Dendrimer

Last updated
Dendrimer and dendron Graphs.jpg
Dendrimer and dendron

Dendrimers are highly ordered, branched polymeric molecules. [1] [2] Synonymous terms for dendrimer include arborols and cascade molecules. Typically, dendrimers are symmetric about the core, and often adopt 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]

Contents

IUPAC definition

Dendrimer Substance composed of identical dendrimer molecules.

Dendrimer molecule

Molecule consisting of one or more dendrons emanating from a single constitutional unit.

Dendron

Part of a molecule with only one free valence, comprising exclusively dendritic and terminal constitutional repeating units and in which each path from the free valence to any end-group comprises the same number of constitutional repeating units. Note 1: For the purpose of determining the nature of constitutional repeating units the free valence is treated as a connection to a CRU. Note 2: A dendrimer molecule comprising only one dendron is sometimes referred to as dendron, monodendron or functionalised dendron. The use of the terms 'dendron' or 'monodendron' in the meaning of molecule or substance is not acceptable. Note 3: In a dendron, macrocycles of constitutional units are absent. [4]

Crystal structure of a first-generation polyphenylene dendrimer reported by Mullen et al Dendrimer ChemEurJ 2002 3858.jpg
Crystal structure of a first-generation polyphenylene dendrimer reported by Müllen et al
A first-generation "cyanostar" dendrimer and its STM image Cyanostar STM.png
A first-generation "cyanostar" dendrimer and its STM image

The first dendrimers were made by divergent synthesis approaches by Fritz Vögtle in 1978, [7] R.G. Denkewalter at Allied Corporation in 1981, [8] [9] Donald Tomalia at Dow Chemical in 1983 [10] and in 1985, [11] [12] and by George R. Newkome in 1985. [13] In 1990 a convergent synthetic approach was introduced by Craig Hawker and Jean Fréchet. [14] 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. [15] [16] [17] Dendritic encapsulation of functional molecules allows for the isolation of the active site, a structure that mimics that of active sites in biomaterials. [18] [19] [20] 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. [21] Dendrimers may have a single surface functional group, or may be modified to allow for multiple functional groups on the surface. [22]

Synthesis

Synthesis to second generation arborol 538 Arborol.png
Synthesis to second generation arborol

One of the 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. [13]

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. [23]

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 [24] commercializes biocompatible bis-MPA dendrimers and Dendritech [25] is the only kilogram-scale producers of PAMAM dendrimers. NanoSynthons, LLC [26] from Mount Pleasant, Michigan, USA produces PAMAM dendrimers and other proprietary dendrimers.

Divergent methods

Schematic of divergent synthesis of dendrimers 538 Divergent synthesis.png
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. [21]

Convergent methods

Schematic of convergent synthesis of dendrimers 538 Convergent synthesis.png
Schematic of convergent synthesis of dendrimers

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. [21]

Click chemistry

Dendrimer Diels-Alder reaction. Dendrimer DA Mullen 1996.svg
Dendrimer Diels-Alder reaction.

Dendrimers have been prepared via click chemistry, employing Diels-Alder reactions, [28] thiol-ene and thiol-yne reactions [29] and azide-alkyne reactions. [30] [31] [32]

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. [33] 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. [23]

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. [34] Dendrimers with hydrophobic core and hydrophilic periphery have shown to exhibit micelle-like behavior and have container properties in solution. [35] The use of dendrimers as unimolecular micelles was proposed by Newkome in 1985. [36] This analogy highlighted the utility of dendrimers as solubilizing agents. [37] 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. [38] [39] [40] [41] [42] [43] Dendrimer labs are trying to manipulate dendrimer's solubilizing trait, to explore dendrimers for drug delivery [44] [45] and to target specific carriers. [46] [47] [48]

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 polyethoxyethylglycinamide (PEE-G) dendrimer. [49] [50] This dendrimer scaffold has been designed and shown to have high HPLC purity, stability, aqueous solubility and low inherent toxicity.

Drug delivery

Scheme of a G-5 PAMAM dendrimer conjugated to both a dye molecule and a strand of DNA. 538 Gene delivery.png
Scheme of a G-5 PAMAM dendrimer conjugated to both a dye molecule and a strand of DNA.

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 accomplished by (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. [51] [52] 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. [53] [54]

Polyethylene glycol (PEG) is a common modification for dendrimers to modify their surface charge and circulation time. Surface charge can influence the interactions of dendrimers with biological systems, such as amine-terminal modified dendrimers which have a propensity to interact with cell membranes with anionic charge. Certain in vivo studies have shown polycationic dendrimers to be cytotoxic through membrane permeabilization, a phenomenon that could be partially mitigated via addition of PEGylation caps on amine groups, resulting in lower cytotoxicity and lower red blood cell hemolysis. [55] [56] 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. [57] [56]

Numerous targeting moieties have been used to modify dendrimer biodistribution and allow for targeting to specific organs. For example, 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. [57] [58]

Antibody-mediated targeting of dendrimers to cell targets has also shown promise for targeted drug delivery. As epidermal growth factor receptors (EGFRs) are often overexpressed in brain tumors, EGFRs are a convenient target for site-specific drug delivery. The delivery of boron to cancerous cells is important for effective 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. [59]

Modifying nanoparticle dendrimers with peptides has also been successful for targeted destruction of colorectal (HCT-116) cancer cells in a co-culture scenario. Targeting peptides can be used to achieve site- or cell-specific delivery, and it has been shown that these peptides increase in targeting specificity 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 of the dendrimer with laminin receptors. Peptide dendrimers may be employed in the future to precisely target cancer cells and deliver chemotherapeutic agents. [60]

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. Conversely, 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. [61]

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 dendrimer size, structure, and surface characteristics. While G9 dendrimers accumulate very heavily to the liver and spleen, G6 dendrimers tend to accumulate more broadly. As molecular weight increases, urinary clearance and plasma clearance decrease while terminal half-life increases. [55]

Routes of delivery

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. [62] 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. [63]

Intravenous dendrimer delivery shows promise 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. [64] [65]

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. [66] 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, which are 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. [67] This result indicates that administered drugs were more active and had increased bioavailability when delivered via dendrimers than their free-drug counterparts. 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. [68]

Brain drug delivery

Dendrimer drug delivery has also 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 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. [69] 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. [70] [71] [72] 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. [73] [69] 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. [69]

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. [74]

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 substrate mediated gene delivery. Research has shown that the fast-degrading functional polymer has great potential for localized transfection. [75] [76] [77]

Sensors

Dendrimers have potential applications in sensors. Studied systems include proton or pH sensors using poly(propylene imine), [78] cadmium-sulfide/polypropylenimine tetrahexacontaamine dendrimer composites to detect fluorescence signal quenching, [79] and poly(propylenamine) first and second generation dendrimers for metal cation photodetection [80] amongst others. Research in this field is vast and ongoing due to the potential for multiple detection and binding sites in dendritic structures.

Nanoparticles

Dendrimers also are used in the synthesis of monodisperse metallic nanoparticles. Poly(amidoamine), 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 complexation, 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]

Other applications

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]

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, [83] [84] and prevents the cytotoxicity exhibited by free heme. Dendritic functional polymer polyamidoamine (PAMAM) is used to prepare core shell structure i.e. microcapsules and utilized in formulation of self-healing coatings of conventional [85] and renewable origins. [86]

Different generations of polyamidoamine dendrimers have recently been implemented as selective contacts in photovoltaic devices. [87]

Drug delivery

Dendrimers in drug-delivery systems is an example of various host–guest interactions. The interaction between host and guest, the dendrimer and the drug, respectively, can either be hydrophobic or covalent. Hydrophobic interaction between host and guest is considered "encapsulated," while covalent interactions are considered to be conjugated. The use of dendrimers in medicine has shown to improve drug delivery by increasing the solubility and bioavailability of the drug. In conjunction, dendrimers can increase both cellular uptake and targeting ability, and decrease drug resistance. [88]

The solubility of various nonsteroidal anti-inflammatory drugs (NSAID) increases when they are encapsulated in PAMAM dendrimers. [89] This study shows the enhancement of NSAID solubility is due to the electrostatic interactions between the surface amine groups in PAMAM and the carboxyl groups found in NSAIDs. Contributing to the increase in solubility are the hydrophobic interactions between the aromatic groups in the drugs and the interior cavities of the dendrimer. [90] When a drug is encapsulated within a dendrimer, its physical and physiological properties remains unaltered, including non-specificity and toxicity. However, when the dendrimer and the drug are covalently linked together, it can be used for specific tissue targeting and controlled release rates. [91] Covalent conjugation of multiple drugs on dendrimer surfaces can pose a problem of insolubility. [91] [92]

This principle is also being studied for cancer treatment application. Several groups have encapsulated anti-cancer medications such as: Camptothecin, Methotrexate, and Doxorubicin. Results from these research has shown that dendrimers have increased aqueous solubility, slowed release rate, and possibly control cytotoxicity of the drugs. [88] Cisplatin has been conjugated to PAMAM dendrimers that resulted in the same pharmacological results as listed above, but the conjugation also helped in accumulating cisplatin in solid tumors in intravenous administration. [93]

See also

Related Research Articles

Nanomedicine is the medical application of nanotechnology. Nanomedicine ranges from the medical applications of nanomaterials and biological devices, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology such as biological machines. Current problems for nanomedicine involve understanding the issues related to toxicity and environmental impact of nanoscale materials.

<span class="mw-page-title-main">Liposome</span> Composite structures made of phospholipids and may contain small amounts of other molecules

A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug delivery vehicles for administration of pharmaceutical drugs and nutrients, such as lipid nanoparticles in mRNA vaccines, and DNA vaccines. Liposomes can be prepared by disrupting biological membranes.

<span class="mw-page-title-main">Cyclodextrin</span> Polysaccharide with six glucose units

Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. They are used in food, pharmaceutical, drug delivery, and chemical industries, as well as agriculture and environmental engineering.

A drug carrier or drug vehicle is a substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness, and/or safety of drug administration. Drug carriers are primarily used to control the release of drugs into systemic circulation. This can be accomplished either by slow release of a particular drug over a long period of time or by triggered release at the drug's target by some stimulus, such as changes in pH, application of heat, and activation by light. Drug carriers are also used to improve the pharmacokinetic properties, specifically the bioavailability, of many drugs with poor water solubility and/or membrane permeability.

Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. This means of delivery is largely founded on nanomedicine, which plans to employ nanoparticle-mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue. The conventional drug delivery system is the absorption of the drug across a biological membrane, whereas the targeted release system releases the drug in a dosage form. The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side-effects, and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost, which makes productivity more difficult, and the reduced ability to adjust the dosages.

Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. The word poloxamer was coined by BASF inventor, Irving Schmolka, who received the patent for these materials in 1973. Poloxamers are also known by the trade names Pluronic, Kolliphor, and Synperonic.

<span class="mw-page-title-main">Mesoporous silica</span> Nano-scale porous silica compound

Mesoporous silica is a form of silica that is characterised by its mesoporous structure, that is, having pores that range from 2 nm to 50 nm in diameter. According to IUPAC's terminology, mesoporosity sits between microporous (<2 nm) and macroporous (>50 nm). Mesoporous silica is a relatively recent development in nanotechnology. The most common types of mesoporous nanoparticles are MCM-41 and SBA-15. Research continues on the particles, which have applications in catalysis, drug delivery and imaging. Mesoporous ordered silica films have been also obtained with different pore topologies.

A nanogel is a polymer-based, crosslinked hydrogel particle on the sub-micron scale. These complex networks of polymers present a unique opportunity in the field of drug delivery at the intersection of nanoparticles and hydrogel synthesis. Nanogels can be natural, synthetic, or a combination of the two and have a high degree of tunability in terms of their size, shape, surface functionalization, and degradation mechanisms. Given these inherent characteristics in addition to their biocompatibility and capacity to encapsulate small drugs and molecules, nanogels are a promising strategy to treat disease and dysfunction by serving as delivery vehicles capable of navigating across challenging physiological barriers within the body. 

<span class="mw-page-title-main">Peptide amphiphile</span>

Peptide amphiphiles (PAs) are peptide-based molecules that self-assemble into supramolecular nanostructures including; spherical micelles, twisted ribbons, and high-aspect-ratio nanofibers. A peptide amphiphile typically comprises a hydrophilic peptide sequence attached to a lipid tail, i.e. a hydrophobic alkyl chain with 10 to 16 carbons. Therefore, they can be considered a type of lipopeptide. A special type of PA, is constituted by alternating charged and neutral residues, in a repeated pattern, such as RADA16-I. The PAs were developed in the 1990s and the early 2000s and could be used in various medical areas including: nanocarriers, nanodrugs, and imaging agents. However, perhaps their main potential is in regenerative medicine to culture and deliver cells and growth factors.

<span class="mw-page-title-main">Vectors in gene therapy</span>

Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by several methods, summarized below. The two major classes of methods are those that use recombinant viruses and those that use naked DNA or DNA complexes.

<span class="mw-page-title-main">Nanocarrier</span>

A nanocarrier is nanomaterial being used as a transport module for another substance, such as a drug. Commonly used nanocarriers include micelles, polymers, carbon-based materials, liposomes and other substances. Nanocarriers are currently being studied for their use in drug delivery and their unique characteristics demonstrate potential use in chemotherapy. This class of materials was first reported by a team of researchers of University of Évora, Alentejo in early 1960's, and grew exponentially in relevance since then.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

Poly(amidoamine), or PAMAM, is a class of dendrimer which is made of repetitively branched subunits of amide and amine functionality. PAMAM dendrimers, sometimes referred to by the trade name Starburst, have been extensively studied since their synthesis in 1985, and represent the most well-characterized dendrimer family as well as the first to be commercialized. Like other dendrimers, PAMAMs have a sphere-like shape overall, and are typified by an internal molecular architecture consisting of tree-like branching, with each outward 'layer', or generation, containing exponentially more branching points. This branched architecture distinguishes PAMAMs and other dendrimers from traditional polymers, as it allows for low polydispersity and a high level of structural control during synthesis, and gives rise to a large number of surface sites relative to the total molecular volume. Moreover, PAMAM dendrimers exhibit greater biocompatibility than other dendrimer families, perhaps due to the combination of surface amines and interior amide bonds; these bonding motifs are highly reminiscent of innate biological chemistry and endow PAMAM dendrimers with properties similar to that of globular proteins. The relative ease/low cost of synthesis of PAMAM dendrimers (especially relative to similarly-sized biological molecules such as proteins and antibodies), along with their biocompatibility, structural control, and functionalizability, have made PAMAMs viable candidates for application in drug development, biochemistry, and nanotechnology.

Nanoparticle drug delivery systems are engineered technologies that use nanoparticles for the targeted delivery and controlled release of therapeutic agents. The modern form of a drug delivery system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery.

Hamid Ghandehari is an Iranian-American drug delivery research scientist, and a professor in the Departments of Pharmaceutics and Pharmaceutical Chemistry and Biomedical Engineering at the University of Utah. His research is focused in recombinant polymers for drug and gene delivery, nanotoxicology of dendritic and inorganic constructs, water-soluble polymers for targeted delivery and poly(amidoamine) dendrimers for oral delivery.

Virgil Percec is a Romanian-American chemist and P. Roy Vagelos Chair and Professor of Chemistry at the University of Pennsylvania. Expert in organic, macromolecular and supramolecular chemistry including self-assembly, biological membrane mimics, complex chiral systems, and catalysis. Pioneered the fields of liquid crystals with complex architecture, supramolecular dendrimers, Janus dendrimers and glycodendrimers, organic Frank-Kasper phases and quasicrystals, supramolecular polymers, helical chirality, Ni-catalyzed cross-coupling and multiple living and self-interrupted polymerizations. Most of these concepts were inspired by Nature and biological principles.

<span class="mw-page-title-main">Dextran drug delivery systems</span> Polymeric drug carrier

Dextran drug delivery systems involve the use of the natural glucose polymer dextran in applications as a prodrug, nanoparticle, microsphere, micelle, and hydrogel drug carrier in the field of targeted and controlled drug delivery. According to several in vitro and animal research studies, dextran carriers reduce off-site toxicity and improve local drug concentration at the target tissue site. This technology has significant implications as a potential strategy for delivering therapeutics to treat cancer, cardiovascular diseases, pulmonary diseases, bone diseases, liver diseases, colonic diseases, infections, and HIV.

Conventional drug delivery is limited by the inability to control dosing, target specific sites, and achieve targeted permeability. Traditional methods of delivering therapeutics to the body experience challenges in achieving and maintaining maximum therapeutic effect while avoiding the effects of drug toxicity. Many drugs that are delivered orally or parenterally do not include mechanisms for sustained release, and as a result they require higher and more frequent dosing to achieve any therapeutic effect for the patient. As a result, the field of drug delivery systems developed into a large focus area for pharmaceutical research to address these limitations and improve quality of care for patients. Within the broad field of drug delivery, the development of stimuli-responsive drug delivery systems has created the ability to tune drug delivery systems to achieve more controlled dosing and targeted specificity based on material response to exogenous and endogenous stimuli.

<span class="mw-page-title-main">Reduction-sensitive nanoparticles</span> Drug delivery method

Reduction-sensitive nanoparticles (RSNP) consist of nanocarriers that are chemically responsive to reduction. Drug delivery systems using RSNP can be loaded with different drugs that are designed to be released within a concentrated reducing environment, such as the tumor-targeted microenvironment. Reduction-Sensitive Nanoparticles provide an efficient method of targeted drug delivery for the improved controlled release of medication within localized areas of the body.

<span class="mw-page-title-main">Aquasome</span> Drug delivery system

Aquasomes are self-assembling nanoparticle drug carrier systems composed of three layers: a ceramic core, an oligomer coat, and a loaded biochemically active molecule. Aquasomes are utilized for targeted drug delivery to achieve specific therapeutic effects, and are biocompatible, biodegradable, and stable. Due to their structure, aquasomes are capable of delivering several types of substrates, and can be used for applications such as delivery of antigens, insulin, and hemoglobin.

References

  1. ↑ Astruc D, Boisselier E, Ornelas C (April 2010). "Dendrimers designed for functions: from physical, photophysical, and supramolecular properties to applications in sensing, catalysis, molecular electronics, photonics, and nanomedicine". Chemical Reviews. 110 (4): 1857–959. doi:10.1021/cr900327d. PMID   20356105.
  2. ↑ Vögtle, Fritz / Richardt, Gabriele / Werner, Nicole Dendrimer Chemistry Concepts, Syntheses, Properties, Applications 2009 ISBN   3-527-32066-0
  3. 1 2 Nanjwade BK, Bechra HM, Derkar GK, Manvi FV, Nanjwade VK (October 2009). "Dendrimers: emerging polymers for drug-delivery systems". European Journal of Pharmaceutical Sciences. 38 (3): 185–96. doi:10.1016/j.ejps.2009.07.008. PMID   19646528.
  4. ↑ Fradet, Alain; Chen, Jiazhong; Hellwich, Karl-Heinz; Horie, Kazuyuki; Kahovec, Jaroslav; Mormann, Werner; Stepto, Robert F. T.; Vohlídal, Jiří; Wilks, Edward S. (2019-03-26). "Nomenclature and terminology for dendrimers with regular dendrons and for hyperbranched polymers (IUPAC Recommendations 2017)". Pure and Applied Chemistry. 91 (3): 523–561. doi: 10.1515/pac-2016-1217 . ISSN   0033-4545.
  5. ↑ Bauer, Roland. E.; Enkelmann, Volker; Wiesler, Uwe M.; Berresheim, Alexander J.; Müllen, Klaus (2002). "Single-Crystal Structures of Polyphenylene Dendrimers". Chemistry: A European Journal . 8 (17): 3858–3864. doi:10.1002/1521-3765(20020902)8:17<3858::AID-CHEM3858>3.0.CO;2-5. PMID   12203280.
  6. ↑ Hirsch BE, Lee S, Qiao B, Chen CH, McDonald KP, Tait SL, Flood AH (September 2014). "Anion-induced dimerization of 5-fold symmetric cyanostars in 3D crystalline solids and 2D self-assembled crystals". Chemical Communications. 50 (69): 9827–30. doi:10.1039/C4CC03725A. PMID   25080328. S2CID   12439952.
  7. ↑ Buhleier E, Wehner W, Vogtle F (1978). ""Cascade"- and "Nonskid-Chain-like" Syntheses of Molecular Cavity Topologies". Synthesis . 1978 (2): 155–158. doi:10.1055/s-1978-24702.
  8. ↑ U.S. patent 4,289,872 Denkewalter, Robert G., Kolc, Jaroslav, Lukasavage, William J.
  9. ↑ Denkewalter, Robert G. et al. (1981) "Macromolecular highly branched homogeneous compound" U.S. patent 4,410,688
  10. ↑ Tomalia, Donald A. and Dewald, James R. (1983) "Dense star polymers having core, core branches, terminal groups" U.S. patent 4,507,466
  11. ↑ Tomalia DA, Baker H, Dewald J, Hall M, Kallos G, Martin S, Roeck J, Ryder J, Smith P (1985). "A New Class of Polymers: Starburst-Dendritic Macromolecules". Polymer Journal. 17: 117–132. doi: 10.1295/polymj.17.117 .
  12. ↑ "Treelike molecules branch out – chemist Donald A. Tomalia synthesized first dendrimer molecule – Chemistry – Brief Article". Science News. 1996.
  13. 1 2 Newkome GR, Yao Z, Baker GR, Gupta VK (1985). "Micelles. Part 1. Cascade molecules: a new approach to micelles. A [27]-arborol". J. Org. Chem. 50 (11): 2003–2004. doi:10.1021/jo00211a052.
  14. ↑ Hawker CJ, Fréchet JM (1990). "Preparation of polymers with controlled molecular architecture. A new convergent approach to dendritic macromolecules". J. Am. Chem. Soc. 112 (21): 7638–7647. Bibcode:1990JAChS.112.7638H. doi:10.1021/ja00177a027.
  15. ↑ Antoni P, Hed Y, Nordberg A, Nyström D, von Holst H, Hult A, Malkoch M (2009). "Bifunctional dendrimers: from robust synthesis and accelerated one-pot postfunctionalization strategy to potential applications". Angewandte Chemie. 48 (12): 2126–30. doi:10.1002/anie.200804987. PMID   19117006.
  16. ↑ McElhanon JR, McGrath DV (June 2000). "Toward chiral polyhydroxylated dendrimers. Preparation and chiroptical properties". The Journal of Organic Chemistry. 65 (11): 3525–9. doi:10.1021/jo000207a. PMID   10843641.
  17. ↑ Liang CO, Fréchet JM (2005). "Incorporation of Functional Guest Molecules into an Internally Functionalizable Dendrimer through Olefin Metathesis". Macromolecules . 38 (15): 6276–6284. Bibcode:2005MaMol..38.6276L. doi:10.1021/ma050818a.
  18. ↑ Hecht S, Fréchet JM (January 2001). "Dendritic Encapsulation of Function: Applying Nature's Site Isolation Principle from Biomimetics to Materials Science". Angewandte Chemie. 40 (1): 74–91. doi:10.1002/1521-3773(20010105)40:1<74::AID-ANIE74>3.0.CO;2-C. PMID   11169692.
  19. ↑ Frechet J, Tomalia DA (March 2002). Dendrimers and Other Dendritic Polymers. New York, NY: John Wiley & Sons. ISBN   978-0-471-63850-6.
  20. ↑ Fischer M, Vögtle F (1999). "Dendrimers: From Design to Application—A Progress Report". Angew. Chem. Int. Ed. 38 (7): 884–905. doi:10.1002/(SICI)1521-3773(19990401)38:7<884::AID-ANIE884>3.0.CO;2-K. PMID   29711851.
  21. 1 2 3 Holister P, Vas CR, Harper T (October 2003). "Dendrimers: Technology White Papers" (PDF). Cientifica. Archived from the original (PDF) on 6 July 2011. Retrieved 17 March 2010.
  22. ↑ Schlick, Kristian H.; Morgan, Joel R.; Weiel, Julianna J.; Kelsey, Melissa S.; Cloninger, Mary J. (September 1, 2011). "Clusters of ligands on dendrimer surfaces". Bioorg Med Chem Lett. 21 (17): 5078–5083. doi:10.1016/j.bmcl.2011.03.100. PMC   3156387 . PMID   21524579.
  23. 1 2 Hermanson GT (2008). "7". Bioconjugate Techniques (2nd ed.). London: Academic Press of Elsevier. ISBN   978-0-12-370501-3.
  24. ↑ Polymer Factory AB, Stockholm, Sweden.Polymer Factory
  25. ↑ Dendritech Inc., from Midland, Michigan, USA.Dendritech.
  26. ↑ Home. NanoSynthons. Retrieved on 2015-09-29.
  27. ↑ Morgenroth F, Reuther E, Müllen K (1997). "Polyphenylene Dendrimers: From Three-Dimensional to Two-Dimensional Structures". Angewandte Chemie International Edition in English. 36 (6): 631–634. doi:10.1002/anie.199706311.
  28. ↑ Franc G, Kakkar AK (June 2009). "Diels-Alder "click" chemistry in designing dendritic macromolecules". Chemistry. 15 (23): 5630–9. doi:10.1002/chem.200900252. PMID   19418515.
  29. ↑ Killops KL, Campos LM, Hawker CJ (April 2008). "Robust, efficient, and orthogonal synthesis of dendrimers via thiol-ene "click" chemistry". Journal of the American Chemical Society. 130 (15): 5062–4. Bibcode:2008JAChS.130.5062K. CiteSeerX   10.1.1.658.8715 . doi:10.1021/ja8006325. PMID   18355008.
  30. ↑ Noda K, Minatogawa Y, Higuchi T (March 1991). "Effects of hippocampal neurotoxicant, trimethyltin, on corticosterone response to a swim stress and glucocorticoid binding capacity in the hippocampus in rats". The Japanese Journal of Psychiatry and Neurology. 45 (1): 107–8. PMID   1753450.
  31. ↑ Machaiah JP (May 1991). "Changes in macrophage membrane proteins in relation to protein deficiency in rats". Indian Journal of Experimental Biology. 29 (5): 463–7. PMID   1916945.
  32. ↑ Franc G, Kakkar A (November 2008). "Dendrimer design using Cu(I)-catalyzed alkyne-azide "click-chemistry"". Chemical Communications (42): 5267–76. doi:10.1039/b809870k. PMID   18985184.
  33. ↑ Kaanumalle LS, Ramesh R, Murthy Maddipatla VS, Nithyanandhan J, Jayaraman N, Ramamurthy V (June 2005). "Dendrimers as photochemical reaction media. Photochemical behavior of unimolecular and bimolecular reactions in water-soluble dendrimers". The Journal of Organic Chemistry. 70 (13): 5062–9. doi:10.1021/jo0503254. PMID   15960506.
  34. ↑ Tomalia DA, Naylor AM, Goddard WA (1990). "Starburst Dendrimers: Molecular-Level Control of Size, Shape, Surface Chemistry, Topology, and Flexibility from Atoms to Macroscopic Matter". Angew. Chem. Int. Ed. Engl. 29 (2): 138–175. doi:10.1002/anie.199001381.
  35. ↑ Fréchet JM (March 1994). "Functional polymers and dendrimers: reactivity, molecular architecture, and interfacial energy". Science. 263 (5154): 1710–5. Bibcode:1994Sci...263.1710F. doi:10.1126/science.8134834. PMID   8134834.
  36. ↑ Liu M, Kono K, Fréchet JM (March 2000). "Water-soluble dendritic unimolecular micelles: their potential as drug delivery agents". Journal of Controlled Release. 65 (1–2): 121–31. doi:10.1016/s0168-3659(99)00245-x. PMID   10699276.
  37. ↑ Newkome GR, Yao Z, Baker GR, Gupta VK (1985). "Micelles Part 1. Cascade molecules: a new approach to micelles, A-arborol". J. Org. Chem. 50 (11): 155–158. doi:10.1021/jo00211a052.
  38. ↑ Stevelmens S, Hest JC, Jansen JF, Boxtel DA, de Bravander-van den B, Miejer EW (1996). "Synthesis, characterisation and guest-host properties of inverted unimolecular micelles". J Am Chem Soc . 118 (31): 7398–7399. doi:10.1021/ja954207h. hdl: 2066/17430 . S2CID   98332942.
  39. ↑ Gupta U, Agashe HB, Asthana A, Jain NK (March 2006). "Dendrimers: novel polymeric nanoarchitectures for solubility enhancement". Biomacromolecules. 7 (3): 649–58. doi:10.1021/bm050802s. PMID   16529394.
  40. ↑ Thomas TP, Majoros IJ, Kotlyar A, Kukowska-Latallo JF, Bielinska A, Myc A, Baker JR (June 2005). "Targeting and inhibition of cell growth by an engineered dendritic nanodevice". Journal of Medicinal Chemistry. 48 (11): 3729–35. doi:10.1021/jm040187v. PMID   15916424.
  41. ↑ Bhadra D, Bhadra S, Jain P, Jain NK (January 2002). "Pegnology: a review of PEG-ylated systems". Die Pharmazie. 57 (1): 5–29. PMID   11836932.
  42. ↑ Asthana A, Chauhan AS, Diwan PV, Jain NK (October 2005). "Poly(amidoamine) (PAMAM) dendritic nanostructures for controlled site-specific delivery of acidic anti-inflammatory active ingredient". AAPS PharmSciTech. 6 (3): E536-42. doi:10.1208/pt060367. PMC   2750401 . PMID   16354015.
  43. ↑ Bhadra D, Bhadra S, Jain S, Jain NK (May 2003). "A PEGylated dendritic nanoparticulate carrier of fluorouracil". International Journal of Pharmaceutics. 257 (1–2): 111–24. doi:10.1016/s0378-5173(03)00132-7. PMID   12711167.
  44. ↑ Khopade AJ, Caruso F, Tripathi P, Nagaich S, Jain NK (January 2002). "Effect of dendrimer on entrapment and release of bioactive from liposomes". International Journal of Pharmaceutics. 232 (1–2): 157–62. doi:10.1016/S0378-5173(01)00901-2. PMID   11790499.
  45. ↑ Prajapati RN, Tekade RK, Gupta U, Gajbhiye V, Jain NK (2009). "Dendimer-mediated solubilization, formulation development and in vitro-in vivo assessment of piroxicam". Molecular Pharmaceutics. 6 (3): 940–50. doi:10.1021/mp8002489. PMID   19231841.
  46. ↑ Chauhan AS, Sridevi S, Chalasani KB, Jain AK, Jain SK, Jain NK, Diwan PV (July 2003). "Dendrimer-mediated transdermal delivery: enhanced bioavailability of indomethacin". Journal of Controlled Release. 90 (3): 335–43. doi:10.1016/s0168-3659(03)00200-1. PMID   12880700.
  47. ↑ Kukowska-Latallo JF, Candido KA, Cao Z, Nigavekar SS, Majoros IJ, Thomas TP, et al. (June 2005). "Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer". Cancer Research. 65 (12): 5317–24. doi: 10.1158/0008-5472.can-04-3921 . PMID   15958579.
  48. ↑ Quintana A, Raczka E, Piehler L, Lee I, Myc A, Majoros I, et al. (September 2002). "Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor" (PDF). Pharmaceutical Research. 19 (9): 1310–6. doi:10.1023/a:1020398624602. hdl: 2027.42/41493 . PMID   12403067. S2CID   9444825.
  49. ↑ Toms S, Carnachan SM, Hermans IF, Johnson KD, Khan AA, O'Hagan SE, et al. (August 2016). "Poly Ethoxy Ethyl Glycinamide (PEE-G) Dendrimers: Dendrimers Specifically Designed for Pharmaceutical Applications". ChemMedChem. 11 (15): 1583–6. doi:10.1002/cmdc.201600270. PMID   27390296. S2CID   5007374.
  50. ↑ GlycoSyn. "PEE-G Dendrimers".
  51. ↑ Morgan MT, Nakanishi Y, Kroll DJ, Griset AP, Carnahan MA, Wathier M, et al. (December 2006). "Dendrimer-encapsulated camptothecins: increased solubility, cellular uptake, and cellular retention affords enhanced anticancer activity in vitro". Cancer Research. 66 (24): 11913–21. doi:10.1158/0008-5472.CAN-06-2066. PMID   17178889.
  52. ↑ Tekade RK, Dutta T, Gajbhiye V, Jain NK (June 2009). "Exploring dendrimer towards dual drug delivery: pH responsive simultaneous drug-release kinetics". Journal of Microencapsulation. 26 (4): 287–96. doi:10.1080/02652040802312572. PMID   18791906. S2CID   44523215.
  53. ↑ Leong NJ, Mehta D, McLeod VM, Kelly BD, Pathak R, Owen DJ, et al. (September 2018). "Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats" (PDF). Journal of Pharmaceutical Sciences. 107 (9): 2509–2513. doi:10.1016/j.xphs.2018.05.013. PMID   29852134. S2CID   46918065.
  54. ↑ da Silva Santos S, Igne Ferreira E, Giarolla J (May 2016). "Dendrimer Prodrugs". Molecules. 21 (6): 686. doi: 10.3390/molecules21060686 . PMC   6274429 . PMID   27258239.
  55. 1 2 Kaminskas LM, Boyd BJ, Porter CJ (August 2011). "Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties". Nanomedicine. 6 (6): 1063–84. doi:10.2217/nnm.11.67. PMID   21955077.
  56. 1 2 Luong D, Kesharwani P, Deshmukh R, Mohd Amin MC, Gupta U, Greish K, Iyer AK (October 2016). "PEGylated PAMAM dendrimers: Enhancing efficacy and mitigating toxicity for effective anticancer drug and gene delivery". Acta Biomaterialia. 43: 14–29. doi:10.1016/j.actbio.2016.07.015. PMID   27422195.
  57. 1 2 Singh P, Gupta U, Asthana A, Jain NK (November 2008). "Folate and folate-PEG-PAMAM dendrimers: synthesis, characterization, and targeted anticancer drug delivery potential in tumor bearing mice". Bioconjugate Chemistry. 19 (11): 2239–52. doi:10.1021/bc800125u. PMID   18950215.
  58. ↑ Majoros IJ, Williams CR, Becker A, Baker JR (September 2009). "Methotrexate delivery via folate targeted dendrimer-based nanotherapeutic platform". Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology. 1 (5): 502–10. doi:10.1002/wnan.37. PMC   2944777 . PMID   20049813.
  59. ↑ Wu G, Barth RF, Yang W, Chatterjee M, Tjarks W, Ciesielski MJ, Fenstermaker RA (January 2004). "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". Bioconjugate Chemistry. 15 (1): 185–94. doi:10.1021/bc0341674. PMID   14733599.
  60. ↑ Carvalho MR, Carvalho CR, Maia FR, Caballero D, Kundu SC, Reis RL, Oliveira JM (November 2019). "Peptide-Modified Dendrimer Nanoparticles for Targeted Therapy of Colorectal Cancer". Advanced Therapeutics. 2 (11): 1900132. doi:10.1002/adtp.201900132. hdl: 1822/61410 . ISSN   2366-3987. S2CID   203135854.
  61. ↑ Sharma A, Porterfield JE, Smith E, Sharma R, Kannan S, Kannan RM (August 2018). "Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model". Journal of Controlled Release. 283: 175–189. doi:10.1016/j.jconrel.2018.06.003. PMC   6091673 . PMID   29883694.
  62. ↑ Csaba N, Garcia-Fuentes M, Alonso MJ (July 2006). "The performance of nanocarriers for transmucosal drug delivery". Expert Opinion on Drug Delivery. 3 (4): 463–78. doi:10.1517/17425247.3.4.463. PMID   16822222. S2CID   13056713.
  63. ↑ Thiagarajan G, Sadekar S, Greish K, Ray A, Ghandehari H (March 2013). "Evidence of oral translocation of anionic G6.5 dendrimers in mice". Molecular Pharmaceutics. 10 (3): 988–98. doi:10.1021/mp300436c. PMC   3715149 . PMID   23286733.
  64. ↑ Dufès C, Uchegbu IF, Schätzlein AG (December 2005). "Dendrimers in gene delivery" (PDF). Advanced Drug Delivery Reviews. 57 (15): 2177–202. doi:10.1016/j.addr.2005.09.017. PMID   16310284.
  65. ↑ Dufès C, Keith WN, Bilsland A, Proutski I, Uchegbu IF, Schätzlein AG (September 2005). "Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors". Cancer Research. 65 (18): 8079–84. doi: 10.1158/0008-5472.CAN-04-4402 . PMID   16166279.
  66. ↑ Cheng Y, Man N, Xu T, Fu R, Wang X, Wang X, Wen L (March 2007). "Transdermal delivery of nonsteroidal anti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers". Journal of Pharmaceutical Sciences. 96 (3): 595–602. doi:10.1002/jps.20745. PMID   17094130.
  67. ↑ Vandamme TF, Brobeck L (January 2005). "Poly(amidoamine) dendrimers as ophthalmic vehicles for ocular delivery of pilocarpine nitrate and tropicamide". Journal of Controlled Release. 102 (1): 23–38. doi:10.1016/j.jconrel.2004.09.015. PMID   15653131.
  68. ↑ Xu Q, Kambhampati SP, Kannan RM (2013). "Nanotechnology approaches for ocular drug delivery". Middle East African Journal of Ophthalmology. 20 (1): 26–37. doi: 10.4103/0974-9233.106384 . PMC   3617524 . PMID   23580849.
  69. 1 2 3 Dai H, Navath RS, Balakrishnan B, Guru BR, Mishra MK, Romero R, et al. (November 2010). "Intrinsic targeting of inflammatory cells in the brain by polyamidoamine dendrimers upon subarachnoid administration". Nanomedicine. 5 (9): 1317–29. doi:10.2217/nnm.10.89. PMC   3095441 . PMID   21128716.
  70. ↑ Kannan G, Kambhampati SP, Kudchadkar SR (October 2017). "Effect of anesthetics on microglial activation and nanoparticle uptake: Implications for drug delivery in traumatic brain injury". Journal of Controlled Release. 263: 192–199. doi:10.1016/j.jconrel.2017.03.032. PMID   28336376. S2CID   8652471.
  71. ↑ Kannan S, Dai H, Navath RS, Balakrishnan B, Jyoti A, Janisse J, et al. (April 2012). "Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model". Science Translational Medicine. 4 (130): 130ra46. doi:10.1126/scitranslmed.3003162. PMC   3492056 . PMID   22517883.
  72. ↑ Mishra MK, Beaty CA, Lesniak WG, Kambhampati SP, Zhang F, Wilson MA, et al. (March 2014). "Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest". ACS Nano. 8 (3): 2134–47. doi:10.1021/nn404872e. PMC   4004292 . PMID   24499315.
  73. ↑ Nance E, Kambhampati SP, Smith ES, Zhang Z, Zhang F, Singh S, et al. (December 2017). "Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome". Journal of Neuroinflammation. 14 (1): 252. doi: 10.1186/s12974-017-1004-5 . PMC   5735803 . PMID   29258545.
  74. ↑ "Starpharma (ASX:SPL) compound shows activity against coronavirus - The Market Herald". themarketherald.com.au. 2020-04-16. Retrieved 2020-04-30.
  75. ↑ Fu HL, Cheng SX, Zhang XZ, Zhuo RX (December 2008). "Dendrimer/DNA complexes encapsulated functional biodegradable polymer for substrate-mediated gene delivery". The Journal of Gene Medicine. 10 (12): 1334–42. doi:10.1002/jgm.1258. PMID   18816481. S2CID   46011138.
  76. ↑ Fu HL, Cheng SX, Zhang XZ, Zhuo RX (December 2007). "Dendrimer/DNA complexes encapsulated in a water soluble polymer and supported on fast degrading star poly(DL-lactide) for localized gene delivery". Journal of Controlled Release. 124 (3): 181–8. doi:10.1016/j.jconrel.2007.08.031. PMID   17900738.
  77. ↑ Dutta T, Garg M, Jain NK (June 2008). "Poly(propyleneimine) dendrimer and dendrosome mediated genetic immunization against hepatitis B". Vaccine. 26 (27–28): 3389–94. doi:10.1016/j.vaccine.2008.04.058. PMID   18511160.
  78. ↑ Fernandes EG, Vieira NC, de Queiroz AA, Guimaraes FE, Zucolotto V (2010). "Immobilization of Poly(propylene imine) Dendrimer/Nickel Phthalocyanine as Nanostructured Multilayer Films To Be Used as Gate Membranes for SEGFET pH Sensors". Journal of Physical Chemistry C. 114 (14): 6478–6483. doi:10.1021/jp9106052.
  79. ↑ Campos BB, Algarra M, Esteves da Silva JC (January 2010). "Fluorescent properties of a hybrid cadmium sulfide-dendrimer nanocomposite and its quenching with nitromethane". Journal of Fluorescence. 20 (1): 143–51. doi:10.1007/s10895-009-0532-5. PMID   19728051. S2CID   10846628.
  80. ↑ Grabchev I, Staneva D, Chovelon JM (2010). "Photophysical investigations on the sensor potential of novel, poly(propylenamine) dendrimers modified with 1,8-naphthalimide units". Dyes and Pigments. 85 (3): 189–193. doi:10.1016/j.dyepig.2009.10.023.
  81. ↑ Scott RW, Wilson OM, Crooks RM (January 2005). "Synthesis, characterization, and applications of dendrimer-encapsulated nanoparticles". The Journal of Physical Chemistry B. 109 (2): 692–704. doi:10.1021/jp0469665. PMID   16866429.
  82. ↑ "Dendrimer technology licensed for herbicide". www.labonline.com.au. Retrieved 2016-09-25.
  83. ↑ Twyman LJ, Ge Y (April 2006). "Porphyrin cored hyperbranched polymers as heme protein models". Chemical Communications (15): 1658–60. doi:10.1039/b600831n. PMID   16583011.
  84. ↑ Twyman LJ, Ellis A, Gittins PJ (January 2012). "Pyridine encapsulated hyperbranched polymers as mimetic models of haeme containing proteins, that also provide interesting and unusual porphyrin-ligand geometries". Chemical Communications. 48 (1): 154–6. doi:10.1039/c1cc14396d. PMID   22039580.
  85. ↑ Tatiya, Pyus D., et al. "Novel polyurea microcapsules using dendritic functional monomer: synthesis, characterization, and its use in self-healing and anticorrosive polyurethane coatings." Industrial & Engineering Chemistry Research 52.4 (2013): 1562-1570.
  86. ↑ Chaudhari, Ashok B., et al. "Polyurethane prepared from neem oil polyesteramides for self-healing anticorrosive coatings." Industrial & Engineering Chemistry Research 52.30 (2013): 10189-10197.
  87. ↑ "Elimination of Interface Energy Barriers Using Dendrimer Polyelectrolytes with Fractal Geometry" E. Ros, T. Tom, P. Ortega, I. Martin, E. Maggi, J. M. Asensi, J. López-Vidrier, E. Saucedo, J. Bertomeu, J. Puigdollers, and C. Voz ACS Applied Materials & Interfaces 2023 15 (23), 28705-28715 DOI: 10.1021/acsami.3c01930
  88. 1 2 Cheng, Y.; Wang, J.; Rao, T.; He, X.; Xu, T. (2008). "Pharmaceutical applications of dendrimers: promising nanocarriers for drug discovery". Frontiers in Bioscience . 13 (13): 1447–1471. doi: 10.2741/2774 . PMID   17981642.
  89. ↑ Cheng, Y.; Xu, T. (2005). "Dendrimers as Potential Drug Carriers. Part I. Solubilization of Non-Steroidal Anti-Inflammatory Drugs in the Presence of Polyamidoamine Dendrimers". European Journal of Medicinal Chemistry . 40 (11): 1188–1192. doi:10.1016/j.ejmech.2005.06.010. PMID   16153746.
  90. ↑ Cheng, Y.; Xu, T; Fu, R (2005). "Polyamidoamine dendrimers used as solubility enhancers of ketoprofen". European Journal of Medicinal Chemistry . 40 (12): 1390–1393. doi:10.1016/j.ejmech.2005.08.002. PMID   16226353.
  91. 1 2 Cheng, Y.; Xu, Z; Ma, M.; Xu, T. (2007). "Dendrimers as drug carriers: Applications in different routes of drug administration". Journal of Pharmaceutical Sciences . 97 (1): 123–143. doi:10.1002/jps.21079. PMID   17721949.
  92. ↑ D’Emanuele, A; Attwood, D (2005). "Dendrimer–drug interactions". Advanced Drug Delivery Reviews . 57 (15): 2147–2162. doi:10.1016/j.addr.2005.09.012. PMID   16310283.
  93. ↑ Malik, N.; Evagorou, E.; Duncan, R. (1999). "Dendrimer-platinate: a novel approach to cancer chemotherapy". Anti-Cancer Drugs . 10 (8): 767–776. doi:10.1097/00001813-199909000-00010. PMID   10573209.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.