Introduction Cancer is a group of diseases which cause an abnormal and uncontrolled cell division coupled with malignant behavior such as invasion and metastasis [ 1 ]. For the treatment of cancer various methods have already been discovered and many others are in the process of discovery e. But the anticancer drugs can fail to kill cancer cells for various reasons, the transport of the anticancer drug being governed by physiological and physicochemical properties of the target cell and of the sarcoma cancer research uk itself [ 4 ].
These properties include pressure, charge, size, configuration, electrochemical properties, hydrophilicity, anemie in cancer. For the therapeutic agents delivery to the tumor cells, the following problems can be addressed, as follows: Drug resistance at the tumor levels non cellular based mechanisms ; Drug resistance at cellular level cellular based mechanisms ; Pharmacokinetic properties of the anticancer agent in the body [ 5 ].
The concept of the nanoparticles which permits higher absorption of the drugs in a specific tissue, and this concept has been applied for hyperthermia, radiation therapy, sarcoma cancer research uk therapy, etc.
Meanwhile, the nanoparticles opened new horizons for drug delivery and bringing the term nanomedicines. Nanomedicine is the medical application for diagnosis and treatment of different human diseases by means of small particles, known as nanoparticles with sizes of nm. The nanoparticles are known by their large surface area, high reactivity, high solubility, reduced side effects and low toxicity [ 7 - 9 ].
The main nanoparticles applied in nanomedicine are: polymeric nanoparticles, liposomes and lipid nanoparticles, micelles, microcapsules, magnetic particles, and carbon nanoparticles fullerenes, carbon nanotubes, carbon nanofibers, etc and the nanoassemblies [ 10 - 12 ].
Photodynamic therapy PDT as a part of photochemotherapy, is a concerted method where, in addition to light and an administered drug, oxygen is required. PDT represents a concerted action of light, with a sensitizers and an oxygen active specie singlet oxygen which preferentially actions on tumor cells and not on healthy cells. The administered drug is generally a substance which can efficiently photosensitize the formation of singlet oxygen or other reactive species derived from oxygenand such species react with different biological targets, and cause cellular damage and finally, the cellular death.
Activation of the photosensitizers by light is an essential condition for a successful PDT. Under such circumstances, this chapter papillomavirus nom anglais the most up—to—date coverage of photodynamic therapy including information on how sarcoma cancer research uk, have evolved within the field of cancer therapy and more recently for drugs controlled release in this field, by using personal data correlated with literature reports.
Short history Photodynamic therapy is dating from ancient time, the Indian civilizations reported from the first time the combined action of psoralens with sunlight to treat vitiligo [ 14 ]. Niels Fiensen used UV light to treat small pox, pustular infections eruptions, cutaneous tuberculosis, and for its results he obtained the Nobel Prize in Medicine in Similar results obtained Niels Raab inby using eosin as sensitizer and combining his results with Jesionek and J.
Prime results for skin tumors and epilepsy generated by light induced dermatitis [ 17 sarcoma cancer research uk. Meyer-Betz was the only experimentalist who tested this method on himself, by injecting haematoporphyrin, reporting the observed effects: oedema, erythema and light sensitivity [ 18 ].
Later, Campbell and Hill studied papillomavirus verrue nez PDT effects on microcirculation, reporting the thrombosis and vascular shutdown [ 19 ]. Lipson in went on to treat a patient with a large cancer of the breast following an injection of a derivative of haematoporphyrin HpD. The modern era of photodynamic therapy was established by Dr.
Dougherty, at the Division of Radiation Biology at Roswell Park Memorial Institute, Buffalo, USA, who reported that a systematically injected sarcoma cancer research uk on activation with red light caused complete eradication of transplanted experimental tumors [ 20 ].
In the photodynamic therapy occur three types of mechanisms: type I mechanism — electron transfer eT where the photosensitizer excited state generates a radical species, for example by electron transfer from or to a substrate, or by hydrogen atom abstraction from a substrate. The type I mechanism of PDT In type II mechanism - energy transfer ET an energy transfer occurs gliste u stolici kod trudnica the excited photosensitizer to molecular oxygen, to give the sensitizer in its ground state and singlet oxygen.
In this mechanism electronic excitation energy is transferred from the excited triplet T1 of the sensitizer generated by intersystem crossing isc from the ecited singlet S1 to triplet molecular oxygen, to give the sensitizer in its ground state S0 and singlet oxygen 1O2.
Sheme 2. The sarcoma cancer research uk II mechanism of PDT Major biological targets are membranes that undergo rupture and the cells are destroyed through the membranes around the mitochondria and the lysosomes.
These organelles induce subsequent cellular destruction by necrosis or apoptosis [ 21 - 24 ]. Except these two types of mechanisms, there is another one: type III mechanism, which take place when the oxygen is absent in the laser pour papillomavirus. Sheme 3.
Photodynamic Nanomedicine Strategies in Cancer Therapy and Drug Delivery
Conventional photosensitizers All the sensitizers could be natural or sarcoma cancer research uk compounds, with proper absorption properties from a light source. They should be pure compounds, soluble in body fluids, with high capacity to be incorporated in malignant cells. Also, they should be fluorescent and able to generate singlet oxygen, which is the excited state of oxygen efficient on malignant cells [ 25 ].
Taking into account all these criteria and knowing the compatibility with human body, the porphyrins are known as ideal sensitizers for photodynamic therapy.
The general chemical structure for some porphyrins and phthalocyanines as PDT sarcoma cancer research uk are represented in Figure 1.
Figure 1. The chemical structure of some porphyrins and phthalocyanines First Generation Photosensitizers, includes Photofrin® and HpD and exist as complex mixtures of monomeric, dimeric, and oligomeric structures.
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At nm, their effective tissue penetration of light is small, 2—3 mm, limiting treatment to surface tumors. In spite of its safe applications in bladder, esophageal and lung cancers, Photofrin tends to be applied to sarcoma cancer research uk human part and thoracic part affected by sarcoma cancer research uk [ 26 ]. The Second Generation Photosensitizers, includes porphyrins and related compounds porphycenes, chlorins, phthalocyanines, so onmany of them being under clinical tests.
TPPS4 exhibited lower photochemical efficiency than meso-substituted porphyrins containing fewer sulphonated groups [ 28 ]. Except the free-bases, the porphyrins can be chelated with a variety of metals, the diamagnetic ones enhancing the phototoxicity.
Paramagnetic metals are shortening the lifetime of the triplet state and as result can make the dyes photoinactive [ 21 ]. The presence of axial ligands to the centrally coordinated metal ion is often advantageous, since it generates some degree of steric hindrance to intermolecular aggregation, without impairing the photophysical properties of the dye [ 21 ].
Their absorption maxima are in the region nm, with very high molar coefficients. A representative compound is aluminium phthalocyanine tetrasulphonated AlPcS4, commercially known as Photosens, in spite of its skin sensitivity, proper absorption maxima at nm, it is well applied in Russian clinics for stomach, skin, oral and breast cancers [ 33 ].
Another clinical phthalocyanine is silicon phthalocyanine 4 Pc4 which was successful tested in different skin cances pre-malignant - actinic keratosis, Bowen disease or even in malgnant forms of cutaneous cancers [ 343536 ]. The central metal ions play an important role in the photophysical properties of phthalocyanines.
In metallophthalocyanines the central metal M has one or two axial ligands or one or more ring substituents or both. When a diamagnetic ion is in the center of the ring e. Silicon phthalocyanine allows two appropriate axial ligands, which forbid the ring laryngeal papillomatosis triad which decrease the clinical efficiency [ 41 - 44 ].
The triplet-state lifetimes of an axially substituted silicon phthalocyanine typically vary from to μs and the yields from 0. Some synthetic silicon phthalocyanine and naphthalocyanine Figure 2 have been used in some laboratory experuiments on K culture cellk with excellent results [ 4546 ].
Third generation photosensitizers contains available drugs that are modified them sarcoma cancer research uk antibody conjugates, biologic conjugates, etc. These terms are still being used although not accepted unanimously and dividing photosensitizing drugs into such generations may be very confusing. The nanostructures are increasingly being used as carriers for the development of 3rd generation Sarcoma cancer research uk, as the most important drug delivery systems used as carriers for PS in the field of anticancer PDT.
Figure 2. Nanoparticles have unusual properties that can improve the drug delivery. Hard nanoparticles Inorganic Nanoparticles is the generic term for several sarcoma cancer research uk including for example metal oxide- and non-oxide ceramics, metals, gold and magnetic nanoparticles.
Ceramic nanoparticles: Ceramic-based nanoparticles have some advantages over organic carriers: particle size, shape, porosity, and mono-dispersibility.
They are water-soluble, extremely stable, and known for their compatibility in biological systems without being subjected to microbial attack. For conventional drug delivery, the carrier vehicle should release the encapsulated drug at the target tissue.
Their silica-based nanoparticles diameter ca. The resulting silica- based nanoparticles were monodispersed with uniform particle size. By irradiation with suitable wavelengths: or nm, silica nanoparticles with porphyrin embedded, could be efficiently taken up by tumor cells and lead to cells death.
Silica nanoparticles SiO2with the following advantages: chemically inert, avoiding interactions with other molecules in the body.
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These interesting properties have made silica nanoparticles the most studied nanoparticle-based PDT systems. The delivery of photosensitisers embedded in porous silica nanoparticles has many advantages: almost any type of photosensitiser can be used. Second, the concentration of photosensitiser can be modulated as needed increasing or decreasing it.
When the photosensitisers are incorporated on to silica nanoparticles trough sarcoma cancer research uk bonds, it is possible to avoid the eventual release of the compounds in the media, and the consequent lost of efficacy or the appearance of side effects. Gold nanoparticles: Gold nanoparticles have been targeted to breast cancer cells by incorporating a primary antibody to the ir surface in addition to a zinc phthalocyanine photosensitiser and a bioavailability and solubility enhancer, with promising results [ 5051 ].
Gold particles with various diameters and uniform size distribution have been demonstrated to have novel and fascinating properties.
The goal of the synthesis methods is to produce size controllable gold nanoparticles. Many methods are based on the reduction of tetrachloric acid HAuCl4 to form gold nanoparticles. The formation and stabilization of nanosized colloidal metal particles demands careful attention to the preparation conditions and to the presence of stabilizers. Nanoparticles of silver, gold, platinum, and copper have been prepared by various methods, but most of their shapes have been limited to spheres [ 5253 ].
Magnetic nanoparticles: The magnetic nanoparticles offer the possibility of being directed towards a specific target in the human body and remaining eventually localised, by means of an applied magnetic field.
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Iron coated nanoparticles are therefore appropriate to be used as magnetic carriers of medical drugs, magnetic resonance imaging contrasts, biological labels etc, adsorbed into the carbon surface. As one of the most important materials, magnetite Fe3O4 nanoparticles have attracted a lot of attentions for their interesting magnetic properties and potential applications in the fields of biology, pharmacy and diagnostics [ 54 ].
The magnetite Fe3O4 with oleic acid nanoparticles analyzed by TEM showed a spherical shape with a narrow size distribution. Figure sarcoma cancer research uk.
The general trend in current research from nanomedicine is the application use of photosensitizers for PDT by development of photoactive nanoparticles and to modify photosensitizers to improve effect of photodynamic therapy. PS can be modified by encapsulated them in delivery agents such as liposomes [ 93 ], micelles [ 81 ], ceramic based nanoparticles [ 49 ], and polymer nanoparticles [ 5767 ].
Some examplification will be shown bellow. Soft nanoparticle 5. Polymeric carriers for drug delivery The polymeric carrier are divided into three groups: Biodegradable polymers. These degrade under biological conditions to nontoxic products that are eliminated from the body.
Drug-conjugated polymers Natural polymers. The used polymers are dextran, polyacrylamides and albumins, and offer a targeted drug controlled releasing by drug-polymer cleavage at the proper site.
Nondegradable polymers. These are stable in biological systems, and used as components of implantable devices for drug delivery. Macromolecular complexes of various polymers can be divided into the following categories according to the nature of molecular interactions: complexes formed by interaction sarcoma cancer research uk oppositely charged polyelectrolytes, charge transfer complexes, hydrogen-bonding complexes and stereocomplexes.
Both synthetic and natural polymers could be used for the production of nanosystems. These polymers may be used alone or in combination to develop nanoparticles. Several fabrication techniques are developed and can generally be subdivided into two categories.
The first category includes solvent evaporation or diffusion, ionotropic gelation, so on. The second one includes emulsion, interfacial polymerization and polycondensation [ 66 ].
Biodegradable polymers Polymer nanoparticles involve natural or biocompatible synthetic polymers as: polysaccharides, poly lactic acid, poly lactides, poly acrylates, poly alkyl cyano acrylates, poly alkyl vinyl pyrrolidones or acryl polymers. The most important seems to be Sarcoma cancer research uk lactic-co-glycolic acid PLGA which has shown several advantages over other biodegradable polymers that are routinely used for photosensitiser delivery [ 49 ] and has become the most popular polymer for PDT.
The size of PLGA nanoparticles with m-THPP as photosensitiser influences their photodynamic activity bigger size, lower activitybut it also affects their interaction with the biological environment protein absorption, cellular uptake or tissue distribution [ 56 ].
Another important polymer - poly vinyl alcohol PVA - seems to have certain affinity for the p-THPP photosensitiser, inducing the adsorption of PVA on to sarcoma cancer research uk surface of the nanoparticle and leading to higher clearance of the complex [ 5776 ].
Many sensitizers from the second generation have been encapsulated into polymer nanoparticles, for example PLGA, the final size of the new system being nm, with a polidispersity index of 0. A specific example is bacteriochlorophyll encapsulated into PLGA prepared by solvent evaporation method. Another porphyrin sensitizer, a synthetic one, 5,10,15,tetrakis 4-methoxyphenyl porphyrin TMPP has been tested on chick embryo chloroallantoic membrane model, showing a longer retention time when is encapsulated into nanoparticles and sarcoma cancer research uk improvement of the vascular effects after light irradiation [ 59 ], due to the fact that the pathological tumoral vasculature is "leaky", most probably due to the pore size nm and to the accumulation in the interstitial tumor tissue [ 6061 ].
Also, pheophorbide a and chlorin e6 have been encapsulated in PLGA nanoparticles [ 6364 ]. Similar results have been registered in choroidal neovascularization associated with AMD [ 62 ], where the lipophilic porphyrins show photothrombic effect and leakage from blood vessels.
Natural polymers The naturally-occurring polymers of particular interest for delivery of sarcoma cancer research uk drugs could be the polysaccharides that include chitosan, hyaluronan, dextran, cellulose, pullulan, chondroitin sulphate and alginate, and polymers as casein and gelatin.
They are nontoxic, biocompatible, biodegradable and hydrophilic. Examples of the natural polymers used to prepare drugs-loaded nanoparticles are: Dextran sulphate is a polysaccharide that consist from linear 1,6-linked D-glucopyranose units with 2.
Because it wears negatively charges, it is used for nanoparticle insulin delivery system based on complexation with oppositely charged polymers [ 65 ]. Some polyphenols have been entrapped in calcium alginate beads and to investigate their encapsulation efficiency and in vitro release [ 67 ]. Addition of 0. This is probably due to increased ionic interactions between the carboxylate groups in the alginate and the protonated amine groups in the chitosan during gelation.
In the presence of more chitosan, the process will go faster [ 68 ]. In vitro polyphenols released of prepared beads was carried out both in simulated gastric fluid SGF and simulated intestinal fluid SIF. The total polyphenols release rate in SGF was between The release rate RR of polyphenols from microcapsules is influenced by the concentration of alginate, this phenomenon is in agreement with the previous study where it is reported that the release rate was quicker for beads prepared in low concentration of alginate but slower for beads prepared in high concentrations [ 69 ].
For microcapsules prepared by adding chitosan in coagulation fluid the best encapsulation efficiency Weak interactions between polyphenols and calcium alginate have allowed most of the polyphenols to be sarcoma cancer research uk in SGF.
With the addition of CS in the coagulation fluid is observed a cancer de piele analize sange increase of polyphenols released in SIF.
Alginate is a linear copolymer composed of β-D-mannuronic acid and α-L-guluronic acid joined by a glycosidic bond. The composition is highly dependent on the used polysaccharide.
The most common source of alginate is the cell wall of brown algae. Alginate is biocompatible, biodegradable and non-toxic polymer and has many biomedical applications due to the reactivity of its carboxylate side groups and its capacity to form spontaneous gelation when sarcoma cancer research uk to divalent cations such as calcium [ 70 ] and specific drug delivery [ 71 ].
Some nanoparticles were prepared by the ionotropic cancer la san palpare of alginate with calcium chloride followed by complexation between alginate and chitosan [ 69 ]. The primary amine groups make chitosan very useful in pharmaceutical applications [ 72 ]. CS nanoparticles proved cytotoxic properties on various tumor cell lines [ 73 ].
Moreover, this polysaccharide had been used as immunoadjuvant in laser immunotherapy with positive effects in the treatment of experimental tumors [ 74 ]. CS proved antioxidant properties. Nanovectors Polymeric micelles have many advantages such as small size 10 to nm for sarcoma cancer research uk accumulation in solid tumors by enhanced permeation and retention EPRimproved stability, biodegradability and high flexibility for structural and chemical modifications [ 7576 ].
Micelles polymers are sarcoma cancer research uk formed into core shell structures by spontaneous assembly when its concentration is above critical micelle concentration CMC.