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Dendrimers are repetitively branched molecules.^[1]^[2] The name comes from the Greek word δένδρον (dendron) which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology. The word dendron is also encountered frequently. A dendron usually contains a single chemically addressable group called the focal point or core. The difference between dendrons and dendrimers is illustrated in the top figure, but the terms are typically encountered interchangeably.^[3]

The first dendrimers were made by divergent synthesis approaches by Fritz Vögtle in 1978,^[5] R.G. Denkewalter at Allied Corporation in 1981,^[6]^[7] Donald Tomalia at Dow Chemical in 1983^[8] and in 1985,^[9]^[10] and by George R. Newkome in 1985.^[11] In 1990 a convergent synthetic approach was introduced by Craig Hawker and Jean Fréchet.^[12] Dendrimer popularity then greatly increased, resulting in more than 5,000 scientific papers and patents by the year 2005.

Properties

Dendritic molecules are characterized by structural perfection. Dendrimers and dendrons are monodisperse and usually highly symmetric, spherical compounds. The field of dendritic molecules can be roughly divided into low-molecular weight and high-molecular weight species. The first category includes dendrimers and dendrons, and the latter includes dendronized polymers, hyperbranched polymers, and the polymer brush.

The properties of dendrimers are dominated by the functional groups on the molecular surface, however, there are examples of dendrimers with internal functionality.^[13]^[14]^[15] Dendritic encapsulation of functional molecules allows for the isolation of the active site, a structure that mimics that of active sites in biomaterials.^[16]^[17]^[18] Also, it is possible to make dendrimers water-soluble, unlike most polymers, by functionalizing their outer shell with charged species or other hydrophilic groups. Other controllable properties of dendrimers include toxicity, crystallinity, tecto-dendrimer formation, and chirality.^[3]

Dendrimers are also classified by generation, which refers to the number of repeated branching cycles that are performed during its synthesis. For example, if a dendrimer is made by convergent synthesis (see below), and the branching reactions are performed onto the core molecule three times, the resulting dendrimer is considered a third generation dendrimer. Each successive generation results in a dendrimer roughly twice the molecular weight of the previous generation. Higher generation dendrimers also have more exposed functional groups on the surface, which can later be used to customize the dendrimer for a given application.^[19]

Synthesis

One of the very first dendrimers, the Newkome dendrimer, was synthesized in 1985. This macromolecule is also commonly known by the name arborol. The figure outlines the mechanism of the first two generations of arborol through a divergent route (discussed below). The synthesis is started by nucleophilic substitution of 1-bromopentane by triethyl sodiomethanetricarboxylate in dimethylformamide and benzene. The ester groups were then reduced by lithium aluminium hydride to a triol in a deprotection step. Activation of the chain ends was achieved by converting the alcohol groups to tosylate groups with tosyl chloride and pyridine. The tosyl group then served as leaving groups in another reaction with the tricarboxylate, forming generation two. Further repetition of the two steps leads to higher generations of arborol.^[11]

Poly(amidoamine), or PAMAM, is perhaps the most well known dendrimer. The core of PAMAM is a diamine (commonly ethylenediamine), which is reacted with methyl acrylate, and then another ethylenediamine to make the generation-0 (G-0) PAMAM. Successive reactions create higher generations, which tend to have different properties. Lower generations can be thought of as flexible molecules with no appreciable inner regions, while medium-sized (G-3 or G-4) do have internal space that is essentially separated from the outer shell of the dendrimer. Very large (G-7 and greater) dendrimers can be thought of more like solid particles with very dense surfaces due to the structure of their outer shell. The functional group on the surface of PAMAM dendrimers is ideal for click chemistry, which gives rise to many potential applications.^[20]

Dendrimers can be considered to have three major portions: a core, an inner shell, and an outer shell. Ideally, a dendrimer can be synthesized to have different functionality in each of these portions to control properties such as solubility, thermal stability, and attachment of compounds for particular applications. Synthetic processes can also precisely control the size and number of branches on the dendrimer. There are two defined methods of dendrimer synthesis, divergent synthesis and convergent synthesis. However, because the actual reactions consist of many steps needed to protect the active site, it is difficult to synthesize dendrimers using either method. This makes dendrimers hard to make and very expensive to purchase. At this time, there are only a few companies that sell dendrimers; Polymer Factory Sweden AB^[21] commercializes biocompatible bis-MPA dendrimers and Dendritech^[22] is the only kilogram-scale producers of PAMAM dendrimers. NanoSynthons, LLC^[23] from Mount Pleasant, Michigan, USA produces PAMAM dendrimers and other proprietary dendrimers.

Divergent methods

Schematic of divergent synthesis of dendrimers

The dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions, commonly a Michael reaction. Each step of the reaction must be driven to full completion to prevent mistakes in the dendrimer, which can cause trailing generations (some branches are shorter than the others). Such impurities can impact the functionality and symmetry of the dendrimer, but are extremely difficult to purify out because the relative size difference between perfect and imperfect dendrimers is very small.^[19]

Convergent methods

Dendrimers are built from small molecules that end up at the surface of the sphere, and reactions proceed inward building inward and are eventually attached to a core. This method makes it much easier to remove impurities and shorter branches along the way, so that the final dendrimer is more monodisperse. However dendrimers made this way are not as large as those made by divergent methods because crowding due to steric effects along the core is limiting.^[19]

Click chemistry

Dendrimers have been prepared via click chemistry, employing Diels-Alder reactions,^[25] thiol-ene and thiol-yne reactions ^[26] and azide-alkyne reactions.^[27]^[28]^[29]

There are ample avenues that can be opened by exploring this chemistry in dendrimer synthesis.

Applications

Applications of dendrimers typically involve conjugating other chemical species to the dendrimer surface that can function as detecting agents (such as a dye molecule), affinity ligands, targeting components, radioligands, imaging agents, or pharmaceutically active compounds. Dendrimers have very strong potential for these applications because their structure can lead to multivalent systems. In other words, one dendrimer molecule has hundreds of possible sites to couple to an active species. Researchers aimed to utilize the hydrophobic environments of the dendritic media to conduct photochemical reactions that generate the products that are synthetically challenged. Carboxylic acid and phenol-terminated water-soluble dendrimers were synthesized to establish their utility in drug delivery as well as conducting chemical reactions in their interiors.^[30] This might allow researchers to attach both targeting molecules and drug molecules to the same dendrimer, which could reduce negative side effects of medications on healthy cells.^[20]

Dendrimers can also be used as a solubilizing agent. Since their introduction in the mid-1980s, this novel class of dendrimer architecture has been a prime candidate for host–guest chemistry.^[31] Dendrimers with hydrophobic core and hydrophilic periphery have shown to exhibit micelle-like behavior and have container properties in solution.^[32] The use of dendrimers as unimolecular micelles was proposed by Newkome in 1985.^[33] This analogy highlighted the utility of dendrimers as solubilizing agents.^[34] The majority of drugs available in pharmaceutical industry are hydrophobic in nature and this property in particular creates major formulation problems. This drawback of drugs can be ameliorated by dendrimeric scaffolding, which can be used to encapsulate as well as to solubilize the drugs because of the capability of such scaffolds to participate in extensive hydrogen bonding with water.^[35]^[36]^[37]^[38]^[39]^[40] Dendrimer labs throughout the planet are persistently trying to manipulate dendrimer's solubilizing trait, in their way to explore dendrimer as drug delivery ^[41]^[42] and target specific carrier.^[43]^[44]^[45]

For dendrimers to be able to be used in pharmaceutical applications, they must surmount the required regulatory hurdles to reach market. One dendrimer scaffold designed to achieve this is the Poly Ethoxy Ethyl Glycinamide (PEE-G) dendrimer.^[46]^[47] This dendrimer scaffold has been designed and shown to have high HPLC purity, stability, aqueous solubility and low inherent toxicity.

Drug delivery

Approaches for delivering unaltered natural products using polymeric carriers is of widespread interest. Dendrimers have been explored for the encapsulation of hydrophobic compounds and for the delivery of anticancer drugs. The physical characteristics of dendrimers, including their monodispersity, water solubility, encapsulation ability, and large number of functionalizable peripheral groups make these macromolecules appropriate candidates for drug delivery vehicles.

Role of Dendrimer Chemical Modifications in Drug Delivery

Dendrimers are particularly versatile drug delivery devices due to the wide range of chemical modifications that can be made to increase in-vivo suitability and allow for site-specific targeted drug delivery.

Drug attachment to the dendrimer may be (1) a covalent attachment or conjugation to the external surface of the dendrimer forming a dendrimer prodrug, (2) ionic coordination to charged outer functional groups, or (3) micelle-like encapsulation of a drug via a dendrimer-drug supramolecular assembly.^[48]^[49] In the case of a dendrimer prodrug structure, linking of a drug to a dendrimer may be direct or linker-mediated depending on desired release kinetics. Such a linker may be pH-sensitive, enzyme catalyzed, or a disulfide bridge. The wide range of terminal functional groups available for dendrimers allows for many different types of linker chemistries, providing yet another tunable component on the system. Key parameters to consider for linker chemistry are (1) release mechanism upon arrival to the target site, whether that be within the cell or in a certain organ system, (2) drug-dendrimer spacing so as to prevent lipophilic drugs from folding into the dendrimer, and (3) linker degradability and post-release trace modifications on drugs.^[50]^[51]

Polyethylene glycol (PEG) is a common modification for dendrimers to modify surface charge and circulation time. The influence of surface charge is present most heavily in cationic dendrimers, such as amine-terminal dendrimers. These have a propensity to interact with membranes with anionic charge such as cell membranes. Polycationic dendrimers have shown cytotoxicity in vivo leading to large changes in Caco-2 membrane permeability.^[52] PEGylation caps amine groups and results in lower cytotoxicity and red blood cell hemolysis.^[53] Additionally, studies have found that PEGylation of dendrimers results in higher drug loading, slower drug release, longer circulation times in vivo, and lower toxicity in comparison to counterparts without PEG modifications.^[54]^[53]

Numerous targeting moieties have been used to modify dendrimer biodistribution and allow for targeting to specific organs.

Folate receptors are overexpressed in tumor cells and are therefore promising targets for localized drug delivery of chemotherapeutics. Folic acid conjugation to PAMAM dendrimers has been shown to increase targeting and decrease off-target toxicity while maintaining on-target cytotoxicity of chemotherapeutics such as methotrexate, in mouse models of cancer.^[54]^[55]

Antibody-mediated targeting of dendrimers to cell targets has also shown promise. As epidermal growth factor receptors (EGFRs) are often overexpressed in brain tumors, they are a convenient target for site-specific drug delivery. The delivery of boron to cancerous cells is important to realize the full potential of neutron capture therapy, a cancer treatment which requires a large concentration of boron in cancerous cells and a low concentration in healthy cells. A boronated dendrimer conjugated with a monoclonal antibody drug that targets EGFRs was used in rats to successfully deliver boron to cancerous cells.^[56]

Modifying nanoparticle dendrimers with peptides has also been successful at targeted destruction of colorectal (HCT-116) cancer cells in a co-culture scenario. It has been shown that these peptides increase in functionality when paired with dendrimers. Specifically, gemcitabine-loaded YIGSR-CMCht/PAMAM, a unique kind of dendrimer nanoparticle, induces a targeted mortality on these cancer cells. This is performed via selective interaction with laminin receptors. Peptide dendrimers may be employed in the future to precisely target cancer cells and deliver chemotherapeutic agents.^[57]

The cellular uptake mechanism of dendrimers can also be tuned using chemical targeting modifications. Non-modified PAMAM-G4 dendrimer is taken up into activated microglia by fluid phase endocytosis. Mannose modification of hydroxyl PAMAM-G4 dendrimers was able to change the mechanism of internalization to mannose-receptor (CD206) mediated endocytosis. Additionally, mannose modification was able to change the biodistribution in the rest of the body in rabbits.^[58]

Pharmacokinetics and Pharmacodynamics

Dendrimers have the potential to completely change the pharmacokinetic and pharmacodynamic (PK/PD) profiles of a drug. As carriers, the PK/PD is no longer determined by the drug itself but by the dendrimer’s localization, drug release, and dendrimer excretion. ADME properties are very highly tunable by varying size, structure, and surface characteristics. While G9 dendrimers distribute very heavily to the liver and spleen, G6 dendrimers tend to distribute more broadly. As molecular weight increases, urinary clearance and plasma clearance decrease while terminal half life increases.^[59]

Routes of Delivery

In order to increase patient compliance with prescribed treatment, delivery of drugs orally is often preferred to other routes of drug administration. However oral bioavailability of many drugs tends to be very low. Dendrimers can be used to increase the solubility and stability of orally administered drugs and increase drug penetration through the intestinal membrane.^[60] The bioavailability of PAMAM dendrimers conjugated to a chemotherapeutic has been studied in mice; it was found that around 9% of dendrimer administered orally was found intact in circulation and that minimal dendrimer degradation occurred in the gut.^[61]

Intravenous dendrimer delivery shows promising potential in acting as gene vectors to deliver genes to various organs in the body, and even tumors. One study found that through intravenous injection, a combination of PPI dendrimers and gene complexes resulted in gene expression in the liver, and another study showed that a similar injection regressed the growth of tumors in observed animals.^[62]^[63]

The primary obstacle to transdermal drug delivery is the epidermis. Hydrophobic drugs have a very difficult time penetrating the skin layer, as they partition heavily into skin oils. Recently, PAMAM dendrimers have been used as delivery vehicles for NSAIDS to increase hydrophilicity, allowing greater drug penetration.^[64] These modifications act as polymeric transdermal enhancers allowing drugs to more easily penetrate the skin barrier.

Dendrimers may also act as new ophthalmic vehicles for drug delivery, radically different from the polymers currently used for this purpose. A study by Vanndamme and Bobeck used PAMAM dendrimers as ophthalmic delivery vehicles in rabbits for two model drugs and measured the ocular residence time of this delivery to be comparable and in some cases greater than current bioadhesive polymers used in ocular delivery.^[65] This indicates that administered drugs were more active and had increased bioavailability when delivered via dendrimers. Additionally, photo-curable, drug-eluting dendrimer-hyaluronic acid hydrogels have been used as corneal sutures applied directly to the eye. These hydrogel sutures have shown efficacy as a medical device in rabbit models that surpasses traditional sutures and minimizes corneal scarring.^[66]

Brain Drug Delivery

Dendrimer drug delivery has shown major promise as a potential solution for many traditionally difficult drug delivery problems. In the case of drug delivery to the brain, dendrimers are able to uniquely take advantage of the EPR effect and blood-brain barrier (BBB) impairment to cross the BBB effectively in vivo. For example, hydroxyl-terminated PAMAM dendrimers possess an intrinsic targeting ability to inflamed macrophages in the brain, verified using fluorescently labeled neutral generation dendrimers in a rabbit model of cerebral palsy.^[67] This intrinsic targeting has enabled drug delivery in a variety of conditions, ranging from cerebral palsy and other neuroinflammatory disorders to traumatic brain injury and hypothermic circulatory arrest, across a variety of animal models ranging from mice and rabbits to canines.^[68]^[69]^[70] Dendrimer uptake into the brain correlates with severity of inflammation and BBB impairment and it is believed that the BBB impairment is the key driving factor allowing dendrimer penetration.^[71]^[67] Localization is heavily skewed towards activated microglia. Dendrimer-conjugated N-acetyl cysteine has shown efficacy in vivo as an anti-inflammatory at more than 1000-fold lower dose than free drug on a drug basis, reversing the phenotype of cerebral palsy, Rett syndrome, macular degeneration and other inflammatory diseases.^[67]

Clinical Trials

Starpharma, an Australian pharmaceutical company, has multiple products that have either already been approved for use or are in the clinical trial phase. SPL7013, also known as astodrimer sodium, is a hyperbranched polymer used in Starpharma’s VivaGel line of pharmaceuticals that is currently approved to treat bacterial vaginosis and prevent the spread of HIV, HPV, and HSV in Europe, Southeast Asia, Japan, Canada, and Australia. Due to SPL7013’s broad antiviral action, it has recently been tested by the company as a potential drug to treat SARS-CoV-2. The company states preliminary in-vitro studies show high efficacy in preventing SARS-CoV-2 infection in cells.^[72]

Gene delivery and transfection

The ability to deliver pieces of DNA to the required parts of a cell includes many challenges. Current research is being performed to find ways to use dendrimers to traffic genes into cells without damaging or deactivating the DNA. To maintain the activity of DNA during dehydration, the dendrimer/DNA complexes were encapsulated in a water-soluble polymer, and then deposited on or sandwiched in functional polymer films with a fast degradation rate to mediate gene transfection. Based on this method, PAMAM dendrimer/DNA complexes were used to encapsulate functional biodegradable polymer films for substratemediated gene delivery. Research has shown that the fast-degrading functional polymer has great potential for localized transfection.^[73]^[74]^[75]

Sensors

Dendrimers have potential applications in sensors. Studied systems include proton or pH sensors using poly(propylene imine),^[76] cadmium-sulfide/polypropylenimine tetrahexacontaamine dendrimer composites to detect fluorescence signal quenching,^[77] and poly(propylenamine) first and second generation dendrimers for metal cation photodetection^[78] amongst others. Research in this field is vast and ongoing due to the potential for multiple detection and binding sites in dendritic structures.

Blood substitution

Dendrimers are also being investigated for use as blood substitutes. Their steric bulk surrounding a heme-mimetic centre significantly slows degradation compared to free heme,^[79]^[80] and prevents the cytotoxicity exhibited by free heme.

Nanoparticles

Dendrimers also are used in the synthesis of monodisperse metallic nanoparticles. Poly(amidoamide), or PAMAM, dendrimers are utilized for their tertiary amine groups at the branching points within the dendrimer. Metal ions are introduced to an aqueous dendrimer solution and the metal ions form a complex with the lone pair of electrons present at the tertiary amines. After complexion, the ions are reduced to their zerovalent states to form a nanoparticle that is encapsulated within the dendrimer. These nanoparticles range in width from 1.5 to 10 nanometers and are called dendrimer-encapsulated nanoparticles.^[81]

Crop protection and agrochemicals

Given the widespread use of pesticides, herbicides and insecticides in modern farming, dendrimers are also being used by companies to help improve the delivery of agrochemicals to enable healthier plant growth and to help fight plant diseases.^[82]

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@@ Line 1: / Line 1: @@
 [[Image:graphs.jpg|thumb|Dendrimer and dendron]]
-'''Dendrimers''' are repetitively [[Branching (polymer chemistry)|branched]] [[molecules]].<ref>{{cite journal | title = Dendrimers Designed for Functions: From Physical, Photophysical, and Supramolecular Properties to Applications in Sensing, Catalysis, Molecular Electronics, and Nanomedicine | year = 2010 | journal = [[Chem. Rev.]] | volume = 110 | pages = 1857–1959 | pmid = 20356105| doi = 10.1021/cr900327d | issue = 4| last1 = Astruc | first1 = Didier | last2 = Boisselier | first2 = Elodie | last3 = Ornelas | first3 = Cátia }}</ref><ref>Vögtle, Fritz / Richardt, Gabriele / Werner, Nicole ''Dendrimer Chemistry Concepts, Syntheses, Properties, Applications'' 2009 {{ISBN|3-527-32066-0}}</ref> The name comes from the [[Ancient Greek|Greek]] word δένδρον ('''dendron''') which translates to "tree".  Synonymous terms for dendrimer include '''arborols''' and '''cascade molecules'''. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology. The word '''dendron''' is also encountered frequently. A dendron usually contains a single chemically addressable group called the focal point or core. The difference between dendrons and dendrimers is illustrated in the top figure, but the terms are typically encountered interchangeably.<ref name=review>{{cite journal|year=2009|title=Dendrimers: Emerging polymers for drug-delivery systems|journal=European Journal of Pharmaceutical Sciences|volume=38|issue=3|pages=185–196|pmid=19646528| doi=10.1016/j.ejps.2009.07.008|last1=Nanjwade|first1=B. K.|last2=Bechra|first2=H. M.|last3=Derkar|first3=G. K.|last4=Manvi|first4=F. V.|last5=Nanjwade|first5=V. K.}}</ref>
+'''Dendrimers''' are repetitively [[Branching (polymer chemistry)|branched]] [[molecules]].<ref>{{cite journal | title = Dendrimers Designed for Functions: From Physical, Photophysical, and Supramolecular Properties to Applications in Sensing, Catalysis, Molecular Electronics, and Nanomedicine | year = 2010 | journal = [[Chem. Rev.]] | volume = 110 | pages = 1857–1959 | pmid = 20356105| doi = 10.1021/cr900327d | issue = 4| last1 = Astruc | first1 = Didier | last2 = Boisselier | first2 = Elodie | last3 = Ornelas | first3 = Cátia }}</ref><ref>Vögtle, Fritz / Richardt, Gabriele / Werner, Nicole ''Dendrimer Chemistry Concepts, Syntheses, Properties, Applications'' 2009 {{ISBN|3-527-32066-0}}</ref> The name comes from the [[Ancient Greek|Greek]] word δένδρον ('''dendron''') which translates to "tree". Synonymous terms for dendrimer include '''arborols''' and '''cascade molecules'''. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology. The word '''dendron''' is also encountered frequently. A dendron usually contains a single chemically addressable group called the focal point or core. The difference between dendrons and dendrimers is illustrated in the top figure, but the terms are typically encountered interchangeably.<ref name=review>{{cite journal|year=2009|title=Dendrimers: Emerging polymers for drug-delivery systems|journal=European Journal of Pharmaceutical Sciences|volume=38|issue=3|pages=185–196|pmid=19646528| doi=10.1016/j.ejps.2009.07.008|last1=Nanjwade|first1=B. K.|last2=Bechra|first2=H. M.|last3=Derkar|first3=G. K.|last4=Manvi|first4=F. V.|last5=Nanjwade|first5=V. K.}}</ref>
 <!-- [[Image:Dendrimer ChemEurJ 2002 3858.jpg|thum|Crystal structure of a first-generation polyphenylene dendrimer reported by Müllen et al.<ref>
 {{cite journal | doi = 10.1002/1521-3765(20020902)8:17<3858::AID-CHEM3858>3.0.CO;2-5 | title = Single-Crystal Structures of Polyphenylene Dendrimers | year = 2002 | journal = [[Chemistry: A European Journal]] | volume = 8 | pages = 3858–3864 | issue = 17}}</ref>]]-->
 [[File:Cyanostar STM.png|thumb|A first-generation "cyanostar" dendrimer and its [[Scanning tunneling microscopy|STM]] image.<ref>{{cite journal|doi=10.1039/C4CC03725A|pmid=25080328|title=Anion-induced dimerization of 5-fold symmetric cyanostars in 3D crystalline solids and 2D self-assembled crystals|journal=Chemical Communications|volume=50|issue=69|pages=9827–30|year=2014|last1=Hirsch|first1=Brandon E.|last2=Lee|first2=Semin|last3=Qiao|first3=Bo|last4=Chen|first4=Chun-Hsing|last5=McDonald|first5=Kevin P.|last6=Tait|first6=Steven L.|last7=Flood|first7=Amar H.|url=https://zenodo.org/record/889879}}</ref>]]
-The first dendrimers were made by divergent synthesis approaches by Fritz Vögtle in 1978,<ref>{{cite journal | title = "Cascade"- and "Nonskid-Chain-like" Syntheses of Molecular Cavity Topologies | journal = [[Synthesis (journal)|Synthesis]] | year = 1978 | pages = 155–158 | doi = 10.1055/s-1978-24702 | volume = 1978 | issue = 2| last1 = Buhleier | first1 = Egon | last2 = Wehner | first2 = Winfried | last3 = Vögtle | first3 = Fritz }}</ref> R.G. Denkewalter at [[Allied Corporation]] in 1981,<ref>{{US Patent|4289872}} Denkewalter, Robert G., Kolc, Jaroslav, Lukasavage, William J.</ref><ref>Denkewalter, Robert G. et al. (1981) "Macromolecular highly branched homogeneous compound" {{US Patent|4,410,688}}</ref> [[Donald Tomalia]] at [[Dow Chemical]] in 1983<ref>Tomalia, Donald A. and Dewald, James R. (1983) "Dense star polymers having core, core branches, terminal groups" {{US Patent|4507466}}</ref> and in 1985,<ref>{{cite journal | title = A New Class of Polymers: Starburst-Dendritic Macromolecules | journal = Polymer Journal | volume = 17 | year = 1985 | doi = 10.1295/polymj.17.117 | pages = 117–132| last1 = Tomalia | first1 = D A | last2 = Baker | first2 = H | last3 = Dewald | first3 = J | last4 = Hall | first4 = M | last5 = Kallos | first5 = G | last6 = Martin | first6 = S | last7 = Roeck | first7 = J | last8 = Ryder | first8 = J | last9 = Smith | first9 = P  | doi-access = free }}</ref><ref>{{cite news| url=http://www.thefreelibrary.com/Treelike+molecules+branch+out.-a017817461 | work=Science News | title=Treelike molecules branch out – chemist Donald A. Tomalia synthesized first dendrimer molecule – Chemistry – Brief Article | year=1996}}</ref>  and by [[George R. Newkome]] in 1985.<ref name=newkome>{{cite journal | title = Micelles. Part 1. Cascade molecules: a new approach to micelles. A [27]-arborol | journal = [[J. Org. Chem.]] | doi = 10.1021/jo00211a052 | year = 1985 | volume = 50 | pages = 2003–2004 | issue = 11| last1 = Newkome | first1 = George R. | last2 = Yao | first2 = Zhongqi | last3 = Baker | first3 = Gregory R. | last4 = Gupta | first4 = Vinod K. }}</ref> In 1990 a convergent synthetic approach was introduced by [[Craig Hawker]] and [[Jean Fréchet]].<ref>{{cite journal | title = Preparation of polymers with controlled molecular architecture. A new convergent approach to dendritic macromolecules |author1=Hawker, C. J. |author2=Fréchet, J. M. J. | journal = [[J. Am. Chem. Soc.]] | doi = 10.1021/ja00177a027 | year = 1990 | volume = 112 | pages = 7638–7647 | issue = 21}}</ref> Dendrimer popularity then greatly increased, resulting in more than 5,000 scientific papers and patents by the year 2005.
+The first dendrimers were made by divergent synthesis approaches by Fritz Vögtle in 1978,<ref>{{cite journal | title = "Cascade"- and "Nonskid-Chain-like" Syntheses of Molecular Cavity Topologies | journal = [[Synthesis (journal)|Synthesis]] | year = 1978 | pages = 155–158 | doi = 10.1055/s-1978-24702 | volume = 1978 | issue = 2| last1 = Buhleier | first1 = Egon | last2 = Wehner | first2 = Winfried | last3 = Vögtle | first3 = Fritz }}</ref> R.G. Denkewalter at [[Allied Corporation]] in 1981,<ref>{{US Patent|4289872}} Denkewalter, Robert G., Kolc, Jaroslav, Lukasavage, William J.</ref><ref>Denkewalter, Robert G. et al. (1981) "Macromolecular highly branched homogeneous compound" {{US Patent|4,410,688}}</ref> [[Donald Tomalia]] at [[Dow Chemical]] in 1983<ref>Tomalia, Donald A. and Dewald, James R. (1983) "Dense star polymers having core, core branches, terminal groups" {{US Patent|4507466}}</ref> and in 1985,<ref>{{cite journal | title = A New Class of Polymers: Starburst-Dendritic Macromolecules | journal = Polymer Journal | volume = 17 | year = 1985 | doi = 10.1295/polymj.17.117 | pages = 117–132| last1 = Tomalia | first1 = D A | last2 = Baker | first2 = H | last3 = Dewald | first3 = J | last4 = Hall | first4 = M | last5 = Kallos | first5 = G | last6 = Martin | first6 = S | last7 = Roeck | first7 = J | last8 = Ryder | first8 = J | last9 = Smith | first9 = P  | doi-access = free }}</ref><ref>{{cite news| url=http://www.thefreelibrary.com/Treelike+molecules+branch+out.-a017817461 | work=Science News | title=Treelike molecules branch out – chemist Donald A. Tomalia synthesized first dendrimer molecule – Chemistry – Brief Article | year=1996}}</ref> and by [[George R. Newkome]] in 1985.<ref name=newkome>{{cite journal | title = Micelles. Part 1. Cascade molecules: a new approach to micelles. A [27]-arborol | journal = [[J. Org. Chem.]] | doi = 10.1021/jo00211a052 | year = 1985 | volume = 50 | pages = 2003–2004 | issue = 11| last1 = Newkome | first1 = George R. | last2 = Yao | first2 = Zhongqi | last3 = Baker | first3 = Gregory R. | last4 = Gupta | first4 = Vinod K. }}</ref> In 1990 a convergent synthetic approach was introduced by [[Craig Hawker]] and [[Jean Fréchet]].<ref>{{cite journal | title = Preparation of polymers with controlled molecular architecture. A new convergent approach to dendritic macromolecules |author1=Hawker, C. J. |author2=Fréchet, J. M. J. | journal = [[J. Am. Chem. Soc.]] | doi = 10.1021/ja00177a027 | year = 1990 | volume = 112 | pages = 7638–7647 | issue = 21}}</ref> Dendrimer popularity then greatly increased, resulting in more than 5,000 scientific papers and patents by the year 2005.
 ==Properties==
-Dendritic molecules are characterized by structural perfection.  Dendrimers and dendrons are [[monodisperse]] and usually highly [[symmetric]], spherical compounds.  The field of dendritic molecules can be roughly divided into low-[[molecular weight]] and high-molecular weight species. The first category includes dendrimers and dendrons, and the latter includes [[dendronized polymers]], hyperbranched polymers, and the [[polymer brush]].
+Dendritic molecules are characterized by structural perfection. Dendrimers and dendrons are [[monodisperse]] and usually highly [[symmetric]], spherical compounds. The field of dendritic molecules can be roughly divided into low-[[molecular weight]] and high-molecular weight species. The first category includes dendrimers and dendrons, and the latter includes [[dendronized polymers]], hyperbranched polymers, and the [[polymer brush]].
 The properties of dendrimers are dominated by the [[functional groups]] on the [[Van der Waals surface|molecular surface]], however, there are examples of dendrimers with internal functionality.<ref>{{cite journal | last1 = Antoni | first1 = P. | last2 = Hed | first2 = Y. | last3 = Nordberg | first3 = A. | last4 = Nyström | first4 = D. | last5 = Hult | first5 = A. | last6 = Malkoch | first6 = M. | year = 2009 | title = Bifunctional Dendrimers: From Robust Synthesis and Accelerated One-Pot Postfunctionalization Strategy to Potential Applications | journal = Angew. Chem. Int. Ed. | volume = 48 | issue = 12| pages = 2126–2130 | doi = 10.1002/anie.200804987 | pmid = 19117006 }}</ref><ref>{{cite journal | last1 = McElhanon | first1 = J. R. | last2 = McGrath | first2 = D. V. | year = 2000 | title = Toward Chiral Polyhydroxylated Dendrimers. Preparation and Chiroptical Properties| journal = [[Journal of Organic Chemistry]] | volume = 65 | issue = 11| pages = 3525–3529 | doi = 10.1021/jo000207a | pmid = 10843641 }}</ref><ref>{{cite journal | last1 = Liang | first1 = C. O. | last2 = Fréchet | first2 = J. M. J. | year = 2005 | title = Incorporation of Functional Guest Molecules into an Internally Functionalizable Dendrimer through Olefin Metathesis| journal = [[Macromolecules (journal)|Macromolecules]] | volume = 38 | issue = 15| pages = 6276–6284 | doi = 10.1021/ma050818a | bibcode = 2005MaMol..38.6276L }}</ref> Dendritic [[Molecular encapsulation|encapsulation]] of functional molecules allows for the isolation of the active site, a structure that mimics that of active sites in biomaterials.<ref>{{cite journal | journal = [[Angew. Chem. Int. Ed.]] | year = 2001 | volume = 40 | doi = 10.1002/1521-3773(20010105)40:1<74::AID-ANIE74>3.0.CO;2-C | title = Dendritic Encapsulation of Function: Applying Nature's Site Isolation Principle from Biomimetics to Materials Science | pmid=11169692 | issue = 1 | pages = 74–91| last1 = Hecht | first1 = S | last2 = Fréchet | first2 = J. M. }}</ref><ref>{{cite book|last=Frechet|first=Jean M.|author2=Donald A. Tomalia|title=Dendrimers and Other Dendritic Polymers|publisher=John Wiley & Sons|location=New York, NY|date=March 2002|isbn=978-0-471-63850-6}}</ref><ref>{{cite journal | journal = [[Angew. Chem. Int. Ed.]] | year = 1999 | volume = 38 | pages = 884–905 | doi = 10.1002/(SICI)1521-3773(19990401)38:7<884::AID-ANIE884>3.0.CO;2-K | title = Dendrimers: From Design to Application—A Progress Report | issue = 7| last1 = Fischer | first1 = Marco | last2 = Vögtle | first2 = Fritz }}</ref> Also, it is possible to make dendrimers water-soluble, unlike most [[polymers]], by functionalizing their outer shell with charged species or other [[hydrophilic]] groups. Other controllable properties of dendrimers include [[toxicity]], [[crystallinity]], tecto-dendrimer formation, and [[chirality (chemistry)|chirality]].<ref name=review />
@@ Line 17: / Line 17: @@
 ==Synthesis==
 [[image:538 Arborol.png|thumb|Synthesis to second generation arborol]]
-One of the very first dendrimers, the Newkome dendrimer, was synthesized in 1985. This [[macromolecule]] is also commonly known by the name arborol. The figure outlines the mechanism of the first two generations of arborol through a divergent route (discussed below). The synthesis is started by [[nucleophilic substitution]] of 1-bromopentane by ''triethyl sodiomethanetricarboxylate'' in [[dimethylformamide]] and [[benzene]]. The [[ester]] groups were then [[organic reduction|reduced]] by [[lithium aluminium hydride]] to a [[alcohol|triol]] in a [[protective group|deprotection]] step. Activation of the chain ends was achieved by converting the alcohol groups to [[tosylate]] groups with [[tosyl chloride]] and [[pyridine]]. The tosyl group then served as [[leaving group]]s in another reaction with the tricarboxylate, forming generation two.  Further repetition of the two steps leads to higher generations of arborol.<ref name=newkome />
+One of the very first dendrimers, the Newkome dendrimer, was synthesized in 1985. This [[macromolecule]] is also commonly known by the name arborol. The figure outlines the mechanism of the first two generations of arborol through a divergent route (discussed below). The synthesis is started by [[nucleophilic substitution]] of 1-bromopentane by ''triethyl sodiomethanetricarboxylate'' in [[dimethylformamide]] and [[benzene]]. The [[ester]] groups were then [[organic reduction|reduced]] by [[lithium aluminium hydride]] to a [[alcohol|triol]] in a [[protective group|deprotection]] step. Activation of the chain ends was achieved by converting the alcohol groups to [[tosylate]] groups with [[tosyl chloride]] and [[pyridine]]. The tosyl group then served as [[leaving group]]s in another reaction with the tricarboxylate, forming generation two. Further repetition of the two steps leads to higher generations of arborol.<ref name=newkome />
 [[Poly(amidoamine)]], or PAMAM, is perhaps the most well known dendrimer. The core of PAMAM is a diamine (commonly [[ethylenediamine]]), which is reacted with [[methyl acrylate]], and then another ethylenediamine to make the generation-0 (G-0) PAMAM. Successive reactions create higher generations, which tend to have different properties. Lower generations can be thought of as flexible molecules with no appreciable inner regions, while medium-sized (G-3 or G-4) do have internal space that is essentially separated from the outer shell of the dendrimer. Very large (G-7 and greater) dendrimers can be thought of more like solid particles with very dense surfaces due to the structure of their outer shell. The functional group on the surface of PAMAM dendrimers is ideal for [[click chemistry]], which gives rise to many potential applications.<ref name=bioconj />
-Dendrimers can be considered to have three major portions: a core, an inner shell, and an outer  shell. Ideally, a dendrimer can be synthesized to have different functionality in each of these portions to control properties such as solubility, thermal stability, and attachment of compounds for particular applications. Synthetic processes can also precisely control the size and number of branches on the dendrimer. There are two defined methods of dendrimer synthesis, [[divergent synthesis]] and [[convergent synthesis]]. However, because the actual reactions consist of many steps needed to protect the [[active site]], it is difficult to synthesize dendrimers using either method. This makes dendrimers hard to make and very expensive to purchase. At this time, there are only a few companies that sell dendrimers; [[Polymer Factory Sweden AB]]<ref>Polymer Factory AB, Stockholm, Sweden.[http://www.PolymerFactory.com Polymer Factory]</ref> commercializes biocompatible bis-MPA dendrimers and Dendritech<ref>Dendritech Inc., from Midland, Michigan, USA.[http://www.dendritech.com Dendritech].</ref> is the only kilogram-scale producers of PAMAM dendrimers.  NanoSynthons, LLC<ref>[http://www.Nanosynthons.com Home]. NanoSynthons. Retrieved on 2015-09-29.</ref> from Mount Pleasant, Michigan, USA produces PAMAM dendrimers and other proprietary dendrimers.
+Dendrimers can be considered to have three major portions: a core, an inner shell, and an outer shell. Ideally, a dendrimer can be synthesized to have different functionality in each of these portions to control properties such as solubility, thermal stability, and attachment of compounds for particular applications. Synthetic processes can also precisely control the size and number of branches on the dendrimer. There are two defined methods of dendrimer synthesis, [[divergent synthesis]] and [[convergent synthesis]]. However, because the actual reactions consist of many steps needed to protect the [[active site]], it is difficult to synthesize dendrimers using either method. This makes dendrimers hard to make and very expensive to purchase. At this time, there are only a few companies that sell dendrimers; [[Polymer Factory Sweden AB]]<ref>Polymer Factory AB, Stockholm, Sweden.[http://www.PolymerFactory.com Polymer Factory]</ref> commercializes biocompatible bis-MPA dendrimers and Dendritech<ref>Dendritech Inc., from Midland, Michigan, USA.[http://www.dendritech.com Dendritech].</ref> is the only kilogram-scale producers of PAMAM dendrimers. NanoSynthons, LLC<ref>[http://www.Nanosynthons.com Home]. NanoSynthons. Retrieved on 2015-09-29.</ref> from Mount Pleasant, Michigan, USA produces PAMAM dendrimers and other proprietary dendrimers.
 ===Divergent methods===
 [[image:538 Divergent synthesis.png|thumb|Schematic of divergent synthesis of dendrimers]]
-The dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions, commonly a [[Michael reaction]]. Each step of the reaction must be driven to full completion to prevent mistakes in the dendrimer, which can cause trailing generations (some branches are shorter than the others). Such impurities can impact the functionality and symmetry  of the dendrimer, but are extremely difficult to purify out because the relative size difference between perfect and imperfect dendrimers is very small.<ref name=holister />
+The dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions, commonly a [[Michael reaction]]. Each step of the reaction must be driven to full completion to prevent mistakes in the dendrimer, which can cause trailing generations (some branches are shorter than the others). Such impurities can impact the functionality and symmetry of the dendrimer, but are extremely difficult to purify out because the relative size difference between perfect and imperfect dendrimers is very small.<ref name=holister />
 ===Convergent methods===
@@ Line 39: / Line 39: @@
 ==Applications==
-Applications of dendrimers typically involve conjugating other chemical species to the dendrimer surface that can function as detecting agents (such as a [[dye]] molecule), affinity [[ligands]], targeting components, [[radioligand]]s, [[Contrast medium|imaging agent]]s, or [[pharmaceutically active compounds]]. Dendrimers have very strong potential for these applications because their structure can lead to [[multivalent]] systems. In other words, one dendrimer molecule has hundreds of possible sites to couple to an active species. Researchers aimed to utilize the hydrophobic environments of the dendritic media to conduct photochemical reactions that generate the products that are synthetically challenged. Carboxylic acid and phenol-terminated water-soluble dendrimers were synthesized to establish their utility in drug delivery as well as conducting chemical reactions in their interiors.<ref>{{cite journal|doi=10.1021/jo0503254|pmid=15960506|title=Dendrimers as Photochemical Reaction Media. Photochemical Behavior of Unimolecular and Bimolecular Reactions in Water-Soluble Dendrimers|journal=The Journal of Organic Chemistry|volume=70|issue=13|pages=5062–9|year=2005|last1=Kaanumalle|first1=Lakshmi S.|last2=Ramesh|first2=R.|last3=Murthy Maddipatla|first3=V. S. N.|last4=Nithyanandhan|first4=Jayaraj|last5=Jayaraman|first5=Narayanaswamy|last6=Ramamurthy|first6=V.}}</ref>  This might allow researchers to attach both targeting molecules and drug molecules to the same dendrimer, which could reduce negative side effects of medications on healthy cells.<ref name="bioconj">{{cite book|last=Hermanson|first=Greg T.|title=Bioconjugate Techniques|publisher=Academic Press of Elsevier|location=London|year=2008|edition=2nd|chapter=7|isbn=978-0-12-370501-3}}</ref>
+Applications of dendrimers typically involve conjugating other chemical species to the dendrimer surface that can function as detecting agents (such as a [[dye]] molecule), affinity [[ligands]], targeting components, [[radioligand]]s, [[Contrast medium|imaging agent]]s, or [[pharmaceutically active compounds]]. Dendrimers have very strong potential for these applications because their structure can lead to [[multivalent]] systems. In other words, one dendrimer molecule has hundreds of possible sites to couple to an active species. Researchers aimed to utilize the hydrophobic environments of the dendritic media to conduct photochemical reactions that generate the products that are synthetically challenged. Carboxylic acid and phenol-terminated water-soluble dendrimers were synthesized to establish their utility in drug delivery as well as conducting chemical reactions in their interiors.<ref>{{cite journal|doi=10.1021/jo0503254|pmid=15960506|title=Dendrimers as Photochemical Reaction Media. Photochemical Behavior of Unimolecular and Bimolecular Reactions in Water-Soluble Dendrimers|journal=The Journal of Organic Chemistry|volume=70|issue=13|pages=5062–9|year=2005|last1=Kaanumalle|first1=Lakshmi S.|last2=Ramesh|first2=R.|last3=Murthy Maddipatla|first3=V. S. N.|last4=Nithyanandhan|first4=Jayaraj|last5=Jayaraman|first5=Narayanaswamy|last6=Ramamurthy|first6=V.}}</ref> This might allow researchers to attach both targeting molecules and drug molecules to the same dendrimer, which could reduce negative side effects of medications on healthy cells.<ref name="bioconj">{{cite book|last=Hermanson|first=Greg T.|title=Bioconjugate Techniques|publisher=Academic Press of Elsevier|location=London|year=2008|edition=2nd|chapter=7|isbn=978-0-12-370501-3}}</ref>
 Dendrimers can also be used as a solubilizing agent. Since their introduction in the mid-1980s, this novel class of dendrimer architecture has been a prime candidate for [[host–guest chemistry]].<ref>{{cite journal | title =  Starburst Dendrimers: Molecular-Level Control of Size, Shape, Surface Chemistry, Topology, and Flexibility from Atoms to Macroscopic Matter | journal = [[Angew. Chem. Int. Ed. Engl.]] | year = 1990 | pages = 138–175 | volume = 29 | doi =  10.1002/anie.199001381 | issue =  2| last1 = Tomalia | first1 = Donald A. | last2 = Naylor | first2 = Adel M. | last3 = Goddard | first3 = William A. }}</ref> Dendrimers with hydrophobic core and hydrophilic periphery have shown to exhibit micelle-like behavior and have container properties in solution.<ref>{{cite journal | title = Functional Polymers and Dendrimers: Reactivity, Molecular Architecture, and Interfacial Energy | author = Frechet, J. M. J. | journal = [[Science (journal)|Science]] | year = 1994 | pages = 1710–1715 | volume = 263 | doi = 10.1126/science.8134834 | pmid = 8134834 | issue = 5154| bibcode = 1994Sci...263.1710F }}</ref> The use of dendrimers as unimolecular micelles was proposed by Newkome in 1985.<ref>{{cite journal | title = Water-soluble unimolecular micelles: their potential as drug delivery agents | journal = J. Cont. Rel. | year = 2000 | pages = 121–131 | volume = 65 | issue = 1–2 | doi=10.1016/s0168-3659(99)00245-x| pmid = 10699276 | last1 = Liu | first1 = Mingjun | last2 = Kono | first2 = Kenji | last3 = Fréchet | first3 = Jean M.J }}</ref> This analogy highlighted the utility of dendrimers as solubilizing agents.<ref>{{cite journal | title =  Micelles Part 1. Cascade molecules: a new approach to micelles, A-arborol | journal = [[J. Org. Chem.]] | year = 1985 | pages = 155–158 | volume = 50 | issue = 11 | doi=10.1021/jo00211a052| last1 = Newkome | first1 = George R. | last2 = Yao | first2 = Zhongqi | last3 = Baker | first3 = Gregory R. | last4 = Gupta | first4 = Vinod K. }}</ref> The majority of drugs available in pharmaceutical industry are hydrophobic in nature and this property in particular creates major formulation problems. This drawback of drugs can be ameliorated by dendrimeric scaffolding, which can be used to encapsulate as well as to solubilize the drugs because of the capability of such scaffolds to participate in extensive hydrogen bonding with water.<ref>{{cite journal | title =  Synthesis, characterisation and guest-host properties of inverted unimolecular micelles |author1=Stevelmens, S. |author2=Hest, J. C. M. |author3=Jansen, J. F. G. A. |author4=Boxtel, D. A. F. J. |author5=de Bravander-van den, B. |author6=Miejer, E. W. | journal = [[J Am Chem Soc]] | year = 1996 | pages = 7398–7399 | volume = 118 | doi =  10.1021/ja954207h | issue =  31|url=https://research.tue.nl/nl/publications/synthesis-characterization-and-guesthost-properties-of-inverted-unimolecular-dendritic-micelles(947d0f26-7215-44a3-a4ad-49fba0d24282).html }}</ref><ref>{{cite journal | title =  Dendrimers: Novel Polymeric Nanoarchitectures for Solubility Enhancement Biomacromolecules |author1=Gupta, U |author2=Agashe, H.B. |author3=Asthana, A. |author4=Jain, N.K. | journal = [[Biomacromolecules]] | year = 2006 | pages = 649–658 | volume = 7 | issue = 3 | doi = 10.1021/bm050802s |pmid=16529394 }}</ref><ref>{{cite journal | title = Targeting and Inhibition of Cell Growth by an Engineered Dendritic Nanodevice |  journal = [[J. Med. Chem.]] | year = 2005 | pages = 3729–3735 | volume = 48 | doi = 10.1021/jm040187v |  pmid = 15916424 | issue = 11|  last1 = Thomas |  first1 = Thommey P. |  last2 = Majoros |  first2 = Istvan J. |  last3 = Kotlyar |  first3 = Alina |  last4 = Kukowska-Latallo |  first4 = Jolanta F. |  last5 = Bielinska |  first5 = Anna |  last6 = Myc |  first6 = Andrzej |  last7 = Baker |  first7 = James R. }}</ref><ref>{{cite journal | title =  Pegnology: a review of PEG-ylated systems | journal = Pharmazie | year = 2002 | pages = 5–29 | volume = 57 | issue = 1 | pmid = 11836932| last1 = Bhadra | first1 = D | last2 = Bhadra | first2 = S | last3 = Jain | first3 = P | last4 = Jain | first4 = N. K. }}</ref><ref>{{cite journal | title =  Poly (amidoamine) (PAMAM) dendritic nanostructures for controlled site-specific delivery of anti-inflammatory active ingredient |author1=Asthana, A. |author2=Chauhan, A. S. |author3=Diwan, P. V. |author4=Jain, N. K. | journal = AAPS PharmSciTech | year = 2005 | pages = E536–E542 | volume = 6 | doi =  10.1208/pt060367 | pmid = 16354015 | pmc = 2750401 | issue =  3}}</ref><ref>{{cite journal | title =  A PEGylated, dendritic nanoparticulate carrier of fluorouracil | journal = [[Synthesis (journal)|Synthesis]] | year = 2003 | pages = 111–124| volume = 257 | issue = 1–2 | doi=10.1016/s0378-5173(03)00132-7| pmid = 12711167 | last1 = Bhadra | first1 = D. | last2 = Bhadra | first2 = S. | last3 = Jain | first3 = S. | last4 = Jain | first4 = N.K. }}</ref> Dendrimer labs throughout the planet are persistently trying to manipulate dendrimer's solubilizing trait, in their way to explore dendrimer as drug delivery <ref>{{cite journal | title = "Cascade"- and " Effect of dendrimer on entrapment and release of bioactive from liposomes | journal = Int. J. Pharm. | year = 2002 | pages = 157–162 | volume = 232 | issue = 1–2 | doi = 10.1016/S0378-5173(01)00901-2| pmid = 11790499 | last1 = Khopade | first1 = Ajay J. | last2 = Caruso | first2 = Frank | last3 = Tripathi | first3 = Pushpendra | last4 = Nagaich | first4 = Surekha | last5 = Jain | first5 = Narendra K. }}</ref><ref>{{cite journal | title =  Dendimer-Mediated Solubilization, Formulation Development and in Vitro-in Vivo Assessment of Piroxicam |vauthors=Prajapati RN, Tekade RK, Gupta U, Gajbhiye V, Jain NK | journal = [[Synthesis (journal)|Synthesis]] | year = 2009 | pages = 940–950 | volume = 6 | issue = 3 | doi=10.1021/mp8002489|pmid=19231841 }}</ref> and target specific carrier.<ref>{{cite journal | title =  Dendrimer-mediated transdermal delivery: enhanced bioavailability of indomethacin  | journal = [[Synthesis (journal)|Synthesis]] | year = 2003 | pages = 335–343 | volume = 90 | issue = 3 | doi=10.1016/s0168-3659(03)00200-1| last1 = Chauhan | first1 = Abhay S | last2 = Sridevi | first2 = S | last3 = Chalasani | first3 = Kishore B | last4 = Jain | first4 = Akhlesh K | last5 = Jain | first5 = Sanjay K | last6 = Jain | first6 = N.K | last7 = Diwan | first7 = Prakash V | pmid=12880700}}</ref><ref>{{cite journal | title =  Nanoparticle Targeting of Anticancer Drug Improves Therapeutic Response in Animal Model of Human Epithelial| journal =  Cancer Research| year = 2005 | pages = 5317–5324 | volume = 65 | issue = 12 | doi=10.1158/0008-5472.can-04-3921| last1 = Kukowska-Latallo | first1 = J. F. | pmid=15958579| doi-access = free }}</ref><ref>{{cite journal | title =  Design and Function of a Dendrimer-Based Therapeutic nanodevice targeted to tumor cells through the folate receptor | journal = [[Synthesis (journal)|Synthesis]] | year = 2002 | pages = 1310–1316 | volume = 19 | issue = 9 | doi=10.1023/a:1020398624602| pmid = 12403067 | last1 = Quintana | first1 = Antonio | last2 = Raczka | first2 = Ewa | last3 = Piehler | first3 = Lars | last4 = Lee | first4 = Inhan | last5 = Myc | first5 = Andrzej | last6 = Majoros | first6 = Istvan | last7 = Patri | first7 = Anil K. | last8 = Thomas | first8 = Thommey | last9 = Mulé | first9 = James | last10 = Baker Jr. | first10 = James R. | url = https://deepblue.lib.umich.edu/bitstream/2027.42/41493/1/11095_2004_Article_378868.pdf | hdl = 2027.42/41493 }}</ref>
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 Drug attachment to the dendrimer may be (1) a covalent attachment or conjugation to the external surface of the dendrimer forming a dendrimer prodrug, (2) ionic coordination to charged outer functional groups, or (3) micelle-like encapsulation of a drug via a dendrimer-drug supramolecular assembly.<ref>{{Cite journal|last=Morgan|first=M. T.|last2=Nakanishi|first2=Y.|last3=Kroll|first3=D. J.|last4=Griset|first4=A. P.|last5=Carnahan|first5=M. A.|last6=Wathier|first6=M.|last7=Oberlies|first7=N. H.|last8=Manikumar|first8=G.|last9=Wani|first9=M. C.|last10=Grinstaff|first10=M. W.|date=2006-12-15|title=Dendrimer-Encapsulated Camptothecins: Increased Solubility, Cellular Uptake, and Cellular Retention Affords Enhanced Anticancer Activity In vitro|url=http://cancerres.aacrjournals.org/cgi/doi/10.1158/0008-5472.CAN-06-2066|journal=Cancer Research|language=en|volume=66|issue=24|pages=11913–11921|doi=10.1158/0008-5472.CAN-06-2066|issn=0008-5472}}</ref><ref>{{Cite journal|last=Tekade|first=Rakesh Kumar|last2=Dutta|first2=Tathagata|last3=Gajbhiye|first3=Virendra|last4=Jain|first4=Narendra Kumar|date=2009-06|title=Exploring dendrimer towards dual drug delivery: pH responsive simultaneous drug-release kinetics|url=http://www.tandfonline.com/doi/full/10.1080/02652040802312572|journal=Journal of Microencapsulation|language=en|volume=26|issue=4|pages=287–296|doi=10.1080/02652040802312572|issn=0265-2048}}</ref> In the case of a dendrimer prodrug structure, linking of a drug to a dendrimer may be direct or linker-mediated depending on desired release kinetics. Such a linker may be pH-sensitive, enzyme catalyzed, or a disulfide bridge. The wide range of terminal functional groups available for dendrimers allows for many different types of linker chemistries, providing yet another tunable component on the system. Key parameters to consider for linker chemistry are (1) release mechanism upon arrival to the target site, whether that be within the cell or in a certain organ system, (2) drug-dendrimer spacing so as to prevent lipophilic drugs from folding into the dendrimer, and (3) linker degradability and post-release trace modifications on drugs.<ref>{{Cite journal|last=Leong|first=Nathania J.|last2=Mehta|first2=Dharmini|last3=McLeod|first3=Victoria M.|last4=Kelly|first4=Brian D.|last5=Pathak|first5=Rashmi|last6=Owen|first6=David J.|last7=Porter|first7=Christopher J.H.|last8=Kaminskas|first8=Lisa M.|date=2018-09|title=Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats|url=https://linkinghub.elsevier.com/retrieve/pii/S0022354918303174|journal=Journal of Pharmaceutical Sciences|language=en|volume=107|issue=9|pages=2509–2513|doi=10.1016/j.xphs.2018.05.013}}</ref><ref>{{Cite journal|last=da Silva Santos|first=Soraya|last2=Igne Ferreira|first2=Elizabeth|last3=Giarolla|first3=Jeanine|date=2016-05-31|title=Dendrimer Prodrugs|url=http://www.mdpi.com/1420-3049/21/6/686|journal=Molecules|language=en|volume=21|issue=6|pages=686|doi=10.3390/molecules21060686|issn=1420-3049|pmc=PMC6274429|pmid=27258239}}</ref>
-Polyethylene glycol (PEG) is a common modification for dendrimers to modify surface charge and circulation time. The influence of surface charge is present most heavily in cationic dendrimers, such as amine-terminal dendrimers. These have a propensity to interact with membranes with anionic charge such as cell membranes. Polycationic dendrimers have shown cytotoxicity in vivo leading to large changes in Caco-2 membrane permeability.<ref>{{Cite journal|last=Kaminskas|first=Lisa M|last2=Boyd|first2=Ben J|last3=Porter|first3=Christopher JH|date=2011-08|title=Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties|url=https://www.futuremedicine.com/doi/10.2217/nnm.11.67|journal=Nanomedicine|language=en|volume=6|issue=6|pages=1063–1084|doi=10.2217/nnm.11.67|issn=1743-5889}}</ref> PEGylation caps amine groups and results in lower cytotoxicity and red blood cell hemolysis.<ref name=":0">{{Cite journal|last=Luong|first=Duy|last2=Kesharwani|first2=Prashant|last3=Deshmukh|first3=Rahul|last4=Mohd Amin|first4=Mohd Cairul Iqbal|last5=Gupta|first5=Umesh|last6=Greish|first6=Khaled|last7=Iyer|first7=Arun K.|date=2016-10|title=PEGylated PAMAM dendrimers: Enhancing efficacy and mitigating toxicity for effective anticancer drug and gene delivery|url=https://linkinghub.elsevier.com/retrieve/pii/S1742706116303300|journal=Acta Biomaterialia|language=en|volume=43|pages=14–29|doi=10.1016/j.actbio.2016.07.015}}</ref> Additionally, studies have found that PEGylation of dendrimers results in higher drug loading, slower drug release, longer circulation times in vivo, and lower toxicity in comparison to counterparts without PEG modifications.<ref name=":1">{{Cite journal|last=Singh|first=Prateek|last2=Gupta|first2=Umesh|last3=Asthana|first3=Abhay|last4=Jain|first4=Narendra K.|date=2008-11-19|title=Folate and Folate−PEG−PAMAM Dendrimers: Synthesis, Characterization, and Targeted Anticancer Drug Delivery Potential in Tumor Bearing Mice|url=https://pubs.acs.org/doi/10.1021/bc800125u|journal=Bioconjugate Chemistry|language=en|volume=19|issue=11|pages=2239–2252|doi=10.1021/bc800125u|issn=1043-1802}}</ref><ref name=":0" />
+[[Polyethylene glycol]] (PEG) is a common modification for dendrimers to modify surface charge and circulation time. The influence of surface charge is present most heavily in cationic dendrimers, such as amine-terminal dendrimers. These have a propensity to interact with membranes with anionic charge such as cell membranes. Polycationic dendrimers have shown cytotoxicity [[in vivo]] leading to large changes in Caco-2 membrane permeability.<ref>{{Cite journal|last=Kaminskas|first=Lisa M|last2=Boyd|first2=Ben J|last3=Porter|first3=Christopher JH|date=2011-08|title=Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties|url=https://www.futuremedicine.com/doi/10.2217/nnm.11.67|journal=Nanomedicine|language=en|volume=6|issue=6|pages=1063–1084|doi=10.2217/nnm.11.67|issn=1743-5889}}</ref> [[PEGylation]] caps amine groups and results in lower cytotoxicity and red blood cell hemolysis.<ref name=":0">{{Cite journal|last=Luong|first=Duy|last2=Kesharwani|first2=Prashant|last3=Deshmukh|first3=Rahul|last4=Mohd Amin|first4=Mohd Cairul Iqbal|last5=Gupta|first5=Umesh|last6=Greish|first6=Khaled|last7=Iyer|first7=Arun K.|date=2016-10|title=PEGylated PAMAM dendrimers: Enhancing efficacy and mitigating toxicity for effective anticancer drug and gene delivery|url=https://linkinghub.elsevier.com/retrieve/pii/S1742706116303300|journal=Acta Biomaterialia|language=en|volume=43|pages=14–29|doi=10.1016/j.actbio.2016.07.015}}</ref> Additionally, studies have found that PEGylation of dendrimers results in higher drug loading, slower drug release, longer circulation times in vivo, and lower toxicity in comparison to counterparts without PEG modifications.<ref name=":1">{{Cite journal|last=Singh|first=Prateek|last2=Gupta|first2=Umesh|last3=Asthana|first3=Abhay|last4=Jain|first4=Narendra K.|date=2008-11-19|title=Folate and Folate−PEG−PAMAM Dendrimers: Synthesis, Characterization, and Targeted Anticancer Drug Delivery Potential in Tumor Bearing Mice|url=https://pubs.acs.org/doi/10.1021/bc800125u|journal=Bioconjugate Chemistry|language=en|volume=19|issue=11|pages=2239–2252|doi=10.1021/bc800125u|issn=1043-1802}}</ref><ref name=":0" />
 Numerous targeting moieties have been used to modify dendrimer biodistribution and allow for targeting to specific organs.
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 Folate receptors are overexpressed in tumor cells and are therefore promising targets for localized drug delivery of chemotherapeutics. Folic acid conjugation to PAMAM dendrimers has been shown to increase targeting and decrease off-target toxicity while maintaining on-target cytotoxicity of chemotherapeutics such as methotrexate, in mouse models of cancer.<ref name=":1" /><ref>{{Cite journal|last=Majoros|first=István J.|last2=Williams|first2=Christopher R.|last3=Becker|first3=Andrew|last4=Baker|first4=James R.|date=2009-09|title=Methotrexate delivery via folate targeted dendrimer-based nanotherapeutic platform: Methotrexate delivery via nanotherapeutic platform|url=http://doi.wiley.com/10.1002/wnan.37|journal=Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology|language=en|volume=1|issue=5|pages=502–510|doi=10.1002/wnan.37|pmc=PMC2944777|pmid=20049813}}</ref>
-Antibody-mediated targeting of dendrimers to cell targets has also shown promise. As epidermal growth factor receptors (EGFRs) are often overexpressed in brain tumors, they are a convenient target for site-specific drug delivery. The delivery of boron to cancerous cells is important to realize the full potential of neutron capture therapy, a cancer treatment which requires a large concentration of boron in cancerous cells and a low concentration in healthy cells. A boronated dendrimer conjugated with a monoclonal antibody drug that targets EGFRs was used in rats to successfully deliver boron to cancerous cells.<ref>{{Cite journal|last=Wu|first=Gong|last2=Barth|first2=Rolf F.|last3=Yang|first3=Weilian|last4=Chatterjee|first4=Madhumita|last5=Tjarks|first5=Werner|last6=Ciesielski|first6=Michael J.|last7=Fenstermaker|first7=Robert A.|date=2004-01|title=Site-Specific Conjugation of Boron-Containing Dendrimers to Anti-EGF Receptor Monoclonal Antibody Cetuximab (IMC-C225) and Its Evaluation as a Potential Delivery Agent for Neutron Capture Therapy|url=https://pubs.acs.org/doi/10.1021/bc0341674|journal=Bioconjugate Chemistry|language=en|volume=15|issue=1|pages=185–194|doi=10.1021/bc0341674|issn=1043-1802}}</ref>
+Antibody-mediated targeting of dendrimers to cell targets has also shown promise. As [[Epidermal growth factor receptor|epidermal growth factor receptors]] (EGFRs) are often overexpressed in brain tumors, they are a convenient target for site-specific drug delivery. The delivery of boron to cancerous cells is important to realize the full potential of neutron capture therapy, a cancer treatment which requires a large concentration of boron in cancerous cells and a low concentration in healthy cells. A boronated dendrimer conjugated with a monoclonal antibody drug that targets EGFRs was used in rats to successfully deliver boron to cancerous cells.<ref>{{Cite journal|last=Wu|first=Gong|last2=Barth|first2=Rolf F.|last3=Yang|first3=Weilian|last4=Chatterjee|first4=Madhumita|last5=Tjarks|first5=Werner|last6=Ciesielski|first6=Michael J.|last7=Fenstermaker|first7=Robert A.|date=2004-01|title=Site-Specific Conjugation of Boron-Containing Dendrimers to Anti-EGF Receptor Monoclonal Antibody Cetuximab (IMC-C225) and Its Evaluation as a Potential Delivery Agent for Neutron Capture Therapy|url=https://pubs.acs.org/doi/10.1021/bc0341674|journal=Bioconjugate Chemistry|language=en|volume=15|issue=1|pages=185–194|doi=10.1021/bc0341674|issn=1043-1802}}</ref>
-Modifying nanoparticle dendrimers with peptides has also been successful at targeted destruction of colorectal (HCT-116) cancer cells in a co-culture scenario. It has been shown that these peptides increase in functionality when paired with dendrimers. Specifically, gemcitabine-loaded YIGSR-CMCht/PAMAM, a unique kind of dendrimer nanoparticle, induces a targeted mortality on these cancer cells. This is performed via selective interaction with laminin receptors. Peptide dendrimers may be employed in the future to precisely target cancer cells and deliver chemotherapeutic agents.<ref>{{Cite journal|last=Carvalho|first=Mariana R.|last2=Carvalho|first2=Cristiana R.|last3=Maia|first3=F. Raquel|last4=Caballero|first4=David|last5=Kundu|first5=Subhas C.|last6=Reis|first6=Rui L.|last7=Oliveira|first7=Joaquim M.|date=2019-11|title=Peptide‐Modified Dendrimer Nanoparticles for Targeted Therapy of Colorectal Cancer|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/adtp.201900132|journal=Advanced Therapeutics|language=en|volume=2|issue=11|pages=1900132|doi=10.1002/adtp.201900132|issn=2366-3987}}</ref>
+Modifying [[nanoparticle]] dendrimers with [[Peptide|peptides]] has also been successful at targeted destruction of colorectal ([[HCT116 cells|HCT-116]]) cancer cells in a co-culture scenario. It has been shown that these peptides increase in functionality when paired with dendrimers. Specifically, gemcitabine-loaded YIGSR-CMCht/PAMAM, a unique kind of dendrimer nanoparticle, induces a targeted mortality on these cancer cells. This is performed via selective interaction with [[laminin]] receptors. Peptide dendrimers may be employed in the future to precisely target cancer cells and deliver chemotherapeutic agents.<ref>{{Cite journal|last=Carvalho|first=Mariana R.|last2=Carvalho|first2=Cristiana R.|last3=Maia|first3=F. Raquel|last4=Caballero|first4=David|last5=Kundu|first5=Subhas C.|last6=Reis|first6=Rui L.|last7=Oliveira|first7=Joaquim M.|date=2019-11|title=Peptide‐Modified Dendrimer Nanoparticles for Targeted Therapy of Colorectal Cancer|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/adtp.201900132|journal=Advanced Therapeutics|language=en|volume=2|issue=11|pages=1900132|doi=10.1002/adtp.201900132|issn=2366-3987}}</ref>
-The cellular uptake mechanism of dendrimers can also be tuned using chemical targeting modifications. Non-modified PAMAM-G4 dendrimer is taken up into activated microglia by fluid phase endocytosis. Mannose modification of hydroxyl PAMAM-G4 dendrimers was able to change the mechanism of internalization to mannose-receptor (CD206) mediated endocytosis. Additionally, mannose modification was able to change the biodistribution in the rest of the body in rabbits.<ref>{{Cite journal|last=Sharma|first=Anjali|last2=Porterfield|first2=Joshua E.|last3=Smith|first3=Elizabeth|last4=Sharma|first4=Rishi|last5=Kannan|first5=Sujatha|last6=Kannan|first6=Rangaramanujam M.|date=2018-08|title=Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model|url=https://linkinghub.elsevier.com/retrieve/pii/S0168365918303298|journal=Journal of Controlled Release|language=en|volume=283|pages=175–189|doi=10.1016/j.jconrel.2018.06.003|pmc=PMC6091673|pmid=29883694}}</ref>
+The cellular uptake mechanism of dendrimers can also be tuned using chemical targeting modifications. Non-modified PAMAM-G4 dendrimer is taken up into activated microglia by fluid phase endocytosis. Mannose modification of hydroxyl PAMAM-G4 dendrimers was able to change the mechanism of internalization to mannose-receptor (CD206) mediated endocytosis. Additionally, mannose modification was able to change the [[biodistribution]] in the rest of the body in rabbits.<ref>{{Cite journal|last=Sharma|first=Anjali|last2=Porterfield|first2=Joshua E.|last3=Smith|first3=Elizabeth|last4=Sharma|first4=Rishi|last5=Kannan|first5=Sujatha|last6=Kannan|first6=Rangaramanujam M.|date=2018-08|title=Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model|url=https://linkinghub.elsevier.com/retrieve/pii/S0168365918303298|journal=Journal of Controlled Release|language=en|volume=283|pages=175–189|doi=10.1016/j.jconrel.2018.06.003|pmc=PMC6091673|pmid=29883694}}</ref>
 ==== Pharmacokinetics and Pharmacodynamics ====
-Dendrimers have the potential to completely change the pharmacokinetic and pharmacodynamic (PK/PD) profiles of a drug. As carriers, the PK/PD is no longer determined by the drug itself but by the dendrimer’s localization, drug release, and dendrimer excretion. ADME properties are very highly tunable by varying size, structure, and surface characteristics. While G9 dendrimers distribute very heavily to the liver and spleen, G6 dendrimers tend to distribute more broadly. As molecular weight increases, urinary clearance and plasma clearance decrease while terminal half life increases.<ref>{{Cite journal|last=Kaminskas|first=Lisa M|last2=Boyd|first2=Ben J|last3=Porter|first3=Christopher JH|date=2011-08|title=Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties|url=https://www.futuremedicine.com/doi/10.2217/nnm.11.67|journal=Nanomedicine|language=en|volume=6|issue=6|pages=1063–1084|doi=10.2217/nnm.11.67|issn=1743-5889}}</ref>
+Dendrimers have the potential to completely change the [[Pharmacokinetics|pharmacokinetic]] and [[Pharmacodynamics|pharmacodynamic]] (PK/PD) profiles of a drug. As carriers, the PK/PD is no longer determined by the drug itself but by the dendrimer’s localization, drug release, and dendrimer excretion. [[ADME]] properties are very highly tunable by varying size, structure, and surface characteristics. While G9 dendrimers distribute very heavily to the liver and spleen, G6 dendrimers tend to distribute more broadly. As molecular weight increases, urinary clearance and plasma clearance decrease while terminal half life increases.<ref>{{Cite journal|last=Kaminskas|first=Lisa M|last2=Boyd|first2=Ben J|last3=Porter|first3=Christopher JH|date=2011-08|title=Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties|url=https://www.futuremedicine.com/doi/10.2217/nnm.11.67|journal=Nanomedicine|language=en|volume=6|issue=6|pages=1063–1084|doi=10.2217/nnm.11.67|issn=1743-5889}}</ref>
 ==== Routes of Delivery ====
-In order to increase patient compliance with prescribed treatment, delivery of drugs orally is often preferred to other routes of drug administration. However oral bioavailability of many drugs tends to be very low. Dendrimers can be used to increase the solubility and stability of orally administered drugs and increase drug penetration through the intestinal membrane.<ref>{{Cite journal|last=Csaba|first=Noémi|last2=Garcia-Fuentes|first2=Marcos|last3=Alonso|first3=María José|date=2006-07|title=The performance of nanocarriers for transmucosal drug delivery|url=http://www.tandfonline.com/doi/full/10.1517/17425247.3.4.463|journal=Expert Opinion on Drug Delivery|language=en|volume=3|issue=4|pages=463–478|doi=10.1517/17425247.3.4.463|issn=1742-5247}}</ref> The bioavailability of PAMAM dendrimers conjugated to a chemotherapeutic has been studied in mice; it was found that around 9% of dendrimer administered orally was found intact in circulation and that minimal dendrimer degradation occurred in the gut.<ref>{{Cite journal|last=Thiagarajan|first=Giridhar|last2=Sadekar|first2=Shraddha|last3=Greish|first3=Khaled|last4=Ray|first4=Abhijit|last5=Ghandehari|first5=Hamidreza|date=2013-03-04|title=Evidence of Oral Translocation of Anionic G6.5 Dendrimers in Mice|url=https://pubs.acs.org/doi/10.1021/mp300436c|journal=Molecular Pharmaceutics|language=en|volume=10|issue=3|pages=988–998|doi=10.1021/mp300436c|issn=1543-8384|pmc=PMC3715149|pmid=23286733}}</ref>
+In order to increase patient compliance with prescribed treatment, delivery of drugs orally is often preferred to other routes of drug administration. However oral [[bioavailability]] of many drugs tends to be very low. Dendrimers can be used to increase the solubility and stability of orally administered drugs and increase drug penetration through the intestinal membrane.<ref>{{Cite journal|last=Csaba|first=Noémi|last2=Garcia-Fuentes|first2=Marcos|last3=Alonso|first3=María José|date=2006-07|title=The performance of nanocarriers for transmucosal drug delivery|url=http://www.tandfonline.com/doi/full/10.1517/17425247.3.4.463|journal=Expert Opinion on Drug Delivery|language=en|volume=3|issue=4|pages=463–478|doi=10.1517/17425247.3.4.463|issn=1742-5247}}</ref> The bioavailability of PAMAM dendrimers conjugated to a chemotherapeutic has been studied in mice; it was found that around 9% of dendrimer administered orally was found intact in circulation and that minimal dendrimer degradation occurred in the gut.<ref>{{Cite journal|last=Thiagarajan|first=Giridhar|last2=Sadekar|first2=Shraddha|last3=Greish|first3=Khaled|last4=Ray|first4=Abhijit|last5=Ghandehari|first5=Hamidreza|date=2013-03-04|title=Evidence of Oral Translocation of Anionic G6.5 Dendrimers in Mice|url=https://pubs.acs.org/doi/10.1021/mp300436c|journal=Molecular Pharmaceutics|language=en|volume=10|issue=3|pages=988–998|doi=10.1021/mp300436c|issn=1543-8384|pmc=PMC3715149|pmid=23286733}}</ref>
-Intravenous dendrimer delivery shows promising potential in acting as gene vectors to deliver genes to various organs in the body, and even tumors. One study found that through intravenous injection, a combination of PPI dendrimers and gene complexes resulted in gene expression in the liver, and another study showed that a similar injection regressed the growth of tumors in observed animals.
+Intravenous dendrimer delivery shows promising potential in acting as gene vectors to deliver genes to various organs in the body, and even tumors. One study found that through intravenous injection, a combination of PPI dendrimers and gene complexes resulted in gene expression in the liver, and another study showed that a similar injection regressed the growth of tumors in observed animals.<ref>{{Cite journal|last=Dufes|first=C|last2=Uchegbu|first2=I|last3=Schatzlein|first3=A|date=2005-12-14|title=Dendrimers in gene delivery|url=https://linkinghub.elsevier.com/retrieve/pii/S0169409X05001936|journal=Advanced Drug Delivery Reviews|language=en|volume=57|issue=15|pages=2177–2202|doi=10.1016/j.addr.2005.09.017}}</ref><ref>{{Cite journal|last=Dufès|first=Christine|last2=Keith|first2=W. Nicol|last3=Bilsland|first3=Alan|last4=Proutski|first4=Irina|last5=Uchegbu|first5=Ijeoma F.|last6=Schätzlein|first6=Andreas G.|date=2005-09-15|title=Synthetic Anticancer Gene Medicine Exploits Intrinsic Antitumor Activity of Cationic Vector to Cure Established Tumors|url=http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-04-4402|journal=Cancer Research|language=en|volume=65|issue=18|pages=8079–8084|doi=10.1158/0008-5472.CAN-04-4402|issn=0008-5472}}</ref>
-The primary obstacle to transdermal drug delivery is the epidermis. Hydrophobic drugs have a very difficult time penetrating the skin layer, as they partition heavily into skin oils. Recently, PAMAM dendrimers have been used as delivery vehicles for NSAIDS to increase hydrophilicity, allowing greater drug penetration. These modifications act as polymeric transdermal enhancers allowing drugs to more easily penetrate the skin barrier.
+The primary obstacle to transdermal drug delivery is the epidermis. Hydrophobic drugs have a very difficult time penetrating the skin layer, as they partition heavily into skin oils. Recently, PAMAM dendrimers have been used as delivery vehicles for [[Nonsteroidal anti-inflammatory drug|NSAIDS]] to increase hydrophilicity, allowing greater drug penetration.<ref>{{Cite journal|last=Yiyun|first=Cheng|last2=Na|first2=Man|last3=Tongwen|first3=Xu|last4=Rongqiang|first4=Fu|last5=Xueyuan|first5=Wang|last6=Xiaomin|first6=Wang|last7=Longping|first7=Wen|date=2007-03|title=Transdermal Delivery of Nonsteroidal Anti-Inflammatory Drugs Mediated by Polyamidoamine (PAMAM) Dendrimers**Cheng Yiyun and Wen Longping designed the experiments and wrote this manuscript, Man Na and other coauthors did the experiments and analyzed the data.|url=https://linkinghub.elsevier.com/retrieve/pii/S0022354916322092|journal=Journal of Pharmaceutical Sciences|language=en|volume=96|issue=3|pages=595–602|doi=10.1002/jps.20745}}</ref> These modifications act as polymeric transdermal enhancers allowing drugs to more easily penetrate the skin barrier.
-Dendrimers may also act as new ophthalmic vehicles for drug delivery, radically different from the polymers currently used for this purpose. A study by Vanndamme and Bobeck used PAMAM dendrimers as ophthalmic delivery vehicles in rabbits for two model drugs and measured the ocular residence time of this delivery to be comparable and in some cases greater than current bioadhesive polymers used in ocular delivery. This indicates that administered drugs were more active and had increased bioavailability when delivered via dendrimers. Additionally, photocurable, drug-eluting dendrimer-hyaluronic acid hydrogels have been used as corneal sutures applied directly to the eye. These hydrogel sutures have shown efficacy as a medical device in rabbit models that surpasses traditional sutures and minimizes corneal scarring.<ref>{{Cite journal|last=Kannan|first=RangaramanujamM|last2=Xu|first2=Qingguo|last3=Kambhampati|first3=SivaP|date=2013|title=Nanotechnology approaches for ocular drug delivery|url=http://www.meajo.org/text.asp?2013/20/1/26/106384|journal=Middle East African Journal of Ophthalmology|language=en|volume=20|issue=1|pages=26|doi=10.4103/0974-9233.106384|issn=0974-9233|pmc=PMC3617524|pmid=23580849}}</ref>
+Dendrimers may also act as new [[Ophthalmic drug administration|ophthalmic]] vehicles for drug delivery, radically different from the polymers currently used for this purpose. A study by Vanndamme and Bobeck used PAMAM dendrimers as ophthalmic delivery vehicles in rabbits for two model drugs and measured the ocular residence time of this delivery to be comparable and in some cases greater than current [[bioadhesive]] polymers used in ocular delivery.<ref>{{Cite journal|last=Vandamme|first=Th.F.|last2=Brobeck|first2=L.|date=2005-01|title=Poly(amidoamine) dendrimers as ophthalmic vehicles for ocular delivery of pilocarpine nitrate and tropicamide|url=https://linkinghub.elsevier.com/retrieve/pii/S0168365904004456|journal=Journal of Controlled Release|language=en|volume=102|issue=1|pages=23–38|doi=10.1016/j.jconrel.2004.09.015}}</ref> This indicates that administered drugs were more active and had increased bioavailability when delivered via dendrimers. Additionally, photo-curable, drug-eluting dendrimer-hyaluronic acid hydrogels have been used as corneal sutures applied directly to the eye. These hydrogel sutures have shown efficacy as a medical device in rabbit models that surpasses traditional sutures and minimizes corneal scarring.<ref>{{Cite journal|last=Kannan|first=RangaramanujamM|last2=Xu|first2=Qingguo|last3=Kambhampati|first3=SivaP|date=2013|title=Nanotechnology approaches for ocular drug delivery|url=http://www.meajo.org/text.asp?2013/20/1/26/106384|journal=Middle East African Journal of Ophthalmology|language=en|volume=20|issue=1|pages=26|doi=10.4103/0974-9233.106384|issn=0974-9233|pmc=PMC3617524|pmid=23580849}}</ref>
 ==== Brain Drug Delivery ====
-Dendrimer drug delivery has shown major promise as a potential solution for many traditionally difficult drug delivery problems. In the case of drug delivery to the brain, dendrimers are able to uniquely take advantage of the EPR effect and blood-brain-barrier impairment to cross the blood-brain barrier (BBB) effectively in vivo. For example, hydroxyl-terminated PAMAM dendrimers possess an intrinsic targeting ability to inflamed macrophages in the brain, verified using fluorescently labeled neutral generation dendrimers in a rabbit model of cerebral palsy.<ref name=":2">{{Cite journal|last=Dai|first=Hui|last2=Navath|first2=Raghavendra S|last3=Balakrishnan|first3=Bindu|last4=Guru|first4=Bharath Raja|last5=Mishra|first5=Manoj K|last6=Romero|first6=Roberto|last7=Kannan|first7=Rangaramanujam M|last8=Kannan|first8=Sujatha|date=2010-11|title=Intrinsic targeting of inflammatory cells in the brain by polyamidoamine dendrimers upon subarachnoid administration|url=https://www.futuremedicine.com/doi/10.2217/nnm.10.89|journal=Nanomedicine|language=en|volume=5|issue=9|pages=1317–1329|doi=10.2217/nnm.10.89|issn=1743-5889|pmc=PMC3095441|pmid=21128716}}</ref> This intrinsic targeting has enabled drug delivery in a variety of conditions, ranging from cerebral palsy and other neuroinflammatory disorders to traumatic brain injury and hypothermic circulatory arrest, across a variety of animal models ranging from mice and rabbits to canines.<ref>{{Cite journal|last=Kannan|first=Gokul|last2=Kambhampati|first2=Siva P.|last3=Kudchadkar|first3=Sapna R.|date=2017-10|title=Effect of anesthetics on microglial activation and nanoparticle uptake: Implications for drug delivery in traumatic brain injury|url=https://linkinghub.elsevier.com/retrieve/pii/S0168365917301438|journal=Journal of Controlled Release|language=en|volume=263|pages=192–199|doi=10.1016/j.jconrel.2017.03.032}}</ref><ref>{{Cite journal|last=Kannan|first=S.|last2=Dai|first2=H.|last3=Navath|first3=R. S.|last4=Balakrishnan|first4=B.|last5=Jyoti|first5=A.|last6=Janisse|first6=J.|last7=Romero|first7=R.|last8=Kannan|first8=R. M.|date=2012-04-18|title=Dendrimer-Based Postnatal Therapy for Neuroinflammation and Cerebral Palsy in a Rabbit Model|url=https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.3003162|journal=Science Translational Medicine|language=en|volume=4|issue=130|pages=130ra46–130ra46|doi=10.1126/scitranslmed.3003162|issn=1946-6234|pmc=PMC3492056|pmid=22517883}}</ref><ref>{{Cite journal|last=Mishra|first=Manoj K.|last2=Beaty|first2=Claude A.|last3=Lesniak|first3=Wojciech G.|last4=Kambhampati|first4=Siva P.|last5=Zhang|first5=Fan|last6=Wilson|first6=Mary A.|last7=Blue|first7=Mary E.|last8=Troncoso|first8=Juan C.|last9=Kannan|first9=Sujatha|last10=Johnston|first10=Michael V.|last11=Baumgartner|first11=William A.|date=2014-03-25|title=Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest|url=https://pubs.acs.org/doi/10.1021/nn404872e|journal=ACS Nano|language=en|volume=8|issue=3|pages=2134–2147|doi=10.1021/nn404872e|issn=1936-0851|pmc=PMC4004292|pmid=24499315}}</ref> Dendrimer uptake into the brain correlates with severity of inflammation and BBB impairment and it is believed that the BBB impairment is the key driving factor allowing dendrimer penetration.<ref>{{Cite journal|last=Nance|first=Elizabeth|last2=Kambhampati|first2=Siva P.|last3=Smith|first3=Elizabeth S.|last4=Zhang|first4=Zhi|last5=Zhang|first5=Fan|last6=Singh|first6=Sarabdeep|last7=Johnston|first7=Michael V.|last8=Kannan|first8=Rangaramanujam M.|last9=Blue|first9=Mary E.|last10=Kannan|first10=Sujatha|date=2017-12|title=Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome|url=https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-1004-5|journal=Journal of Neuroinflammation|language=en|volume=14|issue=1|pages=252|doi=10.1186/s12974-017-1004-5|issn=1742-2094|pmc=PMC5735803|pmid=29258545}}</ref><ref name=":2" /> Localization is heavily skewed towards activated microglia. Dendrimer-conjugated N-acetyl cysteine has shown efficacy in vivo as an anti-inflammatory at more than 1000-fold lower dose than free drug on a drug basis, reversing the phenotype of cerebral palsy, Rett syndrome, macular degeneration and other inflammatory diseases.<ref name=":2" />
+Dendrimer drug delivery has shown major promise as a potential solution for many traditionally difficult drug delivery problems. In the case of drug delivery to the brain, dendrimers are able to uniquely take advantage of the [[Enhanced permeability and retention effect|EPR effect]] and [[Blood–brain barrier|blood-brain barrier]] (BBB) impairment to cross the BBB effectively in vivo. For example, hydroxyl-terminated PAMAM dendrimers possess an intrinsic targeting ability to inflamed [[Macrophage|macrophages]] in the brain, verified using fluorescently labeled neutral generation dendrimers in a rabbit model of [[cerebral palsy]].<ref name=":2">{{Cite journal|last=Dai|first=Hui|last2=Navath|first2=Raghavendra S|last3=Balakrishnan|first3=Bindu|last4=Guru|first4=Bharath Raja|last5=Mishra|first5=Manoj K|last6=Romero|first6=Roberto|last7=Kannan|first7=Rangaramanujam M|last8=Kannan|first8=Sujatha|date=2010-11|title=Intrinsic targeting of inflammatory cells in the brain by polyamidoamine dendrimers upon subarachnoid administration|url=https://www.futuremedicine.com/doi/10.2217/nnm.10.89|journal=Nanomedicine|language=en|volume=5|issue=9|pages=1317–1329|doi=10.2217/nnm.10.89|issn=1743-5889|pmc=PMC3095441|pmid=21128716}}</ref> This intrinsic targeting has enabled drug delivery in a variety of conditions, ranging from cerebral palsy and other neuroinflammatory disorders to traumatic brain injury and hypothermic circulatory arrest, across a variety of animal models ranging from mice and rabbits to canines.<ref>{{Cite journal|last=Kannan|first=Gokul|last2=Kambhampati|first2=Siva P.|last3=Kudchadkar|first3=Sapna R.|date=2017-10|title=Effect of anesthetics on microglial activation and nanoparticle uptake: Implications for drug delivery in traumatic brain injury|url=https://linkinghub.elsevier.com/retrieve/pii/S0168365917301438|journal=Journal of Controlled Release|language=en|volume=263|pages=192–199|doi=10.1016/j.jconrel.2017.03.032}}</ref><ref>{{Cite journal|last=Kannan|first=S.|last2=Dai|first2=H.|last3=Navath|first3=R. S.|last4=Balakrishnan|first4=B.|last5=Jyoti|first5=A.|last6=Janisse|first6=J.|last7=Romero|first7=R.|last8=Kannan|first8=R. M.|date=2012-04-18|title=Dendrimer-Based Postnatal Therapy for Neuroinflammation and Cerebral Palsy in a Rabbit Model|url=https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.3003162|journal=Science Translational Medicine|language=en|volume=4|issue=130|pages=130ra46–130ra46|doi=10.1126/scitranslmed.3003162|issn=1946-6234|pmc=PMC3492056|pmid=22517883}}</ref><ref>{{Cite journal|last=Mishra|first=Manoj K.|last2=Beaty|first2=Claude A.|last3=Lesniak|first3=Wojciech G.|last4=Kambhampati|first4=Siva P.|last5=Zhang|first5=Fan|last6=Wilson|first6=Mary A.|last7=Blue|first7=Mary E.|last8=Troncoso|first8=Juan C.|last9=Kannan|first9=Sujatha|last10=Johnston|first10=Michael V.|last11=Baumgartner|first11=William A.|date=2014-03-25|title=Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest|url=https://pubs.acs.org/doi/10.1021/nn404872e|journal=ACS Nano|language=en|volume=8|issue=3|pages=2134–2147|doi=10.1021/nn404872e|issn=1936-0851|pmc=PMC4004292|pmid=24499315}}</ref> Dendrimer uptake into the brain correlates with severity of inflammation and BBB impairment and it is believed that the BBB impairment is the key driving factor allowing dendrimer penetration.<ref>{{Cite journal|last=Nance|first=Elizabeth|last2=Kambhampati|first2=Siva P.|last3=Smith|first3=Elizabeth S.|last4=Zhang|first4=Zhi|last5=Zhang|first5=Fan|last6=Singh|first6=Sarabdeep|last7=Johnston|first7=Michael V.|last8=Kannan|first8=Rangaramanujam M.|last9=Blue|first9=Mary E.|last10=Kannan|first10=Sujatha|date=2017-12|title=Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome|url=https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-1004-5|journal=Journal of Neuroinflammation|language=en|volume=14|issue=1|pages=252|doi=10.1186/s12974-017-1004-5|issn=1742-2094|pmc=PMC5735803|pmid=29258545}}</ref><ref name=":2" /> Localization is heavily skewed towards activated [[microglia]]. Dendrimer-conjugated N-acetyl cysteine has shown efficacy in vivo as an anti-inflammatory at more than 1000-fold lower dose than free drug on a drug basis, reversing the phenotype of cerebral palsy, [[Rett syndrome]], [[macular degeneration]] and other inflammatory diseases.<ref name=":2" />
 ==== Clinical Trials ====