2013, Cilt 26, Sayı 1, Sayfa(lar) 001-004
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Klinik onkoloji alanında nanoteknoloji
Mehmet Rıfkı TOPÇUL1, İdil ÇETİN2
1Biology Department, Faculty of Science, İstanbul University, İstanbul, Turkey
2Radiobiology Department, Intitute of Science , Istanbul University, İstanbul,Turkey
Keywords: Onkoloji, Kanser, Nanoteknoloji, Nanoilaç, Radyoterapi, Hipertermi
Abstract
Cerrahi, radyoterapi ve kemoterapi kanser tedavisinde kullanılan geleneksel yöntemlerdir. Bu yöntemlerin bazı sınırlamaları olduğu için hastalığı tamamen tedavi etmek güçtür. Son yıllarda bu sınırlamaların üstesinden gelmek ve aynı zamanda tedavi etkinliğini arttırmak için yeni yöntemler geliştirilmektedir. Bu bağlamda nanoteknoloji umut verici bir yaklaşımdır. Bu nedenle kanser nanoteknolojisi dikkat çekici bir alan haline gelmiştir. Geleneksel kanser ilaçlarının yan etkilerini azaltan ve tedavi etkinliğini arttıran yeni nano ilaçlar, radyoterapiye duyarlılığı arttıran altın nano partiküller ve termal ablasyon tedavisinde kullanılan nano partiküller kanser nanoteknolojisi alanında kullanılan uygulamalardan sadece bazılarıdır.
  • Top
  • Abstract
  • Introduction
  • Conclusion
  • References
  • Introduction
    Clinically, cancer is defined as a large number (up to a hundred) of complex diseases that behave differently depending on the cell types from which they originate. Cancers vary in age of onset, growth rate, invasiveness, prognosis, and responsiveness to treatment 1. The most common cancer treatments are limited to chemotherapy, radiation, and surgery. Frequent challenges encountered by current cancer therapies include the nonspecific systemic distribution of antitumor agents, inadequate drug concentrations reaching the tumor, and the limited ability to monitor therapeutic responses. Poor drug delivery to the target site leads to significant complications, such as multidrug resistance 2. Nowadays to overcome all these limitations in the treatment of cancer, researchers have started working on nanotechnological applications in the field of clinical oncology.

    Nanotechnology can be defined simply as the technology at the scale of one-billionth of a metre. It is the design, characterization, synthesis and application of materials, structures, devices and systems by controlling shape and size at the nanometre scale 3. Nanomedicine is defined as the application of nanobiotechnology to medicine and is based on the use of nanoscale materials and devices for diagnosis and drug delivery as well as for the development of advanced pharmaceuticals referred to as nanopharmaceuticals 4.

    In this review, some nanodrugs, which can both increase the effectiveness and reduce side effects of cancer treatment, increasing the effectiveness of radiation therapy with gold nanoparticles and the application of hyperthermia through the nanomaterials are discussed.

    Chemotherapy based on nanotechnology
    Most current anticancer agents do not differentiate between cancerous and normal cells, leading to systemic toxicity and adverse effects. This greatly limits the maximum allowable dose of the drug. In addition, rapid elimination and widespread distribution into targeted organs and tissues requires the administration of a drug in large quantities, which is not economical and often results in undesirable toxicity 5. Techniques for controlled drug delivery represents one of the frontier areas of science, which involves multidisciplinary scientific approaches that can contribute to human health care. These delivery systems offer numerous advantages compared to conventional dosage forms, including improved efficacy, reduced toxicity, and improved patient compliance and convenience 6.

    The new generation of nanotechnology-based drug formulations is challenging the accepted ways of cancer treatment. Multi-functional nanomaterial constructs have the capability to be delivered directly to the tumor site and eradicate cancer cells selectively, while sparing healthy cells. Tailoring of the nano-construct design can result in enhanced drug efficacy at lower doses that can free drug treatment, can produce a wider therapeutic window, and lower side effects. Nanoparticle carriers can also address several drug delivery problems that could not be effectively solved in the past, including reduction of multi-drug resistance effects, delivery of small interfering RNA (siRNA), and penetration of the blood-brain-barrier. Although challenges in understanding toxicity, biodistribution, and in paving an effective path for regulating the actions of the nanoscale devices carry a vast promise to change ways cancer is diagnosed and treated 7. The design of a universal nanotechnology formulation with chemotherapeutic agents is crucial. A successful formulation, one that acts as a good therapeutic carrier for cancer therapies, would exhibit the following features: (i) it would be stable in the physiological environment, (ii) have a longer circulation life time than currently available treatments, (iii) avoid opsonization and processing by the reticuloendothelial system (RES), (iv) promote endocytosis, and (v) enhance tumor uptake. The specificity of these formulations can be further enhanced by the conjugation of antibodies to the nanoformulations and these immunoconjugated formulations will have a better therapeutic efficacy than other drug formulations 8.

    Albumin Bound Paclitaxel
    Taxanes are a class of chemotherapy agents that promote the polymerization of tubulin into highly stable, intracellular microtubules. These microtubules cause cell death by interfering with normal cell division. The first taxane developed and tested in the field of oncology was paclitaxel 9. Paclitaxel is a naturally occurring complex product extracted from the bark of the Western yew (Taxus brevifolia) and is widely used for the treatment of breast, lung, and advanced ovarian cancer 10-12. Advances in the use of taxanes clinically have been limited by their chemical formulation: they are highly hydrophobic molecules. To overcome this poor water solubility, lipid-based solvents are used as a vehicle. Solubility of paclitaxel is enhanced with a mixture of 50:50 Cremophor EL® (CrEL, a non-ionic surfactant polyoxyethylated castor oil; BASF, Florham Park, NJ, USA) and ethanol (Taxol® and generic equivalents) 13. The solvent Cremophor-EL used in formulations of paclitaxel causes acute hypersensitive reactions. To reduce the risk of allergic reactions when receiving paclitaxel, patients must undergo pre-medication using steroids and anti-histamines and be given the drug using slow infusions lasting a few hours 14. In order to overcome insolubility problems, albumin bound paclitaxel was developed. This drug is the only example of a regulatory approved (FDA, USA) nanoparticle formulation for intravenous drug delivery in cancer patients. It is paclitaxel bound to albumin nanoparticles, with a mean diameter of 130 nm, for use in individuals with metastatic breast cancer who have failed a combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy 15,16. This formulation overcomes poor solubility of paclitaxel in the blood and allows patients to receive 50% more paclitaxel per dose over a 30-min period 17. Because it is solvent-free solvent related toxicities are also eliminated 14.

    Liposomal Doxorubicin
    Anthracyclines are an important class of antitumor agents with significant biological activities. Anthracyclines are DNA intercalating agents, which can bind to DNA. These agents bind to specific DNA sequences, form topoisomerase- DNA complexes, and cause double strand DNA breaks. Anthracycline is a Doxorubicin that is an essential component of treatment of breast cancer, childhood solid tumors, and soft tissue sarcomas 18,19 . Although anthracyclines are used in many types of cancer, they have cardiotoxic effects. Acute cardiotoxicity may manifest as nonspecific ST-segment and T-wave abnormalities. In contrast to early effects, late anthracycline cardiotoxicity is cumulative, dose related, and, at sufficiently high dosages, can result in congestive heart failure (CHF) and left ventricular (LV) dysfunction 20. Doxorubicin is recognized as one of the most active drugs for breast cancer, but its clinical utility is limited because of a cumulative dose-dependent cardiac myopathy that can lead to potentially fatal congestive heart failure 21-24.

    The mechanism of doxorubicin-induced cardiotoxicity involves the formation of a stable complex of drug with ferric iron, and this reacts with oxygen, forming superoxide anions, hydrogen peroxide, and hydroxyl radicals. These free radicals cause lipid peroxidation. The injury is initially subclinical, but continued treatment results in progressive myocyt damage leading to cumulative dose-dependent cardiac dysfunction that can manifest during therapy, months after the last anthracycline dose or even years later 25. In an effort to minimize anthracycline-induced cardiotoxicity, a liposome-encapsulated doxorubicin (Myocet™, St. Mary’s Pharmaceutical Unit, Quadrant Centre, Cardiff Business Park, Llaninishan, Cardiff Wales; Trade Company, Cephalon Europe, Maison Alfort, France) has been developed 26. Liposomal doxorubicin is approximately 190 nm in size and was approved by the European Agency for the Evaluation of Medicinal Products (EMEA) in 2000 for the treatment of metastatic breast cancer 17. The formulation consists of encapsulation of the water-soluble doxorubicin within a phospholipid membrane to prevent doxorubicin from exiting the circulation through capillary junctions in healthy tissues. However, liposome-encapsulated drug appears to pass easily through the damaged capillaries of tumor tissues 26. Therefore, liposomal encapsulation of doxorubicin is designed to increase safety and tolerability by decreasing cardiac and gastrointestinal toxicity through decreased exposure of these tissues to doxorubicin, while effectively delivering the drug to the tumor 27.

    Nanotechnology-based radiotherapy
    Radiotherapy involves the use of high-energy rays to kill cancer cells 28. Treatment depends upon the sensitivity of dividing cells being destroyed by X-rays or gamma rays emitted from a radioactive source 29. Here, the ionizing radiation presents the advantage of penetrating tissues, which allows the treatment of deeply sited tumors 30. However, radiotherapy has the disadvantage of causing some damage to normal tissues and cells covering and surrounding the cancer in the irradiated treatment area 29. One major difficulty is the lack of selectivity between the tumor and the healthy surrounding tissue. The implementation of such techniques is therefore limited by the tolerance of normal tissues. The challenge of future radiation therapies is to develop methods for targeting the dose deposition to tumors and to enhance the biological effects 30.

    Chemical radiosensitizers have been developed to increase the sensitivity of tumor cells’ to radiation by targeting numerous different biochemical pathways, including targeting of hypoxic cells, suppression of radioprotective thiols, and inhibition of DNA repair 31-34. Although these applications have shown promise in one or more areas, they are generally toxic to normal tissues, have uncertain radiosensitizing mechanisms, and sometimes rely on a subcellular target that is subject to change. It has been concluded that the synergistic gain from these chemical radiosensitizers has been marginal 35.

    Enhancement of the radiation dose by high atomic number (Z) materials has long been of interest 36. It has been reported that loading high Z materials into the tumor could result in greater photoelectric absorption within the tumor than in surrounding tissues, and thereby enhance the dose delivered to a tumor during radiation therapy 36,37. Among other nanoparticle systems, gold nanoparticles have been explored as radiosensitizers 38. While most of the research in this area has focused on either gold nanoparticles with diameters of less than 2 nm or particles with micrometer dimensions, it has been shown that nanoparticles 50 nm in diameter have the highest cellular uptake 39. Gold nanoparticles have properties that make them attractive for use in cancer therapy including their small size, biocompatibility, and passive accumulation in tumors because of the enhanced permeability and retention effect 40. In addition to these properties gold nanoparticles are capable of forming reactive oxygen species when irradiated 41.

    The results suggest that the enhancement of radio sensitivity is due to the production of additional low-energy secondary electrons caused by the increased absorption of ionizing radiation energy by the metal of gold nanoparticles or of a thick gold substrate. Since short-range low-energy secondary electrons are produced in large amounts by any type of ionizing radiation, and since on average only one gold nanoparticle per DNA molecule is needed to increase damage considerably, targeting the DNA of cancer cells with gold nanoparticles may offer a novel approach that is generally applicable to radiotherapy treatments 42.

    Nanotechnology-based thermal ablation therapy
    Thermal ablation therapy (hyperthermia) is defined as a therapy in which tumor temperature is raised to values between 41ºC and 45ºC by external means. It can be applied locally/ regionally or to the whole body depending from the stage of the cancer in patients For decades hyperthermia has been an area of laboratory investigation 43. Hyperthermia therapy is the most promising of these methods but is limited by incomplete tumor destruction and damage to adjacent normal tissues. The radiofrequency ablation technique currently used, is a type of interstitial hypothermia that requires invasive needle placement and is limited by the accuracy of the targeting. Use of nanoparticles has refined noninvasive thermal ablation of tumors, and several nanomaterials have been used for this purpose. These include gold nanomaterials, iron nanoparticles, magnetic nanoparticles, carbon nanotubes and affisomes. Heating of the particles can be induced by magnets, lasers, ultrasound, photodynamic therapy or low-power X-rays 4. Perhaps the most researched property of carbon nanotubes for cancer therapy in recent years has been their strong absorbance in the near-infrared light range (700–1400 nm). This property makes carbon nanotubes an enticing vehicle for selective cell killing because many biological tissues are transparent in the near-infrared range. It is well documented that carbon nanotubes themselves are not toxic to cells but, when combined with near-infrared light therapy, they have been shown to cause cell death by hyperthermia 44.

  • Top
  • Abstract
  • Introduction
  • Conclusion
  • References
  • Conclusion
    Currently cancer is a disease that cannot be cured completely. Conventional therapies cannot target cancer cells exclusively. In addition to cancer cells, normal healthy cells are affected by these therapies. For this reason these therapies have some limitations. To overcome these limitations, new methods are being developed. Adaptation of nanotechnology in the field of oncology includes these new methods.

    Nowadays, nanotechnology based methods are applied in many fields of clinical oncology. Limitations in the treatment of cancer will be eliminated with the development and application of these methods. For this reason nanotechnological approaches are seen as promising developments in clinical oncology.

  • Top
  • Abstract
  • Introduction
  • Conclusion
  • References
  • References

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  • Top
  • Abstract
  • Introduction
  • Conclusion
  • References
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