Modern Era of Industrialization - Essay Example

Photosensitizer Conspectus In this modern era of industrialization and modified lifestyles, human beings come across various agents that could turn out to be hazardous for health. These agents could be carcinogenic, teratogenic or may damage tissues. Carcinogenic agents promote the formation of tumors which could turn out to be malignant. Essential therapies for cancer involve chemotherapy and radiotherapy which have their own predicaments and may be perilous to health. In order to eliminate the side effects of these therapeutic measures, photodynamic therapy has emerged to be of strategic significance. The most imperative aspect of this therapy is nontoxic nature of photosensitizers. Production of singlet oxygen is of paramount significance therefore, agents promoting the formation of singlet oxygen as well as two photons absorption are considered to be highly efficient in the therapy. Numerous receptor molecules are over-expressed in tumor cells which are of considerable importance. Peptides recognizing these receptors are conjugated with photosensitizers to reach the target cells. However, after a certain interval when photosensitizers in normal cells degenerate, the tumor cells are exposed to a particular wavelength of light which cause the excitation of the photosensitizer resulting in the formation of cytotoxic singlet oxygen. This oxygen is very reactive and cause cytotoxicity of the diseased or cancerous cells. The phenomenon is exploited in photodynamic therapy to eliminate the side-effects imposed by other cancer therapeutic measures. Introduction Photosensitizer or photosensitizing agent is a molecule or a drug that is capable of producing a chemical alteration in another molecule or cell during the photochemical process. Photosensitizers, when exposed to a particular wavelength of light. Photosensitizers generate a form of cytotoxic oxygen that can kill the adjoining cells in the living organism. This property of photosensitizers is exploited to treat numerous superficial and localized cancers together with certain noncancerous conditions (Lau et al, 2014). Photosensitizers are involved in medical science under the name photodynamic therapy or phototherapy, as the therapy involves insertion of certain light sensitive non-toxic chemical agents called photosensitizers, it is also known as photochemotherapy. As long as photosensitizers are not exposed to light they remain non-toxic, in the presence of certain wavelength of light they generate cytotoxic oxygen which can destroy, cancerous cells as well as other contaminated cells including pathogenic cells. Thus, Photodynamic therapy (PDT) is a promising treatment intended to eliminate diseased tissues including the malignant tumor cells, involving a photosensitizer (PS) molecule, a source of light of a particular wavelength and tissue required to be treated, blend of all these is responsible for bringing about the destruction of the diseased cell(s). In case of PDT, it is essential that the photosensitizer molecule gets excited by the wavelength of light falling upon it to release the reactive oxygen species (ROS) which acts as a free radical (Hammerer et al., 2014). PDT is potentially a curative therapy which possess a non-invasive curative modality for numerous solid tumors and also certain obstructing esophageal cancers, neck and head cancers, microinvasive endobronchial nonsmall cell lung cancer, cervical cancer and also effective in curing precancerous lesions in patients with Barrett esophagus (Usacheva et al., 2014). One of the chief advantages of PDT is that in the absence of light activation the photosensitizer remains silent and is well tolerated by the body cells without inducing any cytotoxic implications. Thus PDT involves a selective procedure to destroy malignant cells and carefully leave the non-irradiated normal cells. The therapy has benefit over other cancer treatment procedures such as chemotherapy and radiotherapy which do not spare normal cells (Hammerer et al., 2014). Photosensitizer Agents The singlet oxygen generated on excitation of the photosensitizer agent upon excitation with a particular wavelength of light is cytotoxic in nature, it is essential to select such a photosensitizer agent which is capable of giving out the cytotoxic oxygen radically. Essentially a large number of carrier molecules and functional dyes were studied with a view to identify the required photosensitizing systems as well as to optimize their photodynamic effectiveness. In order to select the photosensitizing agents for malignant tissues numerous approaches were used namely 1. The biconjugation to tumor explicit vehicles encompassing epidermal growth factor (EGF) and monoclonal antibodies. 2. Encapsulation in colloidal nano-carriers encompassing polymeric micelles and silica-based nano-particles (Lau et al., 2014). At present smart photosensitizing agents are being selected which can potentially get activated by tumor-associated stimulus, such agents are gaining attention and popularity. These agents are fastidious in the sense that they are either self-quenched due to deactivation or aggregation displayed by the surrounding or neighboring quenchers. As soon as such agents interact with the reducing or the acidic environment of tumors or with cancer related proteases or with mRNAs with high tumor specificity, the photosensitizer disaggregates or gets detached from the quenchers. This results in restoration of fluorescence as well as photosensitizing properties of the photosensitizer. This approach is highly beneficial and surmounts the drawbacks of nonspecific activation (Lau et al., 2014). Conjugates between the photosensitizers as well as small molecules are designed in a manner to enhance cell type target-specific agents. As antibodies and protein molecules are large and are difficult targeting vehicles, efforts are directed to generate smaller peptides capable of recognizing specific receptors are used as targeting vehicles. These peptide molecules bind with the specific receptors which are over-expressed on the tumor cells. One such receptor which is seeking attention of various researchers for tumor imaging and for therapeutic targeting is αvβ3 integrin. αvβ3 is known to be over-expressed in tumor cells as well as in activated endothelial cells of neovasculature during the process of tumor invasion, regrowth, metastasis. In present epoch, a variety of cRGD (cyclic Arg-Gly-Asp) peptides are labeled with numerous radionuclides, the products so formed displayed distinct target specificity for breast and brain cancers. However, conjugation of monovalent or multivalent cRGD peptides with cyanine dye-based fluorophores displays increased tumor-specificity in U87 tumors of brain as well as 4T1 tumors of breast (Srivatsan et al., 2011). Active targeting of membrane receptors is also a concern in the study of Hammerer et al., (2014). Their study targeted the lectin-receptors which are over-expressed in a few malignant cells; it is evident that carbohydrates like α-mannose and β-galactose interact with these receptors specifically. It is therefore, Hammerer et al., (2014), developed glycoconjugated vectorized porphyrin oligomers for 2PA PDT. Srivastan et al., (2011), have explored chlorophyll a and bacteriochlorophyll a based photosensitizers for PDT. They found that 2-(1’-hexyloxyethyl)-2-devinylpyropheophorbide a (HPPH), obtained from chlorophyll a and longer wavelength agents; purpurinimide (700 nm); and bacteriopurpurinimide (800 nm) displayed excellent photosensitizing effectiveness with restricted skin phototoxicity. As these molecules absorb the longer wavelength of light to carry out the process of photosynthesis, they must be photosensitive inside the body and could serve to good photosensitizers. Therefore, conjugation of HPPH with cRGD peptide makes sense (Srivatsan et al., 2011). Agents Selected as Photosensitizer It is evident that photosensitizers are used for diverse treatments but they all aim to accomplish certain features such as- these agents should be capable of absorbing specific wavelength inside the tissue, should generate sufficiently high singlet oxygen and should not get photobelached easily else the action of photosensitizer would not be accomplished. It must display its natural fluorescence; above all it should be nontoxic and stable inside the living tissue and should not interfere with the normal metabolic process of the tissues. However, photosensitizers fulfilling these requirements are the most ideal ones. So far the most activatable photosensitizer known entails self-quenched polymeric systems and are popularly known as the photodynamic molecular beacons. They involve photosensitizing unit linked with a quencher by means of a cleavable nucleic acid or a peptide. The photoactivity of these molecules is triggered by means of a single stimulus. Phthalocyanine-based photosensitizer exhibits dual acid and thiol activation. Since both these stimuli are related to the tumor characteristics and therefore they acts as the desirable targets for activation (Lau et al., 2014). Photosensitizers used to perform photodynamic therapy use cyclic tetrapyrroles or porphynoids as they display long excited triple-state lifetime. The photosensitizer in free-base state have five one-photon absorption (1PA) bands in the range of visible light (400-700 nm). However, the penetration of this range of wavelength is confined only to the surface tissues. On the other hand, absorption is considerably less in the optical pane of biological tissues for the range 700 to 1300 nm to get an efficacious photobiological effect. The two-photon absorption (2PA) process is utilized to overcome the predicament, in the process two photons of lower energy are absorbed at the same time. Two photon absorption for photodynamic therapy, permits better precision as compared to the one-photon excitation. Excitation of porphyrin derivatives is also based on two-photon absorption. Compounds exhibiting 2PA light harvesting system encompass porphyrin-triphenylamine hybrids as it possesses pi-conjugation between porphyrin and triphenylamine. The structure potentially is capable of high singlet oxygen quantum yield (Hammerer et al., 2014). Mechanism of Action The most primitive step involved in the process of PDT encompasses an injection of a photosensitizing agent into the bloodstream. The photosensitizer travels with the blood and reaches all the cells of the body including the normal cells as well as the diseased or the cancer cells. In normal cells the photosensitizers get degenerated soon as compared to the diseased or the tumor cells where they stay for a longer duration. The process of injection is followed by the process of exposure which is carried out after a certain interval when the photosensitizer of the normal cells gets degenerated. In the process of exposure, the tumor cells are exposed to a particular wavelength of light. As soon as the light is absorbed by the photosensitizer, it gets activated from its ground state to the transient excited state, thereby it undergoes intersystem crossing where it gets converted to a triplet state. As compared to the singlet state, triplet state is long lived. Photosensitizer in the triplet state is capable of transferring electrons to the surrounding substrate molecules encompassing biomolecules or oxygen by means of type I reaction or it can transfer energy to the oxygen molecule through type II reaction. As a result of this transfer of electron and energy, singlet oxygen or cytotoxic reactive oxygen species are generated which eventually kill the diseased cell(s) (Usacheva et al., 2014). Type I Reaction In type I reaction, radical species are generated by transferring an electron or H-atom to molecules other than oxygen. Thus, type I reactions are less sensitive to local oxygen concentrations, it is manifested that for the success of PDT sufficient oxygen concentration is necessary which impose a jeopardy as cancer stem cells and tumors in low oxygen concentration cannot be treated with PDT but type I reaction can overcome this predicament (Usacheva et al., 2014). Type II Reaction Both type I and type II reactions occur simultaneously, but most of the photosensitizers display their fluorescence through type II reactions. Type II reaction involves transfer of energy to the oxygen molecule, it is evident that presence of molecular oxygen is essential for the success of PDT. Tumor cells are hypotoxic due to poor vasculature as well as due to solid stress on the tumor blood vessels, the photodynamic therapy utilizes this poor or limited oxygen condition within the tumor and exhausts its oxygen, thus PDT acts in a self limiting manner to destroy the tumor cells. However, there are certain hypoxic areas where cancer stem cells (CSCs) thrive well, in such cases PDT finds its limitations. It could be inferred that in limited oxygen environment PDT does not work well (Usacheva et al., 2014). In their study, Usacheva et al., (2014), encapsulated photosensitizer molecule, methylene blue in polymer- surfactant docusate sodium an aerosol. It is believed that encapsulation of methylene blue in surfactant polymer, transfer for charge take place leading to the formation of free radicals. Polymer- surfactant docusate sodium attracts the molecules of methylene blue forming dye dimmers in ground and excited states. Further the study determined the impact of nanoencapsulating methylene blue on formation of electron transfer complexes inside the polymer- surfactant docusate sodium matrix, leading to the generation of reactive oxygen species (ROS) in both the environments normoxic and hypoxic. As a result of this, CSCs under hypoxic conditions could be conquered. Thus, their findings about the encapsulation of methylene blue in polymer- surfactant docusate sodium, enhanced the ROS generation as well as the process is able to eliminate cancer stem cells in hypoxic condition (Usacheva et al., 2014). (Usacheva et al., 2014) The chemical agent called porfimer sodium or the Photofrin is approved by FDA to be used for the photodynamic therapy (Srivastan et al., 2011). Photofrin is used to eliminate the symptoms of various cancers encompassing esophageal cancer and non-small cell lung cancer. In both these types of cancer there is an obstruction in the air passage. PDT is a boon to the patients suffering with these two types of cancers. Limitations of PDT The entire photodynamic therapy is based on the excitation of the photosensitizer molecule by a specific wavelength of light, however, light can penetrate only a centimetre of so of the body. Tumors present deep inside the body and inside the organs, cavities of the body and in internal organs remain untreated with this therapeutic measure. In a similar manner PDT finds its limitations in treating large tumors and metastatic cancers. However, constant efforts are going on to overcome numerous hurdles of the PDT and to make the therapeutic method efficacious to treat cancer. Side-effects of PDT There are certain photosensitizers that make an individual sensitive to light for instance porfimer sodium displays its complications in the form of sensitivity to light and therefore patients who take PDT are advised to stay away from sunlight. As PDT involves exposure to light, there cannot be 100 percent protection to the neighboring healthy tissues, during the process there occurs damage to the adjoining tissues or cells around the tumor cells. Damage to skin cells may occur, causing burns and etching. However, these are the temporary conditions and can be well tolerated when compared with the pain and suffering caused by the cancer cells and the side effects of the cancer drugs and chemotherapy. A constant research is going around the world to improve the efficacy of PDT. Research is going on to develop effective photosensitizers which could be more powerful, highly specific to the tumor or other diseased cells. Research is going on to design conjugated molecules to target all types f cancer cells of various organs, stomach, intestine, prostate skin, liver, cervix, throat, lungs, for large and hypoxic tumors to enhance the PDT therapy for betterment of mankind. Summary Photodynamic therapy (PDT) is a curative therapeutic measure for diverse kinds of cancer. PDT is solely based on the excitation of the electrons from the photosensitizer molecules. These excited photosensitizers are capable of transferring their energy to the surrounding oxygen molecules which are present in the tissues to generate cytotoxic singlet oxygen species or the reactive oxygen species. This process is called type II reaction. However, tumor cells are poorly supplied with the oxygen, therefore little oxygen present in the cell could be exhausted to kill the cell. On the other hand, cancer stem cells thrive well in the hypoxic conditions or in the microenvironments as a result of this nature of CSCs, the PDT finds its limitation. The photodynamic therapy works efficiently when the level of oxygen is sufficient enough to generate cytotoxic singlet oxygen. Still the PDT holds good option for various cancers encompassing skin, lung, esophageal cancers where the light is not required to penetrate deep in the tissues. Efforts are going on across the world to enhance this therapeutic method as it is found to be superior in many aspects when compared to other cancer therapies such as radiotherapy and chemotherapy which result in numerous side effects. Conversely, phtotodynamic therapy is nontoxic and does not cause any pain to the patient. If its efficacy could be enhanced with the help of research methods and by designing various cancer cell receptor specific conjugated target molecules, the therapy would turn out to be a real revolution in the cancer treatment. Human beings are on the tip of iceberg of cellular biology and there are lot of things to be explored, essentially health is considered as the priority for all the dwelling and exploration, dreaded disease hamper the pace of development in such a competitive era where people can do everything but for health, photodynamic therapy is cost-effective, non-toxic health provider. PDT not only saves life and prevent the patient from the dreaded influences, stress and pain of cancer but also saves time. The article highlights various features of photosensitizers and its importance in photodynamic therapy. It is the need of time to understand the disease condition to the molecular level in order to target the diseased cell and save the patient from the numerous side effects imposed by drugs and chemical agents. Chlorophyll a is one such option which does not show any side effect. There is need to explore other photosensitive agents which could help to make the photodynamic therapy an excellent cure to cancer. Another method where encapsulation of photosensitive dye methylene blue was performed is also one option to attract more of the dye molecules to create an environment where excitation generates more amount of cytotoxic singlet oxygen to kill the diseased or tumor cells. The future of the photodynamic theory is highly promising. Photosensitizers are not only confined to the cancer therapy but also could be utilized to target many microbial diseases such as bacterial infections and viral diseases. Various skin diseases and diseases of mouth and oral cavities can be treated with the help of PD therapy. PD therapy holds importance in today’s scenario where microorganisms are becoming multiple drug resistant. PDT is the best alternative to antibiotics and other predicaments where photosensitizers could be used. Works Cited Lau, J T F., Lo, P C., Jiang, X J., Wang, Q., Ng, D K P. “A Dual Activatable Photosensitizer toward Targeted Photodynamic Therapy”. J of Med Chem, 57, 4088-4097. 2014. Print. Hammerer, F., Garcia, G., Chen, S., Poyer, F., et al. “Synthesis and Characterization of Glycoconjugated Porphyrin Triphenylamine Hybrids for Targeted Two-Photon Photodynamic Therapy”. J Org Chem. 79, 1406-1417. 2014. Print. Srivatsan, A., Ethirajan, M., Pandey, S K., Dubey, S., et al. “Conjugation of cRGD Peptide to Chlorophyll a Based Photosensitizer (HPPH) Alters Its Pharmacokinetics with Enhanced Tumor-Imaging and Photosensitizing (PDT) Efficacy”. Mol Pharmaceutics. 8, 1186-1197. 2011. Print. Usacheva, M., Swaminathan, S K., Kirtane, A R., Panyam, J. “Enhanced Photodynamic Therapy and Effective Elimination of Cancer Stem Cells Using Surfactant-Polymer Nanoparticles”. Mol. Pharmaceutics. 11, 3186-3195. 2014. Print. Read More