnose cancer and more recently has been used to treat cancer cells. Scientists produce monoclonal antibodies that are specifically targeted to chemical components of cancer cells. Refinements to these methods, using recombinant DNA technology, have improved the effectiveness and decreased the side effects of these treatments. The first therapeutic monoclonal antibodies, rituximab (Rituxan) and trastuzumab (Herceptin) were approved during the late 1990s to treat lymphoma and breast cancer, respectively. Monoclonal antibodies are now routinely used to treat certain cancers.
Scientists are also studying vaccines that boost the body’s immune response to cancer cells. For instance, a 2009 lymphoma study looked at personalized vaccines made from tissue from each patient’s tumor. Encouraging results showed that patients who received the vaccine lived longer disease-free than those who did not.
In 2010, the FDA approved Sipuleucel-T (Provenge), a cancer vaccine for metastatic hormone-refractory prostate cancer (prostate cancer that has spread and is no longer responding to hormone treatment). Unlike a preventive vaccine, which is given to prevent disease, Provenge boosts the body’s immune system’s ability to attack cancer cells in the body. This treatment helps certain men with prostate cancer live longer, though it does not cure the disease.
Until the late 1990s nearly all drugs used in cancer treatment (with the exception of hormone treatments) worked by killing cells that were in the process of replicating their DNA and dividing to form 2 new cells. These chemotherapy drugs also killed some normal cells but had a greater effect on cancer cells.
Targeted therapies work by influencing the processes that control growth, division, and spread of cancer cells, as well as the signals that cause cancer cells to die naturally (the way normal cells do when they are damaged or old). Targeted therapies work in several ways.
Growth signal inhibitors:
Growth factors are hormone-like substances that help to tell cells when to grow and divide. Their role in fatal growth and repair of injured tissue was first recognized in the 1960s. Later it was realized that abnormal forms of growth factors or abnormally high levels of growth factors contribute to the growth and spread of cancer cells. Researchers also started to understand how cells recognize and respond to these factors, and how that can lead to signals inside the cells that cause the abnormal features found in cancer cells. Changes in these signal pathways have also been identified as a cause of the abnormal behaviour of cancer cells.
During the 1980s, scientists found that many of the growth factors and other substances responsible for recognizing and responding to growth factor are actually products of oncogenes. Among the earliest targeted therapies that block growth signals are trastuzumab (Herceptin), gefitinib (Iressa), imatinib (Gleevec), and cetuximab (Erbitux). Current research has shown great promise for treatments in some of the more deadly and hard-to-treat forms of cancer, such as non-small cell lung cancer, advanced kidney cancer, and glioblastoma. Second-generation targeted therapies, like dasatinib (Sprycel) and nilotinib (Tasigna), have already been found to produce faster and stronger responses in certain types of cancer and were better tolerated.
Angiogenesis is the creation of new blood vessels. The term comes from 2 Greek words: angio, meaning “blood vessel,” and genesis, meaning “beginning.” Normally, this is a healthy process. New blood vessels, for instance, help the body heal wounds and repair damaged tissues. But in a person with cancer, this same process creates new, very small blood vessels that give a tumor its own blood supply and allow it to grow.
Anti-angiogenesis agents are types of targeted therapy that use drugs or other substances to stop tumors from making the new blood vessels they need to keep growing. This concept was first proposed by Judah Folk man in the early 1970s, but it wasn’t until 2004 that the first angiogenesis inhibitor, bevacizumab (Avastin), was approved. Currently used to treat advanced colorectal, kidney, and lung cancers, bevacizumab is being studied as treatment for many other types of cancer, too. Many new drugs that block angiogenesis have become available since 2004.
Apoptosis is a natural process through which cells with DNA too damaged to repair – such as cancer cells – can be forced to die. Many anti-cancer treatments (including radiation and chemotherapy) cause cell changes that eventually lead to apoptosis. But targeted drugs in this group are different, because they are aimed specifically at the cell substances that control cell survival and death.
Novel Approaches for Cancer Treatment
Liposomes: Liposomes were first introduced by Bangham in 1965 and afterwards became the most popular and versatile tool in controlled and targeted drug delivery.Since liposomes were first described 45 years ago  they have gained interests for a variety of applications including drug delivery .Liposomes used for drug delivery are usually about 100 nm in size and are made up of a single bilayer. As liposomes comprise an aqueous core sealed off by a PL membrane both hydrophilic and lipophilic drugs can be accommodated in their respective compartments .Liposomes consist of spherical lipid bilayers that can be produced from phospholipids and cholesterol. Liposomes can encapsulate a variety of molecules, such as small drug molecules, proteins and many other bioactive(s). These vesicles are generally considered as biodegradable and imperceptibly immunogenic,and can also be used for a large number of biomedical applications. Recently, DOX and fluoxetine encapsulated liposomes have been reported to be effective formulation against drug-resistant MCF-7 cells. It was observed that liposomes significantly reduced tissue bio distribution of anticancer agents with improvedcytotoxicity. Liposomes are simple colloidal vesicles with an aqueous interior enclosed by a membrane usually composed of phospholipid (PL) molecules. PLs, the major components of biological membrane are amphiphilic compounds with a polar head group and lipophilic acyl chains. PLs can be classified according to type of polar head group, fatty acid chain length and degree of saturation.When bilayer forming PLs are dispersed in aqueous media they will spontaneously align themselves in a manner to reduce interactions between the polar media and the hydrophobic fatty acid chains. Consequently, bilayer structures, i.e. liposomes, may be formed. Liposomes may consist of one or more bilayers (lamellae) and of sizes ranging from tens of nanometres to tens of micrometres in diameter. For a review see . Liposomes are broadly classified into small unilamellar vesicles (SUV); single bilayer, size 10 - 100 nm), large unilamellar vesicles (LUV); single bilayer, size 100 - 1000 nm), multilamellar vesicles (MLV), several bilayers, size 100 nm - 20 um and multivesicular vesicles (MVV), size 100 nm – 20um).
Today there are about 15 liposomal based formulationdrugs approved for clinical applications or undergoing clinical evaluation,Liposomes in cancer treatment Conventional cytostatic used in cancer treatment are small molecular weight molecules . Such molecules distribute non-specifically to both healthy and tumour tissue resulting in therapy limiting toxicities. To increase the therapeutic-to-toxicity ratio cytostatic can be encapsulated into small liposomes (~100 nm), which accumulate in tumours due to the 14enhanced permeability and retention effect . Here, leaky tumour vessels allow macromolecules to extravagate into tumour tissue, whilst reduced lymphatic tumour drainage results in particle accumulation. First generation liposomes used for drug delivery suffered from fast clearance by cells of the monocyte phagocyte system (MPS). By coating liposomes with polyethylene glycol (PEG), i.e. PEGylated liposomes, adhesion of plasma proteins and opsonin to liposomes are decreased. Consequently, immune system recognition is reduced, decreasing MPS uptake and prolongs circulation time . Today, most liposomes used for drug delivery are PEGylated. Cancer is a class of diseases. Which is characterized by out-of-control cell growth.There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected.
Nanotechnology has been extensively exploited to improve conventional cancer therapy in the recent years [1–5]. The designed nanocarriers for achieving precise drug delivery to cancer cells are expected to be non-cytotoxic, efficiently load the drugs, enhance the circulation time in bloodstream, and actively target the cancer cells. The nanocarriers currently under intensive investigation can be divided into two categories in generalise. The lipid-based and the polymer-based with liposomes and polymeric nanoparticle as their typical representative respectively. Liposomes, the spherical vesicles formed by single or multiple lipid bilayer, have been widely used due to their high biocompatibility, favourable pharmacokinetic profile, high delivery efficiency and ease of surface modification. In the recent years, several liposomal drug formulations have been approved for clinical use .
Limitations of liposomal drug delivery: - include insufficient drug loading, fast drug release, and instability in storage .
Historically, lipids have been used for several decades in various drug delivery systems including liposomes solid lipid NPs, nano structured lipid carriers, andlipid–drug conjugates. Over the last decade, lipid based nano carriers are viewed as potential tool to encapsulate and deliver variety of pharmaceutical actives[44,45]. The solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are the first and second generation of lipid nanoparticles, respectively. The SLNs are composed of solid lipid or a blend of solid lipids while NLCs contain a mixed lipid core (solid fat and oil). generally regarded as safe [GRAS] nature of lipid and the structural integrity of the polymer. Thus far, the polymers such as polylactic-co-glycolic acid (PLGA) [46,47], hydrolysed polymer of epoxidized soybean oil (HPESO) [48,49], dextran , polyethyleneimine (PEI) , LPNs, are prepared by at least three main components are i.e., the lipid, the polymer, and a drug. The first way to prepare the LPNPs is to mix the polymeric NPs with liposomes to form the lipid-shell and polymer-core nanoparticles such as lipoparticles where the lipid bilayer or lipid multilayer of the liposomes fuses on the surface of the polymeric NPs.[52–53] The second way to prepare the LPNPs has advantage over the first way in formulating the structured NPs in a single step and thus provides a simpler technology, which combines the nanoprecipiation method and the self-assembly technique to produce the desired structured NPs of lipid shell and polymer core [54,55]Folic acid is selected as the model molecular probe for targeted delivery of the drug to the cancer cells of folate overexpression such as certain breast cancer and ovarian cancer cells. Poly (lactide-co-glycolide) (PLGA), one of the most popular FDA approved non-cytotoxic and biodegradable polymers,is used to form the polymer core matrix, which is wrapped by the mixed lipid monolayer shell of three distinct functional components:(i) 1,2-dilauroylphosphatidylocholine (DLPC), a phospholipid of an appropriate hydrophilic-lipophilic balance (HLB) value which is employed to stabilize the NPs in the aqueous phase;(ii) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2k), a PEGlyated DSPE to facilitate stealth NPs formulation to escape from recognition by the reticuloendothelial system (RES) and thus increase the systemic circulation time of the LPNPs[28,29],and(iii)1,2-distearoyl-snglycero-3-phosphoethanolamineN[folate(polyethylene glycol)-5000] (DSPE-PEG5k-FOL), a PEGylated DSPE of longer PEG chains for the LPNPs to be functionalized by folic acid conjugation for targeted delivery purpose.
Superparamagnetic iron oxide nanoparticles (SPIONS as delivery systems)
Super paramagnetic iron oxide nanoparticles (SPION) have emerged as an MRI contrast agent for tumor imaging due to their efficacy and safety. Their utility has been proven in clinical applications with a series of marketed SPION-based contrast agents. Extensive research has been performed to study various strategies that could improve SPION by tailoring the surface chemistry and by applying additional therapeutic functionality. Research into the dual-modal contrast uses of SPION has developed because these applications can save time and effort by reducing the number of imaging sessions. In addition to multimodal strategies, efforts have been made to develop multifunctional nanoparticles that carry both diagnostic and therapeutic cargos specifically for cancer. Advances in nanotechnology have permitted new possibilities for theranostics, which are defined as the combination of therapy and imaging within a single platform [56, 57]. Nanotechnology is applied to molecular imaging in the form of imaging probes capable of enhancing the sensitivity of the image and the specificity toward the target tissue. Usually, the imaging probeconsists of nanoparticles conjugated with active targeting ligands [58, 59].
Superparamagnetic iron oxide nanoparticles (SPION) have a superparamagnetic iron core, which makes them useful as T2 contrast agents for MRI. SPION can be detected withhigh sensitivity, and both the iron and polymer components of SPION are biocompatible and degradable .The size of iron oxide nanoparticles plays a major rolein target cell uptake and elimination from the body. Spleen and liver capture nanoparticles of more than 200 nm in diameter whereas particles having sizes below 10 nm are selectively filtered by renal systems and eliminated from body .The majority of nanoparticles in development include drug conjugates and complexes, micelles, dendrimers, vesicles, core–shell particles, microbubbles, and carbon nanotubes .
Dendrimer-based Nanoparticles for Cancer Treatment
Nanotechnology has led to a remarkable convergence of disparate fields including biology, applied physics, optics, computational analysis, and modeling, as well as materials science. Because of this, the application of nano scale analytical, computational, and synthetic approaches to understanding and manipulating complex biological systems offers incredible potential for advances in the diagnosis and treatment of cancer. Recent work has suggested that nanoparticles in the form of dendrimers may be a keystone in the future of therapeutics. The field of oncology could soon be revolutionized by novel strategies for diagnosis and therapy employing dendrimer-based nano therapeutics. Several aspects of cancer therapy would be involved. Diagnosis using imaging techniques such as MRI will be improved by the incorporation of dendrimers as advanced contrast agents. This might involve novel contrast agents targeted specifically to cancer cells. Dendrimers can also be being applied to a variety of cancer therapies to improve their safety and efficacy. A strategy, somewhat akin to the “Trojan horse,” involves targeting anti-metabolite drugs via vitamins or hormones that tumors need for growth. Further applications of dendrimers in photodynamic therapy, boron neutron capture therapy, and gene therapy for cancer are being examined.Most cancer therapeutics are small drug molecules that after being ingested or injected into the bloodstream can easily diffuse through vascular pores and the extracellular matrix to reach tumors. Complex therapeutics that involve drug delivery mechanisms or imaging moieties have tended to be much larger. While the exact size of molecules thatcan easily transverse vascular pores from the bloodstream and reach tumor tissue is unclear, it is probably limited to the size of proteins (<20 nm). Studies have documented that molecules 100 nm in diameter do not effectively diffuse across the vascular endothelium and even molecules 40 nm in diameter are problematic unless the endothelium is traumatized by radiation or heating. Two technical advances underlie our research. The first is the successful development of multifunctional nano devices based on the dendritic polymer or dendrimer. The second is the development of a linking strategy that allows the dendrimer molecules to be linked via complementary oligonucleotides[66, 67]. Nanoparticle therapeutics based on dendrimers and oligonucleotide linked dendrimers appear to be able to improve the therapeutic index of cytotoxic drugs by direct delivery of the drugs to cancer cells. There is also hope that delivering drug by this approach could overcome drug resistance in tumour cells via bypassing p-glycoprotein pumps that would normally export drugs that must diffuse into cells.
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