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Various drug delivery and drug targeting systems are currently under development. Targeting is the ability to direct the drug1. The method by which a drug is delivered can have a significant effect on its efficacy. Some drugs have an optimum concentration range within which maximum benefit is derived, and concentrations above or below this range can be toxic or produce no therapeutic benefit at all2. To minimize drug degradation and loss to prevent harmful side-effects and to increase drug bioavailability and the fraction of the drug accumulated in the required zone, various drug delivery and drug targeting systems are currently under development3. Among drug carriers one can name metal nanoparticles, soluble polymers, micro particles made of insoluble or biodegradable natural and synthetic polymers, Microchips microcapsules, cells, cell ghosts, lipoproteins, liposomes and micelles1. The carriers can be made slowly degradable, stimuli-reactive (e.g., pH or temperature-sensitive), and even targeted (e.g., by conjugating them with specific antibodies against certain characteristic components of the area of interest). Targeting drug action by using carriers or chemical derivatization2 to deliver drugs to a particular target cell type in order to maintain a constant drug level in either plasma or target tissue. Release rate from the controlled release system should be equal to the elimination rate from the plasma or target tissue.
The basic rationale for controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and / or physiological parameters inherent in a selected route of administration4. The primary objective of controlled drug delivery system is to ensure safety and to improve the efficacy of drugs as well as patient compliance. This is achieved by better control of plasma drug levels and less frequent dosing5,6.
In order to minimize the unwanted side effects it is desirable to maximize the fraction of applied dose reaching the target organ or tissue. This can be partially achieved by local administration or by the use of carriers7.
Two major mechanisms can be distinguished for addressing the desired sites for drug release: (i) passive and (ii) active targeting2,3. Controlled drug release and subsequent biodegradation are important for developing successful formulations. Potential release mechanisms involve: (i) desorption of surface-bound/adsorbed drugs; (ii) diffusion through the carrier matrix; (iii) diffusion (in the case of nanocapsules) through the carrier wall; (iv) carrier matrix erosion; and (v) a combined erosion /diffusion process. The mode of delivery can be the difference between a drug's success and failure, as the choice of a drug is often influenced by the way the medicine is administered. Sustained (or continuous) release of a drug involves polymers that release the drug at a controlled rate due to diffusion out of the polymer or by degradation of the polymer over time8. Pulsatile release is often the preferred method of drug delivery, as it closely mimics the way by which the body naturally produces hormones such as insulin1.
When developing these formulations, the goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possesses amphiphilic and/or mesogenic properties9.
1.2. Future Opportunities and Challenge
Nanoparticles and nanoformulations have already been applied as drug delivery systems with great success; and nanoparticulate drug delivery systems have still greater potential for many applications, including anti-tumor therapy, gene therapy, and AIDS therapy, radiotherapy, in the delivery of proteins, antibiotics, virostatics, vaccines and as vesicles to pass the blood-brain barrier10.
Nanoscience and nanotechnology refers to the control and manipulation of matter at nanometer dimensions. Regarding the word nanotechnology, is derived from the words nano and technology. Nano, typically is defined as one billionth of a quantity or term that is represented mathematically as 1Ã-10-9, or simply as 10-9 . This control has made it possible to have life, which is a collection of most efficient nanoscale processes.
Nanoparticles possess large surface areas and essentially no inner mass, that is, their surface-to-mass ratio is extremely high. This new "science" is based on the knowledge that particles in the nanometer range, and nanostructures or nanomachines that are developed from these nanoparticles, possess special properties and exhibit unique behavior. These special properties, in conjunction with their unique behavior, can significantly impact physical, chemical, electrical, biological, mechanical and functional qualities.
The production of nanoparticles can be promoted by number of techniques namely10,
The solvent displacement method
The salting out technique
Ultrasound and microwave reactors
ADVANTAGES OF NANOPARTICLES
Smaller dosage form (i.e. smaller tablets )
Stable dosage forms of drugs which are either unstable or have unacceptably low bioavailability in non-particulate dosage form
Increased surface area results in a faster dissolution of the active agent in an aqueous environment, such as the human body.
Faster dissolution generally equates with greater bioavailability, smaller drug doses and less toxicity.
Most of the biological pore size are in the nanometer size, hence nanoparticle enter in to the cells easily.
Various therapeutic application of nanoparticles11
Prolonged systemic circulation
Nanosystems can be prepared to entrap, encapsulate or otherwise bind small and large molecules. The challenges faced in the delivery of small and large molecules such as poor solubility, stability, and limited absorption can be overcome by using nanosystems. Several anticancer drugs including Paclitaxel, Doxorubicin and 5-Fluorouracil have been successfully formulated using nanotechnology.
1.4. CHARACTERISATION OF NANO PARTICLES:
The nanoparticles are generally characterized for size, density, electrophoretic mobility, angle of contact and specific surface area5.
Partical size and size distribution
Photon correlation spectroscopy (PCS), Laser defractrometry, Transmission electron microscopy, Scanning electron icroscopy(SEM), Atomic force microscopy(AFM), Mercury porositometry
Laser Doppler Anemometry, Zeta potentiometer
Water contact angle measurements, Rose Bengal (dye) binding, Hydrophobic interaction chromatography, X-ray photoelectron spectroscopy
Chemical analysis of surface
Static secondary ion mass spectrometry, Sorptometer
Carrier drug interaction
FTIR, XRD, Differential Scanning Calorimetry
Nanoparticle dispersion stability
Critical flocculation temperature
1.5. Gold Nanoparticles:
Eric Drexler has suggested an alternate way of producing things, by assembling things from the bottom, which can be called molecular nanotechnology. One of the earliest nano-sized object known to us was made of gold. Faraday prepared colloidal gold in 1856 and called it 'divided metals'. The solutions he prepared are preserved in the Royal Institution.
Metallic gold, when divided into fine particles ranging from sizes of 10-500nm particles, can be suspended in water. In 1890, the German bacteriologist Robert Koch found that compounds made with gold inhibited the growth of bacteria. In 1905 he won the Nobel prize for medicine. In the Indian medical system called Ayurveda, gold is used in several medicinal preparations. One popular preparation is called 'saraswatharishtam', prescribed for memory enhancement. Gold is also added in certain medicinal preparation for babies, in order to enhance their mental capability. All these preparations use finely ground gold. The metal was also used for medical purposes in ancient Egypt. Over 5,000 years ago, gold was used by the Egyptians in dentistry. In Alexandria, alchemists developed a powerful colloidal elixir known as 'liquid gold', a preparation that was meant to restore youth. The great alchemist and founder of modern medicine, Paracelsus, developed many highly successful treatments from metallic minerals including gold. In China, people cook their rice with a gold coin in order to help replenish gold in their bodies. Colloidal gold has been incorporated in glasses and vases to give them color. The oldest of these is the fourth Century AD Lycurgus cup made by the Romans. The cup appears red in transmitted light and appears green in reflected light. Modern chemical analysis shows that the glass is not much different from that used today. Recently, nanoparticles based on gold chemistry have attracted significant research and practical attention because of their size, unique shape and surface-dependant properties. They are versatile agents with a variety of biomedical applications in biomedical fields, including cell labeling, highly sensitive diagnostic assays, image enhancement, thermal ablation and sensing, as well as drug and gene delivery due to their good biocompatibility and ease of bioconjugation14.
The modified gold nanocarriers can selectively interact with cells or biomolecules for recognition of specific target sites in the body to detect disease15.
Scheme 1. Illustration of drug delivery via 'active' and 'passive' targeting, solid and dotted line respectively14.
For biomedical applications, surface functionalization of Gold nanoparticles (AuNPs) is essential to target them to specific disease areas and allow them to selectively interact with cells or biomolecules. Surface conjugation of antibodies and other targeting moieties like drugs is usually achieved by adsorption of the ligand to the gold surface. However, surface adsorption, can denature the proteins or, in some cases, limit the interactions of the ligand with the target on the cell surface due to its steric hinderance. Additionally, for systemic applications, long-circulating nanoparticles are employed for passive targeting to tumors and inflammatory sites16.
Recently, nanocarriers are of interest for target-specific delivery of therapeutic agents. AuNPs have emerged as an attractive candidate for delivery of various payloads into their targets. Generally, this has been achieved by modifying the surface of the AuNPs so that they can bind to the specific targeting drugs or other biomolecules.
The molecules are adsorbed on the surface of the AuNPs particles and the whole conjugate is introduced into the cells. Introduction into cells can either be forced as in the case of gene guns or achieved naturally by ingestion of particles. Inside cells the molecules will eventually detach themselves from the Au nanoparticles. The delivery of drugs with nanoparticles can result in higher concentrations than possible with normal drug delivery systems17.
Scheme 2: Applications of AuNPs
Thiol-gold nanoparticle interaction is strong and makes AuNPs to be highly stable. Therefore, such AuNPs once stabilized by thiols cannot be further conjugated to useful drug moieties including peptides, proteins and other biochemical vectors that are normally used to target diagnostic and therapeutic AuNPs on to tumor and various disease sites in the body. Hence the thiol-stabilized AuNPs will have limited applicability in the development of AuNP-labeled biomolecules for use in the design of target specific nanoscale imaging or therapeutic agents. Other methods that have been described in the literature utilize different chemicals in their production protocols. Such techniques are not environmentally friendly and have many drawbacks that restrict the efficient utilization of AuNPs in biomedicine application18.
1.5.2. Green Chemistry:
Green chemistry is the utilization of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture and application of chemical products19.
Although there are several methods reported for the synthesis of metal and alloy nanoparticles, only few of these methods result in the formation of alloy nanoparticles below the size range of 10nm, where their properties exhibit considerable size-dependent variations. With significant growth in the cross-disciplinary nanoscience research involving chemists, physicists, biologists and engineers, researchers have begun concern about the need for developing more environmentally friendly and sustainable methods for the synthesis of nanomaterials. There is a current trend to integrate all the ''green chemistry'' approaches to design environmentally benign materials and processes. Such an approach will be of advantage for the integration of metal and alloy quantum dots into biologically relevant systems20.
Several of the current nanoparticle-production processes utilize toxic chemicals either in the form of reducing agents to reduce various metal salts to their corresponding nanoparticles or as stabilizing agents to prevent agglomeration of nanoparticles. Hydrazine and Sodium borohydride are powerful reducing agents which are currently used in the reduction of gold (and metal compounds) to produce gold and various metallic nanoparticles. Both are highly toxic to living organism and the environment. It is important to recognize that various herbs, spices and plant sources contain powerful antioxidants as photochemical constituents. This connection between plant sciences and nanotechnology provides an inherently green approach to nanotechnology referred to as green nanotechnology21.
1.5.3. Synthesis of gold nanoparticles:
Gold nanoparticles are synthesized on the reduction capabilities pullulan to reduce gold salts to the corresponding AuNPs is presented in this work. The pullulan serve a dual role as a effective reducing agents to reduce gold and also as stabilizers to provide a robust coating on the AuNPs in a single step. The pullulan-generated AuNPs, have demonstrated remarkable in vitro stability in various buffers including saline, histidine, HSA and cysteine solutions22.
Gold nanoparticles ranging from 2.0 to 50.0nm in diameter have attracted tremendous attention due to its unique optical, electronic, magnetic and catalytic properties. Nowadays AuNP-based nanotechnology is becoming more and more important, and a wide range of applications of AuNPs have been explored both in chemical and biological research. Depending on their size, shape, and degree of aggregation, AuNPs appear red, blue and other colors, and therefore, AuNPs have been explored as probes for highly sensitive colorimetric detection of heavy metal ions. Also, Au3+ has high oxidation-reduction potential, which suggests that Au (III) ions may play a role as oxidants when they come into contact with the AuNPs23.
Formation of gold nanoparticles24:
Scheme 3: A schematic illustration of the formation of monodisperse AuNPs.
It is well known that AuNPs exhibit ruby red colour in water, these colors arising due to excitation of the surface Plasmon vibrations in the metal nanoparticles. UV-Vis spectra recorded from the aqueous chloroauric acid-pullulan reaction medium as a function of time of reaction. It is observed that the gold surface Plasmon resonance band occur at 525nm and steadily increase in intensity as a function of time of reaction without any shift in the peak wavelength versus time of reaction the reduction of the metal ions occurs fairly rapidly; more than 90% of reduction of Au3+ ions is complete within 3 minutes, after addition of the pullulan to the metal ion solutions. In earlier studies on the synthesis of silver and AuNPs using bacteria and fungi, the time required for completion of the reaction (i.e., complete reduction of the metal ions) ranged from 24 to 120 hour and is thus rather slow20. This is one big drawback of the biosynthetic procedures that needs to be focused on if they are to compete with chemical methods for nanoparticles synthesis. The sharp fall in reaction time from a few days to a couple of minutes observed for pullulan is a significant advance in attempts towards achieving this goal for AuNPs. The metal particles were observed to be stable in solution even 1 week after their synthesis. By stability, we mean that there was no observable variation in the optical properties of the nanoparticle solutions with time. No significant changes were detected in stability test 25.
Scheme 4: Reduction of colloidal gold by pullulan and conjugating it with 5-Fu
220.127.116.11-Fluorouracil in Cancer treatment26:
Cancer can affect every organ in human body. The various treatments of cancer include chemotherapy, radiation therapy, surgery, biological therapy, hormone and gene therapies. Chemotherapy employs chemical agents (anticancer or cytotoxic drugs) to interact with cancer cells to eradicate or control the growth of cancer. Depending on the type of cancer and kind of drug used, chemotherapy drugs may be administered differently. 5Fluorouracil (5-Fu) is one of the oldest chemotherapeutic drug and has been used for decades for the treatment of cancer. It is used as an active medicine against many cancers. Over the past 20 years, the mechanism of action of 5-Fu has led to the development of strategies that increase its anticancer activity. 5-Fu is given for treatment of cancers like bowel, breast, stomach, and liver cancer. However, anticancer drugs normally attack both normal cells and cancerous cells when the drug was given as an injection, infusion or tablet form for a long time. In order to over come this side effect, targeting the drug and sustained release of drugs are required. Many research investigations are focused on the preparation of drug encapsulated polymer nanoparticles for the controlled release applications. Biodegradable polymers have also become increasingly important in the development of drug delivery systems27.
1.5.5. 5-fluorouracil loaded Gold nanoparticles for liver cancer28:
So the main objective of the study is to target 5-Fu in liver by conjugating it with the surface modified gold nanocarriers by pullulan which is used as a reducing agent which is also a liver targeting polymer. Hence the toxicity of 5-fu is reduced by site specifically targeting the drug.