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Dendrimers: A New Carrier System For Drug Delivery
Abstract
Dendrimers are a new class of synthetic polymers which have the structure like a tree or star shape, with a central core, interior branches and terminal groups which decorate the surface. Cavities inside the core and the interior branches can be modified to carry hydrophobic and hydrophilic drugs. The terminal groups on the surface can also be adapted to carry drugs or antibodies for neutralizing or targeting purposes. These artificial macromolecules may be synthesized to reach the size of nano objects having dimensions similar to proteins. Recently, dendrimers have successfully proved themselves as promising nanocarriers for drug delivery because they can render drug molecules a greater water-solubility, bioavailability, and biocompatibility. These features have made their application in pharmaceutical, nanotechnology and medicinal chemistry particularly attractive. This review focuses on properties and various applications of dendrimers.
... Dendrimers are being used in drug delivery systems due to their flexible dimensions and sizes ranging from 1-100 nm [37]. Silica nanoparticles, also known as silicon dioxide, have received great attention due to their large surface area-volume ratios, adjustable pore size, and unique properties such as connectivity, biocompatibility, and ease of surface modification [38,39]. ...
Nanoparticles increase their availability and diversity in the environment day by day with the natural formation processes of the world geography and the development of advanced technological industry. Due to their intelligent and kaleidoscopic physico-chemical structural forms, they can cause toxic effects in various metabolic steps (in structural proteins, genetic structure, organelles, cells, tissues, organs, metabolic systems) in the organism. Despite these harmful situations some magnetite nanoparticles such as gold nanoparticles, silver nanoparticles, nanodiamonds, dendrimers, polymeric and liposomic smart nanoparticles can be used in medical studies, pharmaceutical industry, nanotheranostic studies and molecular methods. Zebrafish (Danio rerio), which is used a model species in many study disciplines, has been used in many studies to reveal the potential toxic effects and positive effects of the tested nanoparticles. Both in vivo and in vitro test systems and interdisciplinary studies conducted in recent years were analyzed and evaluated via the traditional review method in the current study. Besides, many studies were grouped in order to obtain fast and efficient results on the characterization of nanoparticles and understanding their mechanism of action. A systematic search was conducted based on the keywords of this study in databases such as PubMed, Google Scholar, Web of Science and Carrot², in May 2022. In addition to recognizing the toxic effects of nanoparticles, several studies were emphasized, in which the utilitarian status of nanoparticles in medical, pharmaceutical, molecular and genetic applied studies was understood more clearly day by day.
... Dendrimerler, iç boşlukların varlığı ve son grupları sayısı ile karakterize edilir (19). (20). ...
... This precisely controlled architecture allows modification of dendrimers as per the requirements, which makes these compounds ideal carrier in the field of medicine. The tailor made surface of dendrimers provides opportunities for designing and tuning properties that are not possible with other types of nanocarriers [119]. ...
... Dendrimers are spherical polymeric molecules, which consist of a central core and monomer molecules are attached with core to form different branches [83]. By means of the number of branches attached to the core molecule, dendrimers are classified by their generations such as G0, G0.5, G1, G2, G3 G4 and G5 (Fig. 5) [84]. Dendrimers have longer half-life and multifunctional region; therefore, it mainly used to deliver cytotoxic drugs [85,86]. ...
Background:
Delivery of chemotherapeutic drugs for the diagnosis and treatment of cancer is becoming advanced day by day. However, the challenge of the effective delivery system still does exist. In various types of cancers, breast cancer is the most commonly diagnosed cancer among women. Breast cancer is a combination of different diseases. It cannot be considered as only one entity because there are many specific patient factors, which are involved in the development of this disease. Nanotechnology has opened a new area in the effective treatment of breast cancer due to the several benefits offered by this technology.
Methods:
Polymeric nanocarriers are among one of the effective delivery systems, which has given promising results in the treatment of breast cancers. Nanocarriers does exert their anticancer effect either through active or passive targeting mode.
Results:
The use of nanocarriers has been resolute about the adverse effects of chemotherapeutic drugs such as poor solubility and less penetrability in tumor cells.
Conclusion:
The present review is focused on recent developments regarding polymeric nanocarriers, such as polymeric micelles, polymeric nanoparticles, dendrimers, liposomes, nanoshells, fullerenes, carbon nanotubes (CNT) and quantum dots, etc. for their recent advancements in breast cancer therapy.
... Some of the applications of dendrimers include solubilization, gene therapy, and immunoassay. However, the conjugation and encapsulation of drug with dendrimers have provided a platform for oral delivery of hydrophobic drugs like antihypertensive drugs or anticancer drugs [29,42,56,57]. The improvement in solubility through dendrimers depends upon dendrimer concentration, pH, generation size, core, terminal functionality, and temperature. ...
Oral administration is the most convenient route among various routes of drug delivery as it offers high patient compliance. However, the poor aqueous solubility and poor enzymatic/metabolic stability of drugs are major limitations in successful oral drug delivery. There are several approaches to improve problems related to hydrophobic drugs. Among various approaches, nanotechnology based drug delivery system has potential to overcome the challenges associated with the oral route of administration. Novel drug delivery systems are available in many areas of medicine. The application of these systems in the treatment of hypertension continues to broaden. The present review focuses on various nanocarriers available in oral drug administration for improving solubility profile, dissolution, and consequently bioavailability of hydrophobic antihypertensive drugs.
... Cationic dendrimers are suitable as non-viral vectors for gene delivery because of their ability to form compact complexes with negatively charged DNA and RNA. They constitute a support for the attachment of drugs or genes and their release by various mechanisms [86]. ...
Biopharmaceuticals are a generation of drugs that include peptides, proteins, nucleic acids and cells products. According to their particular molecular characteristics (e.g. high molecular size, susceptibility to enzymatic activity), these products present some limitations for administration and usually parenteral routes are the only option. To avoid these drawbacks, different colloidal carriers (e.g. liposomes, micelles, microemulsions and dendrimers) have been proposed to improve biopharmaceuticals delivery. Liposomes are promising drug delivery systems, despite some limitations have been reported (e.g. in vivo failure, poor long-term stability and low transfection efficiency), and only a limited number of formulations have reached the market. Micelles and microemulsions require more studies to exclude some of the observed drawbacks and guarantee their potential for use in clinic. According to their peculiar structures, dendrimers have been showing good results for nucleic acids delivery and a great development of these systems during next years is expected. This is the Part II of two review articles, which provides the state of the art of biopharmaceuticals delivery systems. Part II deals with liposomes, micelles, microemulsions and dendrimers.
... Dendrimerler, iç boşlukların varlığı ve son grupları sayısı ile karakterize edilir (19). (20). ...
... Dendrimers can be classified depending on the number of branches, called generations like G1, G2, G3 and G4. They are approximately 2-10 nm in diameter [72]. They offer many advantages over conventional polymers. ...
Abstract Breast cancer is a leading cause of death for woman in the world. Cancer has the potential to spread to different organs around the body, and form metastases that can even develop after surgical removal of the primary tumour. Nanotechnology offers new promising strategies for the treatment of breast cancer, and has emerged as a powerful tool for fighting cancer. Nanoparticles can be fabricated to perform more than one task simultaneously, and can have a number of roles, such as acting as a therapeutic agent, drug delivery vehicle and/or tumour imaging agent. This review will focus on various forms of nanoparticles serving as potential agents for cancer therapeutics, illustrating their use in breast cancer therapies. This article also highlights the properties, current progress in the design and engineering of nanoparticles.
... This precisely controlled architecture allows modification of dendrimers as per the requirements, which makes these compounds ideal carrier in the field of medicine. The tailor made surface of dendrimers provides opportunities for designing and tuning properties that are not possible with other types of nanocarriers [119]. ...
International Union of Pure and Applied Chemistry (IUPAC) has defined nanomaterials as materials having sizes smaller than 100 nanometers (1 nm = 10−9 m) along at least one dimension (length, width, or height) [1]. Nanomaterials are a new step in the evolution of understanding and utilization of materials. They are investigated as promising tools for the advancement of diagnostic biosensors, drug/gene delivery and biomedical imaging for their unique physicochemical and biological properties. Many properties of nanomaterials, such as size, shape, chemical composition, surface structure, surface charge, aggregation, agglomeration, and solubility can greatly influence their interactions with biomolecules and cells [2]. The uniqueness of the structural characteristics, energetics, response, dynamics, and chemistry of nanostructures constitutes the basis of nanoscience [3]. Suitable control of these properties and responses of nanostructures can lead to new devices and technologies. Although it is basically impossible to cover all the areas where nanoscale materials are involved, we have made a choice of topics for this book that will provide the reader not only with a broad overview of current hot topics in materials chemistry, but also with specific examples of the special properties of these materials and some particular applications of interest.
Background
Worldwide, lung cancer is the major cause of deaths due to cancer. Most of the lung cancer cases are categorized as 85% cases of non-small cell lung cancer, while remainder 15% cases are known as small cell lung cancer. The long survival time as well as the improved quality of life for patients undergoing lung cancer using conventional chemotherapy is still not satisfactory. Therefore, robust research undergoes development of drug delivery system which increased drug at target side with reduced systemic side effect.
Method
Bibliography database reviewed various inhalable nanostructured drug delivery strategies for effective delivery of anticancer drugs to lung cancer which are designed to improve the therapeutic index of anticancer drugs throughout improvement of their stability as well as bioavailability.
Results
It has been reported that nanostructure based inhalation chemotherapy is more successful targeting system and also offers reduced side effects than conventional chemotherapy.
Conclusion
Thus, the review highlights the critical issues, strategies for delivery and provides detail on various inhalable nanostructures for anticancer drug delivery along with toxicity concerns as well as rationale behind development of inhalable nanostructures.
Dendrimer are highly branched molecule having a well defined size, shape, molecular weight, and monodispersity as compared to linear polymer. Dendrimer have tree like shape consist of central core, branches and terminal group. The bioactive agents may either be encapsulated into the interior of the dendrimers or they may be chemically attached or physically adsorbed onto the Dendrimer surface. Dendrimer have wide application in pharmaceutical field, in gene transfection, as a diagnostic agent, as blood substituent, as solubility enhancer. Surface-modified dendrimers themselves may act as nano-drugs against tumours, bacteria and viruses. This review focus on structure, property, method of synthesis, various method of characterisation, application of Dendrimer, formulation of Dendrimer.
Dendrimers are novel synthetic polymeric systems having improved physical and chemical properties due to their unique three dimensional architecture. Dendrimers have a well defined size, shape, molecular weight and monodispersity. These are compatible with drug moieties as well as bioactive molecules like DNA, heparin and other polyanions. The nanoscopic size and recognition abilities make dendrimers as ideal building blocks for self-assembly and self-organization systems. The cavities inside the dendritic structure can be modified to incorporate hydrophobic and hydrophilic drugs. The terminal groups are modified to attach antibodies and bioactive substances fortargeting purpose along with providing miscibility, reactivity and solubility. Currently, dendrimers are of great interest for delivering drug molecules via different routes as a nanocarrier. Toxicity problems associated withcationic dendrimers are overcome by PEGylation, which neutralizes the charge on them. Dendrimers possess suitable properties to establish itself as a potential carrier for delivery of therapeutic agents irrespective of certain synthetic and regulatory constraints. This review contains various structural aspects and properties of dendrimers along with their pharmaceutical application as a potential novel drug delivery carrier.
Dendrimer are highly branched molecule having a well defined size, shape, molecular weight, and monodispersity as compared to
linear polymer. Dendrimer have tree like shape consist of central core, branches and terminal group. The bioactive agents may
either be encapsulated into the interior of the dendrimers or they may be chemically attached or physically adsorbed onto the
Dendrimer surface. Dendrimer have wide application in pharmaceutical field, in gene transfection, as a diagnostic agent, as blood
substituent, as solubility enhancer. Surface-modified dendrimers themselves may act as nano-drugs against tumours, bacteria and
viruses. This review focus on structure, property, method of synthesis, various method of characterisation, application of Dendrimer,
formulation of Dendrimer.
Multidrug resistance (MDR) is a major barrier against effective cancer treatment. Dual-delivering a therapeutic small interfering RNA (siRNA) and chemotherapeutic agents has been developed to reverse drug resistance in tumor cells. In this study, amine-terminated generation 5 polyamidoamine (PAMAM) dendrimers (G5.NH2) modified selenium nanoparticles (G5@Se NPs) were synthesized for the systemic dual-delivering mdr1 siRNA and cisplatin (DDP), which was demonstrated to enhance siRNA loading, releasing efficiency and gene-silencing efficacy. When the mdr1 siRNA was conjugated with G5@Se NPs via electrostatic interaction, a significant down-regulation of P-glycoprotein and multidrug resistance-associated protein expression was observed; G5@Se-DDP-siRNA arrested A549/DDP cells at G1 phase and led to an enhanced cytotoxicity in A549/DDP cells through induction of apoptosis involving the AKT and ERK signaling pathways. Interestingly, G5@Se-DDP NPs were much less reactive than DDP in the reactions with both MT and GSH, indicating that loading of DDP in a nano-delivery system could effectively prevent cell detoxification. Furthermore, animal studies demonstrated that the new delivery system of G5@Se-DDP-siRNA significantly enhanced the anti-tumor effect on tumor-bearing nude mice with no appreciable abnormality in the major organs. These results suggest that G5@Se NPs could be a potential platform to combine chemotherapy and gene therapy technology in the treatment of human disease.
Biocompatible dendrimers with well-defined nanosizes are increasingly being used as carriers for drug delivery. 5-Aminosalicylic acid (5-ASA) is an FDA approved therapeutic agent recently found effective in treating retinal degeneration of animal models. Here, a water-soluble dendrimer conjugate of 5-ASA (AGFB-ASA) was designed to treat such retinal degeneration. The drug was conjugated to a generation 2 (G2) lysine dendrimer with a silsesquioxane core (nanoglobule) by using a hydrolysable Schiff base spacer. Incubation of nanoglobular G2 dendrimer conjugates containing a 4-formylbenzoate (FB) Schiff base spacer in pH 7.4 phosphate buffers at 37 °C gradually released 5-ASA. Drug release from the dendrimer conjugate was significantly slower than from the low molecular weight free Schiff base of 5-ASA (FB-ASA). 5-ASA release from the dendrimer conjugate was dependent on steric hindrance around the spacer. After intraperitoneal injection, the nanoglobular 5-ASA conjugate provided more effective 7-day protection against light-induced retinal degeneration at a reduced dose than free 5-ASA in Abca4-/-Rdh8-/- mice. The dendrimer 5-ASA conjugate with a degradable spacer could be a good candidate for controlled delivery of 5-ASA to the eye for treatment of retinal degeneration.
Transdermal route is an evolving panorama in novel drug deliverance and with oral route they proffer immense potential. Most recently there is hastening in approaches for delivering bioactives via these routes, amongst them revolution has been made by dendrimers. Encapsulation and conjugation of bioactives with these virus sized robots have shown immense employment for delivery of hydrophobic and labile remedies. Transport of these nano-cruises from corner to corner of skin and through epithelial hurdle of gastrointestinal tract depends upon dendrimer characteristics. An improved thoughtful of these characteristics is an obligation for their use in these rambling fields. These characteristics embrace generation size, molecular weight, surface charge, incubation time and concentration. This context demarcates the imperative role of dendrimers in transdermal and oral drug delivery. This review also highlights concerning mechanism of convey of nanoarrays via epithelial hurdle of GIT.
The emergence of nanotechnology has had a profound effect on many areas of healthcare and scientific research. Having grown exponentially, the focus of nanotechnology has been on engineering diversified novel applications that even go beyond therapeutic activity; nanotechnology also offers the ability to detect diseases, such as cancer, much earlier than ever imaginable. Often, patients diagnosed with breast, lung, colon, prostate, and ovarian cancer have hidden or overt metastatic colonies. With the advent of diagnostic nanotechnology, these numbers are expected to greatly diminish. This review provides a brief description of nanoparticle (liposome, quantum dot, and dendrimer)-mediated cancer therapy in the last decade with an emphasis on the development and use of dendrimers in cancer therapeutics.
Dendrimers have successfully proved themselves as useful additives in different routes of drug administration because they can render drugs greater water-solubility, bioavailability, and biocompatibility. This review demonstrated the potential of dendrimers to be applied in these detailed routes with particular reference to intravenous, oral, transdermal, and ocular delivery systems. As a necessary introduction, the structures, synthesis, and properties of dendrimers were presented. Furthermore, the interaction mechanisms between dendrimers and drug molecules, including simple encapsulation, electrostatic interaction, and covalent conjugation, were elaborated.
In the present study, artemether (ART), a potent anti-malarial drug, was solubilized in PEG-lysine type dendritic peptide-based nanoparticulate carriers for sustained and controlled delivery of the drug through intravenous route of administration. PEG-amine was taken as core in the present system and various generations of dendritic nanoparticles were synthesized by fluorenyl methoxy carbonyl (FMOC)-based liquid phase peptide synthesis process. The systems were further conjugated with chondroitin sulphate A (CSA). ART was solubiliied in these carriers by vortexing, shaking and incubation. The systems were found to be entrapping 10-18 molecules of ART per molecule of dendrimers. The release was prolonged up to 1-2 days, depending upon the increase in generations from 4.0 to 5.0 G. Conjugation with CSA increased the amount of drug loading and prolonged drug release significantly by two- to three-fold on coating with equimolar CSA. CSA conjugation made the systems relatively less hemolytic, larger in particle size and significantly decreased macrophage toxicity. CSA conjugation additionally helped in clearing circulating ring and trophozoite stages of P. falciparum in cultures in vitro. In vivo studies showed prolonged release of ART from both CSA coated and uncoated systems up to 13 h. The mean residence time was found to have increased nearly two- to four-fold, respectively, from such uncoated and coated nanoparticulate carriers as compared to normal i.m. injections. Hence such systems can suitably act as sustained release circulating nanoparticulate carriers for possible controlled delivery of antimalarials to parasitized erythrocytes.
An elegant route to aromatic hydrocarbon dendrimers, such as 1 with pentaphenylbenzene units, and to extremely large polybenzenoid hydrocarbons is based on Diels–Alder cycloadditions of 3,4-bis-[4-(triisopropylsilylethynyl)phenyl]-2, 5-diphenylcyclopenta-2,4-dienone and aromatic oligoethynyl compounds such as 3,3′,5,5′-tetraethynylbiphenyl. The type of linkage and the high packing density of the benzene rings facilitate the cyclodehydrogenation of appropriate dendrimeric subunits to yield planar disks.
Polyamidoamine (PAMAM) dendrimers are used as carriers to deliver complexed Fe(III) ions uniformly onto silicon oxide substrates for the formation of iron oxide nanoparticles with a narrow diameter in the range of 1−2 nm. Chemical vapor deposition (CVD) synthesis with these nanoparticles affords single-walled carbon nanotubes (SWNTs) with a diameter distribution in the range of 1−2 nm, much narrower than that for SWNTs grown from commonly used powder-supported catalyst (1−5 nm) and from artificial ferritin derived nanoparticles (1−3 nm). Thus, the current work represents a step further toward the synthesis of monodispersed SWNTs via the approach of chemically controlling the formation of discrete catalyst nanoparticles.
Polyamidoamine (PAMAM) dendrimers have steadily grown in popularity in the past decade in a variety of disciplines, ranging from materials science to biomedicine. This can be attributed in part to their use in applications that range from computer toners to medical diagnostics. PAMAM dendrimers are safe and nonimmunogenic, and can function as highly efficient cationic polymer vectors for delivering genetic material into cells. They have been shown to be as efficient or more efficient than either cationic liposomes or other cationic polymers (e.g. polyethylenimine, polylysine) for in vitro gene transfer. This article will focus on the application of PAMAM dendrimers as a nonviral gene delivery vector from the initial discovery of this capacity to the most recent experimental findings.
This review is introduced by an examination of the historical roles that quantized building blocks, such as atoms and monomers have played in the development of small molecule and traditional polymer synthesis, respectively. The unique features of traditional macromolecular architectures (i.e. linear, crosslinked, branched), as well as controlled nanostructures in biology were used as frames of reference to anticipate potential new properties, phenomena and synthetic constructs that should be expected to emerge at the interface of the ‘dendritic architectural state’ with the nanotechnology revolution. Intrinsic new properties associated with the ‘dendritic architectural state’, such as the ability to control monodisperse nanoscale sizes, shapes and presentation of surface functionality are reviewed. Unique ‘dendritic effects’ related to de Gennes dense packing (i.e. unimolecular encapsulation, periodic nanocontainer properties), polyvalency (nanoscaffolding), as well as shape designing both within (i.e. cystamine core dendrimers) and beyond dendrimers (i.e. core–shell tecto(dendrimers)) to mimic biological proteins are described. The precise, quantized core–shell architectural properties and monomer shell filling features of dendrimers are compared to the electron shell filling patterns of elemental atoms by utilizing the Niels Bohr Periodic Table. This comparison has provided a rationale for explaining autoreactivity patterns observed at the sub-nanoscale (atoms), lower nanoscale (dendrimers) and higher nanoscale levels involving either unsaturated electron shells, monomer shells or dendrimer shells, respectively. Clearly, dendritic polymers, especially dendrons and dendrimers are expected to fulfill important roles as fundamental, reactive modules for nanoscale polymer syntheses.
A large number of drug delivery systems--mostly in the form of liposomes, microspheres, nanoparticles and hydrogels--have been designed to achieve targeted delivery and sustained release of drugs by exploiting the inherent properties of polymers. The size, shape, and surface properties of the polymer are used to modulate the pharmacokinetic and pharmacodynamic behavior of drugs conjugated with or encapsulated in the polymeric carrier. Recently, a class of well-defined, monodisperse, and tree-like polymers called dendrimers has attracted attention because of the flexibility they offer in terms of their size, shape, branching, length, and surface functionality. A unique characteristic of dendrimers is that they can act as a particulate system while retaining the properties of a polymer. Drugs and diagnostic agents can be encapsulated in the central core or bound to the surface of the dendrimer by noncovalent or covalent interaction. Dendritic polymers can significantly improve pharmacokinetic and pharmacodynamic properties of low molecular weight and protein-based therapeutic agents. Furthermore, fluorescent antibodies and imaging contrast agents can be bound to these new polymers and the resulting complexes can be used for analyzing biological fluids and for diagnosis. Because of their size, shape, and ability to conjugate with a wide range of chemical entities, dendrimers have found many applications in the pharmaceutical and biomedical sciences. This review focuses on the unique carrier properties of biomimetic dendrimers and discusses a wide range of applications of dendrimers in drug delivery, including their use as drug solubilizers, absorption enhancers, release modifiers, and carriers for targeting drugs and diagnostic agents.
This mini review highlights issues associated with the use of dendrimers as drug delivery vehicles. The review introduces dendrimers and summarizes findings on their use in vivo and in vitro. Specifically, this review is limited to examples wherein the drug is non-covalently associated with the dendrimer. Examples wherein the drug is covalently attached to the dendrimer are not discussed.
Dendrimers are new class of polymeric materials. It is generally described as a macromolecule, which is characterized by its extensively branched 3D structure that provides a high degree of surface functionality and versatility. The unique properties associated with these dendrimers such as uniform size, high degree of branching, water solubility, multivalency, well-defined molecular weight and available internal cavities make them attractive for biological and drug-delivery applications. Commercialization of dendrimers is now forthcoming. The present review briefly describes about dendrimer synthesis strategies, types of dendrimers with different functionalities, properties which having crucial importance and their potential applications.
A fourth wheel: Two sets of bifunctional AB(2)C dendrimers having internal acetylene/azides and external hydroxy groups were constructed utilizing benign synthetic protocols. An in situ postfunctionalization strategy was successfully carried out to illustrate the chemoselective nature of these dendrimers. The dendrimers were also transformed into dendritic nanoparticles or utilized as dendritic crosslinkers for the fabrication hydrogels.
To synthesise symmetrical dendritic macromolecules with external lipid surfaces, to investigate their behaviour at the air-water interface and their ability to form supramolecular aggregates, and to gain an understanding of their potential as drug carriers.
Dendrimeric compounds were synthesised with molecular weights ranging from 737 (1st generation dendrimer) to 25,246 (6th generation dendrimer) with carbon numbers ranging from 40 to 1404. The surface behaviour of these compounds was determined using spread films at the air/water interface on a Langmuir trough, and transmission electron microscopy was used to study the supramolecular aggregates formed by the more hydrophobic members of the series.
Dendrimers up to a maximum of 6 generations were synthesised. Surface saturation did not allow the completion of the synthesis of the 7th generation. The limiting surface areas at the air/water interface ranged from 0.4 nm2 to 16.1 nm2 values in good agreement with the areas derived from computer generated molecular models (0.5 nm2 to 14 nm2).
The synthesised dendrimers exhibited a linear relationship between area per molecule and the molecular weight of the compounds. A dendrimer with 16 lipoamino acid branches formed tubular supramolecular aggregates with a helical structure and dimensions in the long axis of 140-200 nm.
The need to develop target-specific MRI contrast agents to aid in disease characterization remains highly essential. In this study, we present a generation four polyamidoamine (PAMAM) folate-dendrimer that specifically targets the high affinity folate receptor (hFR) overexpressed on more than 80% of ovarian tumors. In vitro, mouse erythroleukemia cells expressing the hFR bind the radiolabeled folate-dendrimer chelate resulting in over 2700% increase in binding compared with untreated cells. The binding was inhibited by free folic acid to levels observed on folate-receptor-negative cells. In vivo, ovarian tumor xenografts resulted in a 33% contrast enhancement, following the folate-dendrimer chelate administration, that was significantly different compared with results obtained with a non-specific, extracellular fluid space agent, Gd-HP-DO3A. In addition, this contrast enhancement was absent in saline-treated animals, folate-receptor-negative tumors, and was inhibited by free folic acid. Results suggest that a macromolecular, dendrimeric MRI agent with high molecular relaxivities (1646 mM(-1) s(-1)) can be used in specifically targeting the hFR on tumor cells and ovarian tumors.
Dendrimers are a new class of polymeric materials. They are highly branched, monodisperse macromolecules. The structure of these materials has a great impact on their physical and chemical properties. As a result of their unique behaviour dendrimers are suitable for a wide range of biomedical and industrial applications. The paper gives a concise review of dendrimers' physico-chemical properties and their possible use in various areas of research, technology and treatment.
NOESY-HSQC 3D-NMR and NOESY 2D-NMR techniques have been used on a 750 MHz spectrometer to study the chain conformations of different generation DAB dendrimers (poly[propylene imine] dendrimers) in chloroform and benzene solutions. The high-field multidimensional NMR techniques provided the chemical shift dispersion needed to resolve all of the unique resonances in the dendrimers. By studying the NOE interactions among dendritic chain protons, information about through space interactions between protons on different parts of the dendrimer chain is obtained, which is directly related to the conformation of the dendrimer. These experiments also give further proof of the chemical shift assignments obtained from the HMQC-TOCSY 2D and 3D NMR experiments. The concentration effects on chemical shifts have also been observed, revealing information about the interactions between solvent and different parts of dendrimer molecules. These studies clearly show for DAB dendrimers, that folded chain conformations can occur in nonpolar solvents such as benzene and extended chain conformations are predominant in polar solvents such as chloroform.
High molecular weight polymers (> 20 000 Da) have been widely used as soluble drug carriers to improve drug targeting and therapeutic efficacy. Dendritic polymers are exceptional candidates for the preparation of near monodisperse drug carriers due to their well-defined structure, multivalency, and flexibility for tailored functionalization. We evaluated various dendritic architectures composed of a polyester dendritic scaffold based on the monomer unit 2,2-bis(hydroxymethyl)propanoic acid for their suitability as drug carriers both in vitro and in vivo. These systems are both water soluble and nontoxic. In addition, the potent anticancer drug, doxorubicin, was covalently bound via a hydrazone linkage to a high molecular weight 3-arm poly(ethylene oxide)-dendrimer hybrid. Drug release was a function of pH, and the release rate was more rapid at pH < 6. The cytotoxicity of the DOX-polymer conjugate measured on multiple cancer lines in vitro was reduced but not eliminated, indicating that some active doxorubicin was released from the drug polymer conjugate under physiological conditions. Furthermore, biodistribution experiments show little accumulation of the DOX-polymer conjugate in vital organs, and the serum half-life of doxorubicin attached to an appropriate high molecular weight polymer has been significantly increased when compared to the free drug. Thus, this new macromolecular system exhibits promising characteristics for the development of new polymeric drug carriers.
Peptide dendrimers are radial or wedge-like branched macromolecules consisting of a peptidyl branching core and/or covalently attached surface functional units. The multimeric nature of these constructs, the unambiguous composition and ease of production make this type of dendrimer well suited to various biotechnological and biochemical applications. Applications include use as biomedical diagnostic reagents, protein mimetics, anticancer and antiviral agents, vaccines and drug and gene delivery vehicles. This review focuses on the different types of peptide dendrimers currently in use and the synthetic methods commonly employed to generate peptide dendrimers ranging from stepwise solid-phase synthesis to chemoselective and orthogonal ligation.
Dendrimers are synthetic, highly branched, mono-disperse macromolecules of nanometer dimensions. Started in the mid-1980s, the research investigations into the synthetic methodology, physical and chemical properties of these macromolecules are increasing exponentially with growing interest in this field. Potential applications for dendrimers are now forthcoming. Properties associated with these dendrimers such as uniform size, water solubility, modifiable surface functionality and available internal cavities make them attractive for biological and drug-delivery applications.
Pluronic block copolymers are found to be an efficient drug delivery system with multiple effects. The incorporation of drugs into the core of the micelles formed by Pluronic results in increased solubility, metabolic stability and circulation time for the drug. The interactions of the Pluronic unimers with multidrug-resistant cancer cells result in sensitization of these cells with respect to various anticancer agents. Furthermore, the single molecular chains of copolymer, unimers, inhibit drug efflux transporters in both the blood-brain barrier and in the small intestine, which provides for the enhanced transport of select drugs to the brain and increases oral bioavailability. These and other applications of Pluronic block copolymers in various drug delivery and gene delivery systems are considered.
The present study was aimed at developing and exploring the use of uncoated and PEGylated newer PAMAM dendrimers for delivery of anti-cancer drug 5-fluorouracil. For this study, successive Michael addition and exhaustive amidation reactions were used to synthesize 4.0 G PAMAM dendrimers, using ethylenediamine as core and methylmethacrylate as propagating agent. The dendrimer was PEGylated using N-hydroxysuccinimide-activated carboxymethyl MPEG-5000. IR and NMR data proved the synthesis. Various physicochemical parameters, SEM, TEM, lambda(max) values, hemolytic toxicity, drug entrapment, drug release and blood-level studies of both PEGylated and non-PEGylated systems were determined and compared. The PEGylation of the systems was found to have increased their drug-loading capacity, reduced their drug release rate and hemolytic toxicity. TEM study revealed surface properties of the systems. Stability studies had shown its stability at room temperature in dark. The systems were found suitable for prolonged delivery of an anti-cancer drug by in vitro and blood-level studies in albino rats, without producing any significant hematological disturbances. PEGylation has been found to be suitable for modification of PAMAM dendrimers for reduction of drug leakage and hemolytic toxicity. This, in turn, could improve drug-loading capacity and stabilize such systems in body. The study suggests use of such PEGylated dendrimeric systems as nanoparticulate depot type of system for drug administration.
The transdermal delivery of aqueous formulations of indomethacin, a model drug, with different concentrations of three types of dendrimer showed a linear increase in flux with increasing concentration of each of the dendrimers. This result was in contrast to phase solubility studies, where Higuchi's A(N) profile was observed. The steady-state flux of the drug increased significantly and was highest with the G4-NH2 dendrimer at 0.2% w/v concentration, which showed an enhancement factor of 4.5 compared to the pure drug suspension. In vivo, a steady-state flux was achieved in 5 h, and the C(max) values were significantly higher with G4-NH2 and G4-OH dendrimer formulations. The [AUC](0-24h) of G4-NH2 (2.27 times) and G4-OH (1.95 times) formulations were significantly higher than that of the pure drug, but was only marginally higher in the case of G-4.5 dendrimer formulation. The % inhibition of paw volume showed a trend comparable to the pharmacokinetic data and a maximum of 1.6- and 1.5-fold increase was found with G4-NH2 and G4-OH formulations, respectively, compared to the pure drug suspension.
The unique properties of dendrimers, such as their high degree of branching, multivalency, globular architecture and well-defined molecular weight, make them promising new scaffolds for drug delivery. In the past decade, research has increased on the design and synthesis of biocompatible dendrimers and their application to many areas of bioscience including drug delivery, immunology and the development of vaccines, antimicrobials and antivirals. Recent progress has been made in the application of biocompatible dendrimers to cancer treatment, including their use as delivery systems for potent anticancer drugs such as cisplatin and doxorubicin, as well as agents for both boron neutron capture therapy and photodynamic therapy.
Dendrimers are a unique class of synthetic macromolecules having a highly branched, three-dimensional, nanoscale architecture with very low polydispersity and high functionality. Structural advantages allow dendrimers to play an important role in the fields of nanotechnology, pharmaceutical and medicinal chemistry. This review discusses several aspects of dendrimers, including preparation, dendrimer-drug coupling chemistry, structural models of dendrimer-based drug delivery systems, and physicochemical and toxicological properties.
Ketoprofen, a non-steroidal anti-inflammatory drug with well-known anti-inflammatory, antipyretic and analgesic properties, has low solubility in water and causes local or systemic disturbance in the gastrointestinal tract. In the present study we investigated the potential of polyamidoamine (PAMAM) dendrimers as drug carriers of ketoprofen by in vitro and in vivo studies. The in vitro release of ketoprofen from the drug-dendrimer complex is significantly slower compared to pure ketoprofen. Anti-nociceptive studies using the acetic acid-induced writhing model in mice showed a prolonged pharmacodynamic behavior for the ketoprofen-PAMAM dendrimer complex. Also, the blood level studies were investigated. We concluded that PAMAM dendrimers might be considered as a potential drug carrier of ketoprofen with a sustained release behavior under suitable conditions.
Polymeric micelles, self-assemblies of block copolymers, are promising nanocarrier systems for drug and gene delivery. Until now, several micellar formulations of antitumor drugs have been intensively studied in preclinical and clinical trials, and their utility has been demonstrated. Even compared with long-circulating liposomes, polymeric micelles might have several advantages, such as controlled drug release, tissue-penetrating ability and reduced toxicity such as hand-foot syndrome and hypersensitivity reaction. Importantly, critical features of the polymeric micelles as drug carriers, including particle size, stability, and loading capacity and release kinetics of drugs, can be modulated by the structures and physicochemical properties of the constituent block copolymers. Also, nano-engineering of block copolymers might allow the preparation of polymeric micelles with integrated smart functions, such as specific-tissue targetability, as well as chemical or physical stimuli-sensitivity. Thus, polymeric micelles are nanotechnology-based carrier systems that might exert the activity of potent bioactive compounds in a site-directed manner, ensuring their effectiveness and safety in the clinical use.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs in the world, primarily for symptoms associated with osteoarthritis and other chronic musculoskeletal conditions. However, adverse effects caused by oral administration, such as local or systemic disturbance in the gastrointestinal tract, have limited the clinical applications of these drugs. In the present study we have assessed the ability of polyamidoamine (PAMAM) dendrimers to facilitate transdermal delivery of NSAIDs, using Ketoprofen and Diflunisal as model drugs. In vitro permeation studies with excised rat skins indicated that PAMAM dendrimers significantly enhanced the accumulative permeated amount of both drugs after 24 h, as compared to drug suspensions without PAMAM dendrimers. Similarly, anti-nociceptive studies using the acetic acid-induced writhing model in mice showed a prolonged pharmacodynamic profile for the NSAIDs-PAMAM dendrimer complex after transdermal administration. In addition, blood drug level studies revealed that the bioavailability was 2.73 times higher for the Ketoprofen-PAMAM dendrimer complex and 2.48 times higher for the Diflunisal-PAMAM dendrimer complex, respectively, than the pure drug suspensions. These results demonstrated that PAMAM dendrimers can effectively facilitate skin penetration of NSAIDs and may have the potential applications for the development of new transdermal formulations.
The aim of the study was to determine the effects on the transport of propranolol across monolayers of the human colon adenocarcinoma cell line, Caco-2, of forming a prodrug by conjugating to generation 3 (G3) and lauroyl-G3 PAMAM dendrimers. Propranolol is a poorly soluble drug and known substrate of the P-glycoprotein (P-gp) efflux transporter. Propranolol-G3 dendrimer conjugates were synthesised by surface attachment of two, four or six propranolol molecules. The apical (A) to basolateral (B) apparent permeability coefficient, P(app), of propranolol was increased and its B-->A P(app) decreased following conjugation to G3 dendrimers. Conjugation of propranolol to lauroyl-G3 dendrimers further increased its A-->B P(app). Our findings show that the A-->B P(app) of propranolol conjugates was reduced in the presence of the endocytosis inhibitor colchicine and was lower at 4 degrees C than at 37 degrees C, suggesting that the enhancement mechanism involves endocytosis-mediated transepithelial transport. The A-->B P(app) of conjugated propranolol was not altered in the presence of the P-gp inhibitor cyclosporin A suggesting that conjugation of drug to dendrimer allows the bypassing of the efflux transporter. The results suggest that dendrimer-drug prodrugs may be used to increase drug solubility and bypass drug efflux transporters, therefore increasing drug bioavailability.
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