IJRPC 2012, 2(3) Amulya et al ISSN: 22312781
INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY
Available online at www.ijrpc.com Research Article
CURRENT TRENDS ON ROLE OF NANO PARTICLES ON PULMONARY DISEASES A. Amulya*, V. Sirisha, CH. Babu Rao and Jaya Vaishnavi Chennam Don Bosco PG College of Pharmacy, 5th mile, Pulladigunta, Kornepadu(V), Vatticherukuru [M], Guntur, Andhra Pradesh, India.
ABSTRACT In recent advances in nanotechnology engineering have given rise to rapid development of many novel applications in the biomedical field. The lung is one of the main route of entry for nano particles in to the body and hence a lightly site for accumulation of nanoparticles.In the present study the different types of nano materials for the preparation of nano particles and the use of nano particles in treatment of major pulmonary diseases like lung cancer.Pulmonary fibrosis Tuberculosis and Bronchial asthma and recent specific diagnostic test for lung cancer this article also includes about the present status in treatment of tuberculosis.
Keywords: Nano particles, nano materials, lung cancer, tuberculosis, pulmonary fibrosis.
1. INTRODUCTION It is defined as a small object that behaves as widely accepted definitions at least one of their a whole unit in terms of its transports and dimensions must be less than 100nm but properties. Nanoparticles are particles that some intresting new applications use particles have one dimension that is 100 nanometers or of a few hundred nm so this report will not be less in size.The properties of many overly strict about the 100nm limit. conventional materials change when formed from nanoparticles. This is typically because 2. NANO MATERIALS nanoparticles have a greater surface area per 2.1Carbon nanotube weight than larger particles; this causes them Carbon nanotubes (CNTs) are allotropes of to be more reactive to certain other molecules carbon with a cylindrical nanostructure. [1] .Nanoparticles used for a very long time Nanotubes have been constructed with length- probably the earliest use begin in glazes for to-diameter ratio of up to 132,000,000:12-4 early Chinese procelian.A roman cup called significantly larger than for any other material. the Lycurges cup used nano sized gold These cylindrical carbon molecules have clusters to create different colors depending unusual properties, which are valuable for on whether it was illuminated from the front or nanotechnology, electronics, optics and other back. Carbon black is most famous example of fields of materials science and technology. a nano particulate material that has been Nanotubes are members of the fullerene produced in quantity for decades. structural family, which also includes the Roughly1.5million ton of material is produced spherical buckyballs, and the ends of a every year. Nanoparticles are currently made nanotube may be capped with a hemisphere out of a very wide variety of materials the most of the buckyball structure. Their name is common of the new generation of derived from their long, hollow structure with nanoparticles being ceramics which are the the walls formed by one-atom-thick sheets of best splits in to metal oxides ceramics such as carbon, called graphene. These sheets are titanium zinc aluminium and iron oxides to rolled at specific and discrete ("chiral") angles, name a prominent few and in the form of nano and the combination of the rolling angle and scale flakes of clay. According to the most radius decides the nanotube properties.
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Nanotubes are categorized as single-walled discharge, laser ablation, high-pressure nanotubes (SWNTs) and multi-walled carbon monoxide (HiPco), and chemical vapor nanotubes (MWNTs). Individual nanotubes deposition (CVD). naturally align themselves into "ropes" held Most of these processes take place in vacuum together by van der Waals forces, more or with process gases . Large quantities of specifically, pi-stacking. nanotubes can be synthesized by these methods; advances in catalysis and 2.1a Single-walled continuous growth processes are making Most single-walled nanotubes (SWNT) have a CNTs more commercially viable. diameter of close to 1 nanometer, with a tube length that can be many millions of times Arc discharge longer. The structure of a SWNT can be During this process, the carbon contained in conceptualized by wrapping a one-atom-thick the negative electrode sublimates because of layer of graphite called graphene into a the high-discharge temperatures. Because seamless cylinder. The way the graphene nanotubes were initially discovered using this sheet is wrapped is represented by a pair of technique, it has been the most widely-used indices (n,m) . The integers n and m denote method of nanotube synthesis. the number of unit vectors along two directions The yield for this method is up to 30% by in the honeycomb crystal lattice of graphene. If weight and it produces both single- and multi- m = 0, the nanotubes are called zigzag walled nanotubes with lengths of up to 50 nanotubes, and if n = m, the nanotubes are micrometers with few structural defects. called armchair nanotubes. Otherwise, they are called chiral. The diameter of an ideal Laser ablation nanotube can be calculated from its (n,m) In the laser ablation process, a pulsed laser indices as follows vaporizes a graphite target in a high- temperature reactor while an inert gas is bled into the chamber. Nanotubes develop on the where a = 0.246 nm. cooler surfaces of the reactor as the vaporized SWNTs are an important variety of carbon carbon condenses. A water-cooled surface nanotube because most of their properties may be included in the system to collect the change significantly with the (n,m) value. nanotube. The laser ablation method yields Single-walled nanotubes are dropping around 70% and produces primarily single- precipitously in price, from around $1500 per walled carbon nanotubes with a controllable gram as of 2000 to retail prices of around $50 diameter determined by the reaction per gram of as-produced 40–60% by weight. temperature.
2.1b Multi-walled Chemical vapor deposition (CVD) Multi-walled nanotubes (MWNT) consist of During CVD, a substrate is prepared with a multiple rolled layers (concentric tubes) of layer of metal catalyst particles, most graphite. There are two models that can be commonly nickel, cobalt, iron, or a used to describe the structures of multi-walled combination. The metal nanoparticles can also nanotubes.In the Russian Doll model, sheets be produced by other ways, including of graphite are arranged in concentric reduction of oxides or oxides solid solutions. cylinders, e.g., a (0,8). In the Parchment The diameters of the nanotubes that are to be model, a single sheet of graphite is rolled in grown are related to the size of the metal around itself, resembling a scroll of parchment particles. This can be controlled by patterned or a rolled newspaper. The interlayer distance (or masked) deposition of the metal, in multi-walled nanotubes is close to the annealing, or by plasma etching of a metal distance between graphene layer. s in layer. The substrate is heated to graphite, approximately 3.4 Å. The Russian approximately 700°C. To initiate the growth of doll structure is observed more commonly. nanotubes, two gases are bled into the Double-walled carbon nanotubes (DWNT) reactor: a process gas (such as ammonia, form a special class of nanotubes because nitrogen or hydrogen) and a carbon-containing their morphology and properties are similar to gas (such as acetylene, ethylene, ethanol or those of SWNT but their resistance to methane). Nanotubes grow at the sites of the chemicals is significantly improved. metal catalyst; the carbon-containing gas is broken apart at the surface of the catalyst 2.1c Synthesis particle, and the carbon is transported to the Techniques have been developed to produce edges of the particle, where it forms the nanotubes in sizeable quantities, including arc nanotubes. This mechanism is still being
686 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 studied. The catalyst particles can stay at the Fabrication tips of the growing nanotube during the growth Self-assembled quantum dots are typically process, or remain at the nanotube base, between 5 and 50 nm in size. Quantum dots depending on the adhesion between the defined by lithographically patterned gate catalyst particle and the substrate. electrodes, or by etching on two-dimensional CVD is a common method for the commercial electron gases in semiconductor production of carbon nanotubes. For this heterostructures can have lateral dimensions purpose, exceeding 100 nm.Some quantum dots are the metal nanoparticles are mixed with a small regions of one material buried in another catalyst support such as MgO or Al2O3 to with a larger band gap. These can be so- increase the surface area for higher yield of called core-shell structures, e.g., with CdSe in the catalytic reaction of the carbon feedstock the core and ZnS in the shell or from special with the metal particles. forms of silica called ormosil. Quantum dots sometimes occur spontaneously in quantum 2.2 Quantum dot well structures due to monolayer fluctuations A quantum dot is a portion of matter (e.g., in the well's thickness.Self-assembled semiconductor) whose excitons are confined quantum dots nucleate spontaneously under in all three spatial dimensions. Consequently, certain conditions during molecular beam such materials have electronic properties epitaxy (MBE) and metallorganic vapor phase intermediate between those of bulk epitaxy (MOVPE), when a material is grown on semiconductors and those of discrete a substrate to which it is not lattice matched. molecules. They were discovered at the The resulting strain produces coherently beginning of the 1980s by Alexei Ekimov in a strained islands on top of a two-dimensional glass matrix and by Louis E. Brus in colloidal wetting layer. This growth mode is known as solutions. The term "quantum dot" was coined Stranski–Krastanov growth. The islands can by Mark Reed. be subsequently buried to form the quantum Researchers have studied quantum dots in dot. This fabrication method has potential for transistors, solar cells, LEDs, and diode applications in quantum cryptography (i.e. lasers. They have also investigated quantum single photon sources) and quantum dots as agents for medical imaging and hope computation. The main limitations of this to use them as qubits in quantum computing. method are the cost of fabrication and the lack of control over positioning of individual 2.2a Production dots.Individual quantum dots can be created It can be produced by following types. from two-dimensional electron or hole gases present in remotely doped quantum wells or Colloidal synthesis semiconductor heterostructures called lateral A quantum dot is a portion of matter (e.g., quantum dots. The sample surface is coated semiconductor) whose excitons are confined with a thin layer of resist. A lateral pattern is in all three spatial dimensions. then defined in the resist by electron beam Colloidal semiconductor nanocrystals are lithography. This pattern can then be synthesized from precursor compounds transferred to the electron or hole gas by dissolved in solutions, much like traditional etching, or by depositing metal electrodes (lift- chemical processes. The synthesis of colloidal off process) that allow the application of quantum dots is based on a three-component external voltages between the electron gas system composed of: precursors, organic and the electrodes. Such quantum dots are surfactants, and solvents. When heating a mainly of interest for experiments and reaction medium to a sufficiently high applications involving electron or hole temperature, the precursors chemically transport, i.e., an electrical current. The energy transform into monomers. Once the monomers spectrum of a quantum dot can be engineered reach a high enough supersaturation level, the by controlling the geometrical size, shape, and nanocrystal growth starts with a nucleation the strength of the confinement potential. Also, process. The temperature during the growth in contrast to atoms, it is relatively easy to process is one of the critical factors in connect quantum dots by tunnel barriers to determining optimal conditions for the conducting leads, which allows the application nanocrystal growth. It may be high enough to of the techniques of tunneling spectroscopy for allow for rearrangement and annealing of their investigation. atoms during the synthesis process while being low enough to promote crystal growth. Viral assembly He reported using genetically engineered M13 bacteriophage viruses to create quantum dot
687 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 biocomposite structures. As a background to injection method to a flow system. However as this work, it has previously been shown that of 2011, applications using bulk-manufactured genetically engineered viruses can recognize quantum dots are scarcely available. specific semiconductor surfaces through the method of selection by combinatorial phage 2.2b Cadmium-free quantum dots display.[14] Additionally, it is known that liquid Cadmium-free quantum dots are also called crystalline structures of wild-type viruses (Fd, “CFQD”. In many regions of the world there is M13, and TMV) are adjustable by controlling now a restriction or ban on the use of heavy the solution concentrations, solution ionic metals in many household goods which means strength, and the external magnetic field that most cadmium based quantum dots are applied to the solutions. Consequently, the unusable for consumer-goods specific recognition properties of the virus can applications.Cadmium and other restricted be used to organize inorganic nanocrystals, heavy metals used in conventional quantum forming ordered arrays over the length scale dots is of a major concern in commercial defined by liquid crystal formation. Using this applications. For Quantum Dots to be information, Lee et al. (2000) were able to commercially viable in many applications they create self-assembled, highly oriented, self- must not contain cadmium or other restricted supporting films from a phage and ZnS metal elements.[5-7]A new type of CFQD can precursor solution. This system allowed them be made from rare earth (RE) doped oxide to vary both the length of bacteriophage and colloidal phosphor nanoparticles. Unlike the type of inorganic material through genetic semiconductor nanoparticles, excitation was modification and selection. due to UV absorption of host material, which is same for different RE doped materials using Electrochemical assembly same host. Multiplexing applications can be Highly ordered arrays of quantum dots may thus realized. The emission depends on the also be self-assembled by electrochemical type of RE, which enables very large stokes techniques. A template is created by causing shift and is narrower than CdSe QDs[8] The an ionic reaction at an electrolyte-metal synthesis is aqueous based, which eliminated interface which results in the spontaneous issues of water solubility for biological assembly of nanostructures, including applications. The oxide surface might be quantum dots, onto the metal which is then easier for chemical functionalizion more and used as a mask for mesa-etching these chemically stable in various environments. nanostructures on a chosen substrate. Some reports exist concerning the use of such phosphor nanoparticles on biological targeting Bulk-manufacture and imaging9-12 Conventional, small-scale quantum dot Fluorescence spectra of CdTe quantum dots manufacturing relies on a process called “high of various sizes. Different sized quantum dots temperature dual injection” which is impractical emit different color light due to quantum for most commercial applications that require confinement. An immediate optical feature of large quantities of quantum dots.A colloidal quantum dots is their coloration. reproducible method for creating larger Qdots can be synthesized with larger (thicker) quantities of consistent, high-quality quantum shells (CdSe qdots with CdS shells). The shell dots involves producing nanoparticles from thickness has shown direct correlation to the chemical precursors in the presence of a lifetime and emission intensity. molecular cluster compound under conditions whereby the integrity of the molecular cluster 2.3 Silver nanoparticles is maintained and acts as a prefabricated seed Silver nanoparticles are nanoparticles of silver, template. Individual molecules of a cluster i.e. silver particles of between 1 nm and compound act as a seed or nucleation point 100 nm in size. While frequently described as upon which nanoparticle growth can be being 'silver' some are composed of a large initiated. In this way, a high temperature percentage of silver oxide due to their large nucleation step is not necessary to initiate ratio of surface-to-bulk silver atoms. nanoparticle growth because suitable nucleation sites are already provided in the 2.3a Synthesis system by the molecular clusters. A significant There are many different synthetic routes to advantage of this method is that it is highly silver nanoparticles. They can be divided into scalable.Recently a consortium of U.S. and two broad categories: physical vapor Dutch companies reported a "milestone" in deposition, ion implantation, or wet chemistry. high volume quantum dot manufacturing by applying the traditional high temperature dual
688 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781
Ion implantation Brust method Although it may seem counter-intuitive, ion This method was discovered by Brust and implantation has been used to create silver Schiffrin in early 1990s,[13] and can be used to nanoparticles. This process has been shown to produce gold nanoparticles in organic liquids produce silver particles embedded in glass, that are normally not miscible with water (like polyurethane, silicone, polyethylene, and toluene). It involves the reaction of a chlorauric polymethylmethacrylate. The particles grow in acid solution with tetraoctylammonium the substrate with the bombardment of ions. bromide (TOAB) solution in toluene and The existence of nanoparticles is proven with sodium borohydride as an anti-coagulant and optical absorbance, though the exact nature of a reducing agent, respectively. Here, the gold [14] the particles created with this method is not nanoparticles will be around 5–6 nm. NaBH4 known. is the reducing agent, and TOAB is both the phase transfer catalyst and the stabilizing Wet chemistry agent.It is important to note that TOAB does There are several wet chemical methods for not bind to the gold nanoparticles particularly creating silver nanoparticles. Typically, they strongly, so the solution will aggregate involve the reduction of a silver salt such as gradually over the course of approximately two silver nitrate with a reducing agent like sodium weeks. To prevent this, one can add a borohydride in the presence of a colloidal stronger binding agent, like a thiol (in stabilizer. Sodium borohydride has been used particular, alkanethiols), which will bind to gold with polyvinyl alcohol, poly(vinylpyrrolidone), covalently, producing a near-permanent bovine serum albumin (BSA), citrate and solution. Alkanethiol protected gold cellulose as stabilizing agents. Citrate and nanoparticles can be precipitated and then re cellulose have been used to create silver dissolved. Some of the phase transfer agent nanoparticles independent of a reducing agent may remain bound to the purified as well. An additional novel wet chemistry nanoparticles, this may affect physical method used to create silver nanoparticles properties such as solubility. In order to took advantage of ß-D-glucose as a reducing remove as much of this agent as possible the sugar and a starch as the stabilizer. nanoparticles must be further purified by soxhlet extraction. 2.4 Colloidal gold Colloidal gold is a suspension (or colloid) of Perrault Method sub-micrometre-sized particles of gold in a This approach, discovered by Perrault and fluid usually water. The liquid is usually either Chan in 200915 uses hydroquinone to reduce an intense red colour (for particles less than HAuCl4 in an aqueous solution that contains 100 nm), or a dirty yellowish colour. gold nanoparticle seeds. This seed-based method of synthesis is similar to that used in 2.4a Synthesis photographic film development, in which silver Turkevich method grains within the film grow through addition of Generally, it is used to produce modestly reduced silver onto their surface. Similarly, monodisperse spherical gold Nanoparticles gold nanoparticles can act in conjunction with suspended in water of around 10–20 nm in hydroquinone to catalyze reduction of ionic diameter. Larger particles can be produced, gold onto their surface. The hydroquinone but this comes at the cost of monodispersity method complements that of Frens, as it and shape. It involves the reaction of small extends the range of monodispersed spherical amounts of hot chlorauric acid with small particle sizes that can be produced. Whereas amounts of sodium citrate solution. The the Frens method16-17 is ideal for particles of colloidal gold will form because the citrate ions 12-20 nm, the hydroquinone method can act as both a reducing agent, and a capping produce particles of at least 30-250 nm. agent. To produce larger particles, less sodium citrate should be added (possibly Sonolysis down to 0.05%, after which there simply would Another method for the experimental not be enough to reduce all the gold). The generation of gold particles is by sonolysis. In reduction in the amount of sodium citrate will one such process based on ultrasound, the reduce the amount of the citrate ions available reaction of an aqueous solution of HAuCl4 with for stabilizing the particles, and this will cause glucose], the reducing agents are hydroxyl the small particles to aggregate into bigger radicals and sugar pyrolysis radicals (forming ones (until the total surface area of all particles at the interfacial region between the collapsing becomes small enough to be covered by the cavities and the bulk water) and the existing citrate ions. morphology obtained is that of nanoribbons
689 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 with width 30 -50 nm and length of several 2.6 Platinum nanoparticles micrometers. These ribbons are very flexible Platinum nanoparticles are usually in the form and can bend with angles larger than 90°. of a suspension or colloid of sub-micrometre- When glucose is replaced by cyclodextrin (a sized particles of platinum in a fluid, usually glucose oligomer) only spherical gold particles water. A colloid is technically defined as are obtained suggesting that glucose is particles which remain suspended without essential in directing the morphology towards forming an ionic, or dissolved solution. The a ribbon. platinum nanoparticle25-26 sizes range between 2-3 nanometres (nm). Trillions of platinum Electron Microscopy nanoparticles are suspended in the brownish Colloidal gold and various derivatives have red or black colored colloidal solution. long been among the most widely-used Nanoparticles come in wide variety of shapes contrast agents for biological electron including spheres, rods, cubes, and caps. Due microscopy.18-22 Colloidal gold particles can be to the antioxidant properties of the platinum attached to many traditional biological probes nanoparticles, they are the subject of such as antibodies, lectins, superantigens, substantial research with applications in a glycans, nucleic acids,18 and receptors. wide variety of areas, including Particles of different sizes are easily nanotechnology, medicine. distinguishable in electron micrographs, allowing simultaneous multiple-labelling 2.6a Synthesis experiments. Platinum nanoparticles are fabricated by reduction of hexachloroplatinate. After 2.5 Nanoscale iron particles dissolving hexachloroplatinate, the solution is Nanoscale iron particles are sub-micrometer rapidly stirred while a reducing agent is added. particles of iron metal. They are highly reactive This causes platinum ions to be reduced to because of their large surface area. In the neutral platinum atoms .As more and more of presence of oxygen and water, they rapidly these platinum atoms form, the solution oxidize to form free iron ions. They are widely becomes supersaturated and platinum used in medical and laboratory applications gradually starts to precipitate in the form of and have also been studied for remediation of sub-nanometre particles. The rest of the industrial sites contaminated with chlorinated platinum atoms that form stick to the existing organic compounds[23-24].Research has shown particles, and, if the solution is stirred that nanoscale iron particles can be effectively vigorously enough, the particles will be fairly used to treat several forms of ground uniform in size. Various procedures employed contamination, including grounds to attain platinum nanoparticles include contaminated by polychlorinated biphenyls heating, reflux, cooling, stirring, filtration and (PCBs), chlorinated organic solvents, and filling, examinations & tests and packaging. To organochlorine pesticides. prevent the particles from aggregating, some Nanoscale iron particle are easily sort of stabilizing agent or stabilizer that sticks transportable through ground water, allowing to the nanoparticle surface is usually added. for in situ treatment. Additionally, the They can be functionalized with various nanoparticle-water slurry can be injected into organic ligands to create organic-inorganic the contaminated area and stay there for long hybrids with advanced functionality periods of time. These factors combine to make this method of cheaper than most Nano particles for cancer detection currently used alternative. Researchers have Today nanoparticles are being studied and found that although metallic iron nanoparticles used for detecting and destroying cancer cells remediate contaminants well, they tend to in mice. A couple of these new cancer agglomerate on the soil surfaces. In response, detecting nanoparticles are gold nanoparticles carbon nanoparticles and water-soluble and magnetic iron oxide nanoparticles polyelectrolytes have been used as supports encased in a biocompatible material. Gold to the metallic iron nanoparticles. The nanoparticles can be used as both detecting hydrophobic contaminants adsorb to these and destroying cancer cells. Cancer cells have supports, improving permeability in sand and a protein called Epidermal Growth Factor soil. In field tests have generally confirmed lab Receptor (EGFR) which the gold nanoparticles findings. However, research is still ongoing attach themselves to. “If you add this and nanoscale iron particles are not yet conjugated nanoparticle solution to healthy commonly used for treating ground cells and cancerous cells and you look at the contamination. image, you can tell with a simple microscope that the whole cancer cell is shining,” The
690 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 healthy cell doesn’t bind to the nanoparticles they studied the number of circulating tumour specifically, so you don’t see where the cells cells (CTCs) in 101 lung cancer patients are. With this technique, if you see a well before and after one cycle of chemotherapy. defined cell glowing, that’s cancer.”Similar to The team discovered that patients who had gold nanoparticles is quantum dots. These use five or more CTCs were much less likely to cadmium selenide nanoparticles which glow survive the disease. They believe that by when under ultraviolet light which makes it counting CTCs, doctors will be able to monitor easier to extract the tumor. Magnetic iron how well patients are responding to oxide nanoparticles encased in a chemotherapy soon after starting it and so biocompatible material can make detecting move them on to different treatments if the cancer cells easier, even if the cancer cells are number of cells rises. small and clearer so there is less mistakes in the detecting process. These particles stick to By sniffer dogs the tumor cells turning them into little magnets According to new research published in the which are then attracted to the tip of a biopsy European Respiratory Journal, sniffer dogs needle. “It might also be possible to detect could be used for the early detection of lung cells from breast, prostate, and ovarian cancer Researchers from the Schillerhoehe cancers that have spread to other parts of the Hospital in Germany were the first to discover body in amounts too tiny to sample with an that sniffer dogs can reliably detect lung ordinary needle. Instead of using biopsies, cancer Because current methods of detection MRI’s can be used to distinguish malignant are unreliable, scientists have been examining lymph nodes which can help in telling how far the use of exhaled breath specimens from prostate cancer has spread. “Researchers in patients for future screening tests. The method the Netherlands and Boston, Massachusetts, identifies volatile organic compounds (VOCs) recently reported in the New England Journal that are associated to the presence of cancer. of Medicine that an MRI contrast agent Even though various different technological consisting of highly lymphotropic iron oxide programs have been developed, this method nanoparticles enabled clinicians to detect is still difficult to apply in clinical settings, as it small nodal metastases that otherwise would requires patients not to eat and smoke prior to have gone undetected in 33 of the 80 patients testing. This new study was designed to with prostate cancer. Therefore, cancer examine whether sniffer dogs could be used to patients can get the ideal treatment for there identify a VOC in the breath of patients. Using specific case. dogs with specific training, researchers Treatment of pulmonary diseases with the help conducted a study comprising of 220 of nanoparticles will be seen as follows. participants, including lung cancer patients, chronic obstructive pulmonary disease LUNG CANCER (COPD) patients and healthy volunteers.The Diagnosis researchers conducted a series of tests to A simple new technique could help evaluate whether the dogs were capable to improve diagnosis and treatment options reliably identify lung cancer compared with for sufferers of lung cancer (Fig :1) healthy volunteers, volunteers with COPD and A new technique that may help improve whether the results were still detected with the diagnosis and treatment options for sufferers presence of tobacco. The result reveled, that of lung cancer involves counting the number of the dogs managed to correctly identify 71 tumour cells in blood samples. It involves samples with lung cancer out of a possible 100 counting the number of tumour cells in blood and also successfully detected 372 samples samples before and after chemotherapy, that did not have lung cancer out of a possible allowing doctors to establish how well patients 400.The dogs were able to detect lung cancer are responding to treatment. The technique is independently from COPD and tobacco smoke said to represent an improvement on a current and therefore substantiate the method as a diagnosis test that is invasive and can only be valid indicator for lung cancer that is carried out once. To be able to detect and independent of COPD and also detectable in count these rare tumour cells circulating the presence of tobacco smoke, food odors through the blood, and the link this has to the and drugs. progress of the disease, opens an incredibly exciting new area of research. We could now Treatment look at the genetic faults that are behind the Inhalable nano particles to treat lung disease and start to develop drugs that target cancer in mouse model (Fig :2) these. In a new paper published in the Journal Doxorubicin-loaded nanoparticles (NPs) were of Clinical Oncology, researchers detail how incorporated into Inhalable effervescent and
691 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 non-effervescent carrier particles using a (MMAD) of the prepared powder was 4.80 +/- spray-freeze drying technique[27]. The 2.12 microm, which is suitable for lung prepared inhalable powders were tested in a delivery. The animals that were treated with tumor bearing Balb/c mouse model. Control effervescent powder tolerated the mice were treated with blank inhalable NPs, administration without any changes in their inhalable lactose powder containing free morbidity scores. Our pilot study demonstrates doxorubicin, and intravenous injections of a that pulmonary nanoparticle delivery via suspension of doxorubicin NPs, doxorubicin effervescent carrier particles appears safe in solution, or saline solution. The survival of the present animal model. treatment groups was plotted with Kaplan- Meier curves.Animals treated with inhalable Formulation and cytotoxicity of effervescent nanoparticle powder containing doxorubicin nanoparticles carried by dry 30μg doxorubicin showed a highly significant powder aerosol particles improvement in survival compared to all other Regional drug delivery via dry powder inhalers treatment groups. Mice in control groups offers many advantages in the management of treated with doxorubicin solution or pharmaceutical compounds for the prevention doxorubicin NPs as intravenous injection, died and treatment of respiratory diseases. In the in less than 50 days. Inhalable free present study, doxorubicin (DOX)-loaded doxorubicin showed high cardiac nanoparticles were incorporated as colloidal toxicity.Pathological samples showed large drug delivery system into inhalable carrier tumor masses in the lungs of animals not particles using a spray-freeze-drying treated or treated with i.v. injections of technique. The cytotoxic effects of free DOX, doxorubicin NPs or doxorubicin solution. The carrier particles containing blank nanoparticles lungs of animals treated with inhalable or DOX-loaded nanoparticles on H460 and effervescent doxorubicin NPs showed fewer A549 lung cancer cells were assessed using a and much smaller tumors compared to the colorimetric XTT cell viability assay.The mean control groups, as visualized by MRI imaging geometric carrier particle size of 10 ± 4 μm which confirmed the observed pathology was determined using confocal laser scanning results. The present study demonstrates that microscopy. DOX-loaded nanoparticles had a inhalable effervescent doxorubicin NPs is an particle size of 173 ± 43 nm after re-dissolving effective way to treat lung cancer. This non- of the carrier particles. Compared to H460 invasive route of administration might change cells, A549 cells showed less sensitivity to the the way lung cancer is treated in the future. treatment with free DOX. The DOX- nanoparticles showed in both cell lines a Formulation and in vivo evaluation of higher cytotoxicity at the highest tested effervescent inhalable carrier particles for concentration compared to the blank pulmonary delivery of nanoparticles nanoparticles and the free DOX. The cell The purpose of this study was to evaluate the uptake of free DOX and DOX delivered by safety of a new inhalable effervescent carrier nanoparticles was confirmed using confocal preparation containing model nanoparticles. laser scanning microscopy. This study Spray-freeze drying was used to prepare supports the approach of lung cancer inhalable powders containing butyl cyano treatment using nanoparticles in dry powder acrylate nanoparticles. The particle size of the aerosol form. nanoparticles before incorporation into the effervescent carrier and after dissolving the Formulation and characterization of spray- carrier powder was measured using laser light dried powders containing nanoparticles for scattering. The particle size distribution of the aerosol delivery to the lung: effervescent carrier aerosol particles was Spray-drying is a common practice of powder measured using a cascade impactor. The preparation for a wide range of drugs. Spray- prepared powder was tested in vivo using five dried powders can be used to deliver particles Balb/c nude mice. The animals were treated to the lungs via a dry powder inhaler (DPI). with 1 mg of inhalable powder every week for The present study investigated the feasibility 4 weeks. The body weight and morbidity score of developing a platform for aerosol delivery of of the mice were observed over an 8-week nanoparticles. Lactose was used as the period. The effervescent activity of the excipient and spray-dried with two different inhalable nanoparticle powder was observed types of nanoparticles: gelatin and when the powder was exposed to humidity. polybutylcyanoacrylate nanoparticles. Results The particle size of the nanoparticles did not showed that some carrier particles were change significantly after spray-freeze drying. hollow while others had a continuous matrix. The mass median aerodynamic diameter Gelatin nanoparticles were incorporated
692 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 throughout the matrix and sometimes two types of endocytosis: classical clathrin- accumulated at one end of the lactose. mediated endocytic uptake and caveolae- Polycyanoacrylate nanoparticles mostly mediated clathrin-independent endocytosis. clustered in different spots within the lactose Other evidence points to caveolae-mediated carriers. The mean sizes of both nanoparticle endocytosis involving the formation of types were characterized at two different membrane invaginations composed chiefly of times: before they were spray-dried and after cholesterol and sphingo lipids. Regardless of they were redissolved from the spray-dried the ultimate mechanism of internalization, it is powders. Both nanoparticle types remained in clear that electrostatic interactions between the nano-range size after spray-drying. The the positively charged residues of the TAT mean nanoparticle sizes were increased by peptide and the negatively charged residues of approximately 30% after spray-drying, though heparan sulfate proteoglycons (and other cell this increase was statistically significant only surface receptors) are essential for initial for the gelatin nanoparticles. Dispersion of the membrane binding followed by uptake. powder with an in-house passive dry powder Typically the endocytosed NPs remain inhaler and subsequent cascade impaction sequestered within endocytic vesicles, measurements showed that incorporation of although in some instances nuclear entry has the nanoparticles did not affect the fine particle been noted. The TAT peptide and its fraction (FPF) or mass median aerodynamic derivatives have been used for the cellular diameter (MMAD) of the powders.FPF was delivery. approximately 40% while MMAD was 3.0±0.2 μm, indicating the present formulations yield PULMONARY FIBROSIS aerosols of a suitable particle size for efficient Pulmonary fibrosis is the formation or lung delivery of nanoparticles. The present development of excess fibrous connective work demonstrates that nanoparticles can be tissue (fibrosis) in the lungs. It is also delivered to the lungs via carrier particles that described as "scarring of the lung".38-40 dissolve after coming in contact with the aqueous environment of the lung epithelium. Traetment This opens the way for new drug-targeting The immune system is felt to play a central strategies using nanoparticles for pulmonary role in the development of many forms of delivery of drugs and diagnostics. pulmonary fibrosis. The goal of treatment with immune suppressive agents such as Peptides in the therapeutic delivery of corticosteroids is to decrease lung nanoparticles inflammation and subsequent scarring. The most commonly used peptides that have Responses to treatment are variable. Once been employed for the cellular delivery of NPs. scarring has developed, it is permanent. TAT & TAT-like peptides.The TAT peptide was Those whose conditions improve with immune one of the first cell-penetrating peptides suppressive treatment probably do not have (CPPs) to be described[28-37].Interest in this idiopathic pulmonary fibrosis. Pulmonary peptide stemmed from two independent fibrosis causes decreased oxygen levels in the reports demonstrating that the 86-residue blood. A decrease in blood oxygen level transcriptional activator protein Tat (encoded (hypoxia) can lead to elevated pressure in the by HIV-1) could be efficiently internalized by pulmonary artery (the vessel that carries blood cells when present in the surrounding tissue from the heart to the lungs to receive oxygen), culture media. Subsequent studies to a condition known as pulmonary hypertension determine the domain responsible for cellular which can in turn lead to failure of the right uptake localized the activity to residues 47–57 ventricle of the heart. Therefore, patients with within the native Tat protein. The pulmonary fibrosis are frequently treated with corresponding 11-mer peptide sequence supplemental oxygen to prevent pulmonary (YGRKKRRQRRR) bears six arginines and hypertension. In some cases, new agents two lysine residues and these positively used to lower the blood pressure in the charged residues have been identified as the pulmonary artery. key determinants of cellular uptake as they mediate the initial interactions of the peptide TUBERCULOSIS with the negatively charged cell surface. While Tuberculosis, MTB, or TB (short for tubercle it has been firmly established that the bacillus) is a common, and in many cases positively charged residues are responsible for lethal, infectious disease caused by various uptake, the exact mechanism of cellular strains of mycobacteria, usually uptake remains somewhat less clear. Indeed, Mycobacterium tuberculosis 41 Tuberculosis a number been proposed. Evidence exists for usually attacks the lungs but can also affect
693 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 other parts of the body. It is spread through Treatments with improved sustained release the air when people who have an active MTB profiles and bioavailability can increase infection cough, sneeze, or otherwise transmit compliance through reduced drug their saliva through the air. Most infections in requirements and there in minimize MDR-TB. humans result in an asymptomatic, latent The micro-encapsulation of pharmaceutical infection, and about one in ten latent infections substances in biodegradable polymers used in eventually progress to active disease, which, if controlled drug delivery has seen as an left untreated, kills more than 50% of those emerging technology. Carrier or delivery infected. systems such as liposomes and microspheres have been developed for the sustained General Diagnosis (Fig : 3) delivery of anti-TB drugs and have found Tuberculosis is diagnosed definitively by better chemotherapeutic efficacy when identifying the causative organism investigated in animal models44-46.The (Mycobacterium tuberculosis) in a clinical following are among the important sample (for example, sputum or pus) a technological advantages of nanoparticles as tuberculin skin test (Mantoux test),42 or a, drug carriers: high stability (i.e., long shelf life); Interferon Gamma Release Assay43 (IGRA) high carrier capacity (i.e., many drug was also used to diagnosis.Currently, latent molecules can be incorporated in the particle infection is diagnosed in a non-immunized matrix); feasibility of incorporation of both person by a tuberculin skin test, which yields a hydrophilic and hydrophobic substances; and delayed hypersensitivity type response to an feasibility of variable routes of administration, extract made from M. tuberculosis. Those including oral administration and inhalation. immunized for TB or with past-cleared These carriers can also be designed to enable infection will respond with delayed controlled (sustained) drug release from the hypersensitivity parallel to those currently in a matrix.Indian research group from state of infection, so the test must be used Postgraduate Institute of Medical Education with caution, particularly with regard to and Research (India) has reported increased persons from countries where TB bioavailability and “undetectable bacterial immunization is common. Hodgkin’s counts in the lungs and spleens of lymphoma, malnutrition, or most notably active Mycobacterium tuberculosis-infected mice” 21 tuberculosis disease .The newer interferon days post-inoculation. Sharma et al. (2004)47, release assays (IGRAs) such as T-SPOT.TB conducted a study to explore lectin- and Quanti FERON-TB Gold In Tube functionalized poly (lactide-co-glycolide) overcome many of these problems. IGRAs are nanoparticles (PLG-NPs) as bio adhesive drug in vitro blood tests that are more specific than carriers against tuberculosis (TB), in order to the skin test. IGRAs detect the release of reduce the drug dosage frequency of anti- interferon gamma in response to mycobacteria tubercular drugs and thus improve patient proteins such as ESAT-6. These are not compliance in TB chemotherapy.In this study affected by immunization or environmental they observed the presence of drugs in mycobacteria, so generate fewer false positive plasma for 6–7 days for rifampicin and 13–14 results. There is also evidence that IGRAs are days for isoniazid and pyrazinamide after more sensitive than the skin test. administration of lectin coated PLG-NPs New TB tests have been developed that are through the oral/aerosol route. They also fast and accurate. These include polymerase observed that upon administration of uncoated chain reaction assays for the detection of PLG-NPs (oral/aerosolized) rifampicin was bacterial DNA. One such molecular detectable in plasma for 4–6 days, whereas diagnostics test gives results in 100 minutes isoniazid and pyrazinamide were detectable and is currently being offered to 116 low- and for 8–9 days. All three drugs were present in middle-income countries. Another such test, lungs, liver and spleen for 15 days. Obtaining which was approved by the FDA in 1996, is these results they concluded that WGA- the amplified mycobacterium tuberculosis functionalized PLG-NPs could be potential direct test (MTD, Gen-Probe). This test yields drug carriers for antitubercular drugs through results in 2.5 to 3.5 hours, and it is highly the oral as well as aerosol route for effective sensitive and specific when used to test TB control. smears positive for acid-fast bacilli (AFB). Present Status of Nanoparticle Research Treatment for Treatment of Tuberculosis Nanotechnology in treatment of Liposomes (Fig : 4) tuberculosis Liposomes are small spherical vesicles formed of amphiphilic lipids enclosing an aqueous
694 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 core. They are widely studied as carrier polymeric core and depending upon the systems for hydrophilic drugs48-53.Gentamicin method of preparation, they are called as incorporated liposomes were evaluated for nanoparticles, nanospheres or nanocapsules antibacterial activity in M. avium infected .(Fig :6) Polymeric nanoparticles represent an mouse model. The drug encapsulated attractive alternative to liposomes. Pandey et liposomes significantly reduced the bacterial al., developed sustained release RIF, INH and count in spleen and liver as compared to free PYZ loaded poly (lactideco- glycolide) (PLG) drug. A dose-related reduction in bacterial load nanoparticles for oral delivery. In mice, the was observed, but no sterilization was found drugs could be detected in the plasma up to 4 .Similar results were reported in literature for days for RIF and 9 days for INH and PYZ; second-line antibiotics liposomes. Deol and therapeutic concentrations in the tissues were Khuller54 developed Stealth liposomes for the detected till 9 to 11 days after single oral dose targeted delivery of anti-TB drugs to the lung. administration of nanoparticles whereas free Liposomes were composed of mixture of drugs after administration were cleared within phosphatidylcholine, cholesterol, 12 to 24 h from the plasma. dicetylphosphate, O-steroyl amylopectin and Five oral doses every 10 day of nanoparticles monosialogangliosides / were sufficient to achieve complete bacterial distearylphosphatidylethanolaminepoly clearance from the organs of TB bacillus (ethylene glycol) 2000. In vivo biodistribution infected mice, whereas free drugs took 46 after intravenous administration in healthy and doses to get the same results. tuberculosis infected mice showed pronounced increase in accumulation from Solid lipid nanoparticles (SLN) 5.1% for contional liposome’s to 31% for Nanoparticles showed similar results when PEGylated liposomal systems after 30 min. tested in guinea pigs. The accumulation extent was mainly In SLN, the drug is mainly entrapped in solid associated to the composition of the liposomal lipid matrix to produce lipid nanoparticles of vesicles.103 uptake levels in the lungs size range 50-1000 nm and they produced increased to approximately 40% for the using hot or cold high pressure PEGylated nanocarriers when administered to homogenization technique.[56]. It is noteworthy pretreated infected animals only after 30 min. that the solid lipid nanoparticles display whereas, 30– 50% reduction in uptake was important advantages, such as the observed for modified liposomes for composition (physiologic compounds) and the accumulation in the liver and spleen. Drug- possibility of large-scale production favored by loaded nanocarriers showed a significant the feasibility to avoid organic solvents in the decrease in the toxic effects when evaluated manufacturing process. A sterilizing effect for cytotoxicity in peritoneal macrophages was achieved after administration of solid lipid compared to free drugs. nanoparticles. No tubercle bacilli could be detected in the lungs/spleen after seven doses of treatment of infected guinea pigs with drug Nano emulsions loaded solid lipid nanoparticles.Pandey57-60 R., Nanoemulsion, many times referred as developed RIF, INH and PYZ loaded SLN by miniemulsions or sub-micronemulsions by using emulsion solvent diffusion technique and dispersing mainly oil in tested against experimental tuberculosis. water[55].Thermodynamically stable SLN formulations following a single oral nanoemulsion (mean particle size of 80.9 nm administration to mice maintained therapeutic and polydispersity index of 0.271) of ramipril, drug concentrations in plasma till 8 days and were developed for oral administration. In vitro in the organs rich in MPS (lungs, liver and drug release showed that drug release till 24 h spleen) for 10 days as compared to free drugs from nanoemulsion and was highly significant which were cleared within 1–2 days. In M. (p<0.01) bas compared to marketed capsule tuberculosis H37Rv infected mice, 5 oral formulation and drug suspension. The relative doses at every 10th day of drug loaded SLNs bioavailability of ramipril nanoemulsion to that were sufficient to completely suppress of conventional capsule was 229.62% and to bacterial load in the lungs/spleen whereas free drug suspension was 539.49 suggesting the drug required administration of 46 daily oral use of developed ramipril nanoemulsion for doses to get same effect. SLN incorporated pediatric and geriatric patients antitubercular drug significantly reduced the dosing frequency and improved Polymeric nanoparticles bioavailability61.Nano suspensions Nano In Polymeric nanoparticles, the drug is suspensions, poor water soluble drugs are attached, entrapped or encapsulated in dispersed in aqueous phase containing
695 IJRPC 2012, 2(3) Amulya et al ISSN: 22312781 stabilizing agent. Presently more than 8 Dendrimers candidates are in clinical trials . Clofazimine Dendrimers represent a novel class of was formulated as a nanosuspension (385 structurally controlled three dimensional nm) and administered to mice intravenously. It macromolecules that radiate from a central resulted in a considerable reduction of core and are mainly derived from a branches- bacterial loads in the liver (72.5 mg/kg tissue), upon-branches structural design. Dendrimers spleen (81.4 mg/kg tissue), and lungs (35.0 are well defined, highly branched mg/kg tissue) of mice infected with M. avium macromolecules. Kumar et al. developed when compared with pharmacokinetic data, mannosylated fifth generation (5G) PPI drug concentrations in these organs reached dendrimeric nanoparticles for delivery of RIF to high concentrations, well in excess of the macrophages. Drug encapsulations mainly minimal inhibitory concentration for most M. depend on hydrophobic interactions and avium strains.The effects of clofazimine hydrogen bonding contributing to the physical nanocrystals were comparable to those of the binding of the drug to the core. liposomal formulation used as a control in this study. This study was specially planned to BRONCHIAL ASTHMA overcome the poor solubility and toxicity.(Fig Asthma (from the Greek άσθμα, asthma, :5) "panting") is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible Micelles airflow obstruction, and bronchospasm. Micelles are submicroscopic aggregates (20- 80 nm) of surfactant molecules resulting in Treatment liquid colloid62-64.They can be used for Titanium and gold nanoparticles in asthma development of drug depot system. The sol– In the current issue of the European gel transition temperature was optimized by Respiratory Journal, report for the first time, on selecting optimized GA/CL ratio and length of the effects of two ENMs, titanium dioxide the hydrophobic segments.RIF sustained (TiO2) and gold (Au) NPs, in a murine model release was obtained over 32 days from 25% of toluene-2,4-diisocyanate-induced gel matrix. INH-poly (ethyleneglycol)–poly asthma.NPs were administered by oro (aspartic acid) conjugates were studied for pharyngeal aspiration after repeated dermal sustain release of the drug. sensitization to diisocyanate. The day after NP A 5.6-fold increase in anti-tuberculosis activity administration, animals were oro pharyngeal against M. tuberculosis was found for micelle- challenged with diisocyanate, and the next forming prodrug as compared to the free drug . day, airway reactivity to metacholine was Similar attempts were made to incorporate measured and bronchoalveolar lavage (BAL) PYZ and RIF in micelles ( <100 nm) aiming to inflammation and lung histological features minimize renal filtration and prolonging mean were analyzed. The dose of NPs, based on residence times in the blood stream with the current time-weighted average (TWA) improved antimicrobial activity. values for a single shift in TiO2 level, was 16 mg for a mouse weighing 20 g.The main Niosomes results of the study can be classified into three Niosomes has similarity to that of liposomes groups: 1) effects of diisocyanate sensitization and they are mainly composed of non-ionic and challenge not modified by either one of surfactant and with or without incorporation of the two NPs (increase in matrix lipids65. metalloproteinase-9 in BAL, increase in serum Niosomes (1–2 μm) were prepared using immunoglobulin E levels, increase in BAL sorbitan esters (Span 20, 40, 60, 80 and 85) eosinophils, and increase in airway hyper and cholesterol in a 50:50 percent mol fraction responsiveness (AHR; only in the case of ratio. They showed increase in entrapment TiO2); 2) effects efficiency with increase in hydrophobicity of Induced by both NPs in diisocyanate- the surfactant. In vivo biodistribution showed, sensitised and –challenged animals (increase higher RIF concentrations in thoracic lymph in macrophage inflammatory protein-2 in BAL, nodes via the intraperitoneal route (46.2% of increase in macrophages and neutrophils in the administered dose) for Niosomal BAL, lung macrophages infiltration); and 3) formulations as compared to free drug effects induced only by Au NPs in (13.1%). These findings suggested that diisocyanate-sensitised and -challenged compartmentalization of the drug took place in animals (potentiation of the increase in AHR, the lymphous tissue. diminished tumour necrosis
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Factor (TNF) secretion in BAL, and lung tissue Nanoparticles and their Applications are edema and epithelial damage). The last two summarized in table 1 types of effects of NPs were not observed in CONCLUSION animals not exposed to diisocyanate. The last In the present article the use of nano particle two types of effects were not observed in for the treatment of several major pulmonary animals not exposed to diseases like Lung cancer Tuberculosis diisocyanate.Therefore, both NPs modified Pulmonary fibrosis and Bronchial asthma were some features of the diisocyanate-induced discussed. The nano particles are highly asthma model: TiO2 NPs induced lung advantageous for treatment of pulmonary macrophage and neutrophil recruitment diseases because of the ease of nano particle without affecting AHR, whereas Au NPs penetration in to pulmonary cavity and its of induced these effects along with lung tissue production along with targeting of nano particle edema, epithelial damage and potentiation of to specific site. Inhalable doxorubicin nano AHR. Neither NP induced biological responses particle is an non invasive approach to treat in non sensitised and challenged animals. lung cancer provides a further scope for the Taken together, these results are very study of nano particle use on lung cancer. interesting and open new areas of research in There is a chance of further investigation on the field of nano toxicology the use of nano particles for several major pulmonary diseases.
Fig. 1: New technique for diagnosis of lung cancer . It involves counting the no.of tumor cells in blood sample after chemotherapy
Fig. 2: Inhalable nano particles to treat lung cancer in mouse model
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Fig. 3: tuberculin test sample Table 1:
Property Application
Anti-reflection coatings.
Tailored refractive index of surfaces. Optical Light based sensors for cancer diagnosis.
Increased density storage media. Magnetic Nanomagnetic particles to create improved detail and contrast in MRI images. Enhance heat transfer from solar collectors to storage Thermal tanks. Improve efficiency of coolants in transformers. Improved wear resistance. Mechanical New anti-corrosion properties.
New structural materials, composites, stronger and lighter. High performance and smaller components, e.g, capacitors Electronic for small consumer devices such as mobile phones. Displays that is cheaper, larger, brighter, and more efficient. High conductivity materials. High energy density and more durable batteries. Hydrogen storage applications using metal nanoclusters. Energy Electrocatalysts for high efficiency fuel cells. Renewable energy, ultra high performance solar cells. Catalysts for combustion engines to improve efficiency, hence economy. Clean up of soil contamination and pollution, e.g. oil. Biodegradable polymers. Environmental Aids for germination.
Treatment of industrial emissions. More efficient and effective water filtration. Dissolution rates of materials are highly size dependant. Surfaces Activity of catalysts. Coatings for self cleaning surfaces, Pilkington’s glass for example. Effective clear inorganic sunscreens
Personal care
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Fig. 4: liposome action
Fig. 5: Mechanism by which nanoparticles encapsulated drug can be released in infected macrophages for anti tubercular treatment
Fig. 6: nano capsule
ABBREVATIONS COPD-chronic obstructive pulmonary disease VATS- videoscopic assisted thracoscopic VOCS-volatile organic compound wedge biopsy CTS-circulating tumor cells MMAD-mass median aero dynamic diameter FPF-fine particle fraction DPI-dry powder inhaler
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