DENDRIMER : FOR NOVEL DRUG DELIVERY SYSTEM- A REVIEW ARTICLE

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Characterizations of dendrimer by various methods

METHODS FOR CHARACTERIZATION OF DENDRITIC POLYMER
(A) Spectroscopy and spectrometry methods [34-39]
most widely used for dendrimers Characterization like
Nuclear Magnetic Resonance (NMR) Analysis in step by step synthesis of Dendrimer. To Probe the Size, Morphology and Dynamics of Dendrimers for organic dendrimers such as PPI etc.
Ultra-violet-visible spectroscopy (UV-VIS) Used to monitor synthesis of dendrimers. The intensity of the absorption band is essentially proportional to the number of chromophoric units.
Infra red spectroscopy (IR) for routine analysis of the chemical transformations occurring at the surface of dendrimers.
Near infra red spectroscopy Used to characterize delocalize π-π stacking interaction between end groups of modified PANAM.
Fluorescence The high sensitivity of fluorescence has been used to quantify defects during the synthesis of dendrimers.
Raman spectroscopy gave relevant information about the degree of cyclodehydrogenation of polyphenylene dendrimers, and the characterization of PPI and dendrimers.
Mass spectroscopy Chemical ionization or fast atom phosphorus bombardment can be used only for the characterization of small dendrimers whose mass is below 3000 Da. Electrospray ionization can be used for dendrimers able to form stable multicharged species.
X-ray diffraction (XRD) This technique should allow precise determination of the chemical composition, structure, size and shape of Dendrimer.

(B) Scattering techniques[[40-43]
Small angleX-ray scattering (SAXS)
gives information about their average radius of gyration (Rg) in solution. The intensity of the scattering as a function of angle also provides information on the arrangement of polymer segments, hence on the segment density distribution within the molecule.
Small angle neutron scattering (SANS) gives access to the radius of gyration, but may also reveal more accurate information than SAXS about the internal structure of the entire dendrimer. The location of the end groups has also been determined by SANS experiments conducted with PAMAM dendrimers and PPI dendrimers having labeled (deuterated) or unlabelled end groups.
Laser light scattering (LLS) to determine the hydrodynamic radius of dendrimers. Dynamic LLS is mainly used for the detection of aggregates.

(C) Microscopy methods[44,45]
Transmission microscopy
Electron or light produce images that amplify the original, with a resolution ultimately limited by the wavelength of the source
Scanning microscopy The image is produced by touch contact Q at a few angstroms of a sensitive canilever arm with sample. Ex. Atomic force microscopy.

(D) Size exclusive chromatography[46] allows the separation of molecules according to size.

(E) Electrical techniques[47,48,49]
Electron paramagnetic resonance (EPR)
Quantitative determination of the substitution efficiency on the surface of PANAM dendrimers.
Electrochemistry gives information about the possibility of interaction of electroactive end groups.
Electrophoresis used for the assessment of purify and homogeneity of several type of water soluble dendrimers.

(F) Rheology and Physical properties[50-53]
Intrinsic viscosity
used as analytical probe of the morphological structure of dendrimers.
Differential scanning calorimetry (DSC) used to detect the glass transition temperature which depends on the moleculer weight, entangment and chain composition of polymers.
Dielectric spectroscopy (DS) Gives information about molecular dynamic processes (α-, β)

(G) Miscellaneous[54-56]
X-ray Photoelectron Spectroscopy (XPS)
chemical composition of dendrimers such as poly (aryl ether) dendrons or PMMH dendrimers has been also obtained using XPS, even if this technique is most generally used for the characterization of layers.
Sedimentation for lactosylated PAMAM dendrimers, measurements of dipole moments for PMMH dendrimer.
Titrimetry to determine the number of NH2 end groups of PAMAM dendrimers

APPLICATION OF DENDRIMER

Pharmaceutical application
Dendrimer in ocular drug delivery

Ideal ocular drug-delivery systems should benonirritating, sterile, isotonic, biocompatible, does not run out from the eye and biodegradable.Dendrimers provide unique solutions to complex deliveryproblems for ocular drug delivery. Recent research efforts for improvingresidence time of pilocarpine in the eye was increased by using PAMAM dendrimerswith carboxylic or hydroxyl surface groups. These surface-modified dendrimers werepredicted to enhance pilocarpine bioavailability [57].

Dendrimers in pulmonary drug delivery
Dendrimers have been reported for pulmonary drug delivery of Enoxaparin. G2 and G3 generation positively charged PAMAM dendrimers increased the relative bioavailability of Enoxaparin by 40 % [58].

Dendrimer in transdermal drug delivery-
Dendrimers designed to be highly watersoluble and biocompatible have been shown to be able to improve drug properties such as solubility and plasma circulation time via transdermal formulations and to deliver drugs efficiently. PAMAM dendrimer complex with NSAIDs (e.g. Ketoprofen, Diflunisal) could be improving the drug permeation through  the skin as penetration enhancers [59]. Ketoprofen and Diflunisal were conjugated with G5 PAMAM dendrimer and showed 3.4 and 3.2 times higher permeation. Chauhan et al. investigated enhanced bioavailability of PAMAM dendrimers by using indomethacin as the model drug in transdermal drug application. (chauhan) [60]

Dendrimer in oral drug delivery-
Oral drug delivery studies using the human colon adenocarcinoma cell line, Caco-2, have indicated that low-generation PAMAM dendrimers cross cell membranes, presumably through a combination of two processes, i.e. paracellular transport and adsorptive endocytosis. Remarkably, the Pgp efflux transporter does not appear to affect dendrimers, therefore drug dendrimer complexes are able to bypass the efflux transporter [63]. As increase in the concentration and generation, there was and methotrexate. PAMAM dendrimers conjugated with the folic acid and fluorescein isothiocyanate for targeting the tumor cells and imaging respectively. DNAassembled dendrimer conjugates may allow the combination of different drugs with different targeting and imaging agents so it is easy to develop combinatorial therapeutics [61].

Dendrimers for controlled release drug delivery
The anticancer drugs adriamycin and methotrexate were encapsulated into PAMAM dendrimers (i.e. G=3 and 4) which had been modified with PEG monomethyl ether chains (i.e. 550 and 2000 Da respectively) attached to their surfaces. A similar construct involving PEG chains and PAMAM dendrimers was used to deliver the anticancer drug 5-fluorouracil. Encapsulation of 5-fluorouracil into G=4 increase in the cytotoxicity and permeationof dendrimers.

Dendrimers in targeted drug delivery
Dendrimers have ideal properties which are useful in targeted drug-delivery system. One of the most effective cell-specific targeting agents delivered by dendrimers is folic acid PAMAM dendrimers modified with carboxymethyl PEG5000 surface chains revealed reasonable drug loading, a reduced release rate and reduced haemolytic toxicity compared with the non-PEGylated dendrimer. A third-generation dendritic unimolecular micelle with indomethacin entrapped as model drug gives slow and sustained in vitro release, as compared to cellulose membrane control [62].Controlled release of the Flurbiprofen could be achieved by formation of complex with amine terminated generation 4 (G4) PAMAM Dendrimers [63]. The results found that PEG-dendrimers conjugated with encapsulated drug and sustained release of methotrexate as compare to unencapsulated drug

Dendrimers in gene delivery
Dendrimer-based transfection agents have become routine tools for many molecular and cell biologist’s dendrimers are extensively used as non-viral vector for gene delivery. The use of dendrimers as gene transfection agents and drug-delivery devices have been extensively reviewed part [64]. Various polyatomic compound such as PEI, polylysine, and cationic have been utilized as non-viral gene carrier

Dendrimer as solubility enhancer
Dendrimers have hydrophilic exteriors and hydrophilic interiors, which are responsible for its unimolecular micellar nature. They form covalent as well as non-covalent complexes with drug molecules and hydrophobes, which are responsible for its solubilisation behavior [65].

Cellular delivery using dendrimer carrier
Dendrimer–ibuprofen complexes entered the cells rapidly compared with pure drug (1 hr versus>3 hr), suggesting that dendrimers can efficiently carry the complexes drug inside cells. PAMAM dendrimers were surfaceengineered with lauryl chains to reduce toxicity and enhance cellular uptake [66].

Therapeutic application
Dendrimers in photodynamic therapy

The photosensitizer 5-aminolevulinic acid has been attached to the surface of dendrimers and studied as an agent for PDT of tumorigenic keratinocytes [67]. This cancer treatment involves the administration of a light- activated photosensitizing drug that selectively concentrates in diseased tissue.

Dendrimers for boron neutron capture therapy
Boron neutron capture therapy (BNCT) refers to the radiation generated from the capture reaction of low-energy thermal neutrons by 10B atoms, which containapproximately 20% natural boron, to yield particles and recoiling lithium-7 nuclei. This radiation energy has been used successfully for the selective destruction of tissue. Dendrimers are a very fascinating compound for use as boron carriers due to their well defined structure and multivalency. The first example of a boroncontaining PAMAM dendrimer was synthesized by Barth et al [68]

Diagnostic application
Dendrimers as molecular probes

Dendrimers are fascinating molecules to use as molecular probes because of their distinct morphology and unique characteristics. For example, the immobilization of sensor units on the surface of dendrimers is a very efficient way to generate an integrated molecular probe, because of their large surface area and high density of surface functionalities [69]

Dendrimers as X-ray contrast agents
The X-ray machine is one of the fundamental diagnostic tools in medicine, and is applicable to numerous diseases. To obtain a high resolution X-ray image, several diseases or organs, such as arteriosclerotic vasculature, tumors, infarcts, kidneys or efferent urinary, require the use of an X-ray contrast agent. Dendrimers are currently under investigation as potential polymeric X-ray contrast agents. Krause and co-workers synthesized a number of potential dendritic X-ray contrast agents using various organo metallic complexes such as bismuth and tin [70,71]

Dendrimers as MRI contrast agents
A number of research groups have explored the use of dendrimers as a new class of high molecular weight MRI contrast agents. Wiener and coworkers developed a series of Gd(III)–DTPA-based PAMAM dendrimers [72]. To improve the pharmacokinetic properties of dendrimer contrast agents, introduction of target specific moieties to the dendritic MRI contrast agents have been considered. Wiener et al [73] synthesized a folate conjugated Gd(III)–DTPA PAMAM dendrimer, which increased the longitudinal relaxation rate of tumor cells expressing the high affinity folate receptor.

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