Role of dendrimers in advanced drug delivery and biomedical applications: a review
Summary. Aim: Dendrimers dendritic structural design holds vast promises, predominantly for drug delivery, owing to their unique properties. Dendritic architecture is widespread topology found in nature and offers development of specific properties of chemical substances. Dendrimers are an ideal delivery vehicle candidate for open study of the effects of polymer size, charge, and composition on biologically relevant properties such as lipid bilayer interactions, cytotoxicity, bio-distribution, internalization, blood plasma retention time, and filtration. This article reviews role of dendrimers in advanced drug delivery and biomedical applications.
Submitted: March 15, 2018
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Abbreviations used: DTPA — diethylenetriamine pentaacetic acid; MRI — magnetic resonance imaging; NSAIDs — nonsteroidal anti-inflammatory drugs; PAMAM — polyamidoamine; PDT — photodynamic therapy; PEG — polyethylene glycol; RNAi — RNA interference; siRNA — small interfering RNAs.
Dendrimers are exceedingly branched, globular macromolecules with many arms emanating from a central core [1, 2]. The atomistic feature of dendrimer structure has lagged behind this fast progress in synthesis and design . To date, more than fifty families of dendrimers exist, possessing unique properties, since the surface, interior and core can be tailored to diverse types of applications .The derivatization of low molecular weight and protein-based therapeutics with polymers has been shown to advance their pharmacokinetic and pharmacodynamic properties [5, 6]. One of the most talented applications of nanotechnology is in the field of medicine. Certainly, a whole novel field of “nanomedicine” is promising . Nanomedicine plays a vital role to advance drug delivery, cancer treatment, and so on. Dendrimers are nano-sized, radially symmetric molecules with fine-defined, homogeneous and monodisperse composition consisting of tree-like arms or embranchment [8, 9]. Dendrimers are identified by unique properties like globular shape, well defined three dimensional structure, cavities, high functionality and small size. These properties make them unique for using in nanotechnology and diverse biomedical applications [10–12]. Dendrimer structures are formed with a fundamental atom or group of atoms tagged as the core. From this central structure, branches of other atoms called “dendrons” raise through diverse chemical reactions .
Dendrimers show considerably enhanced physical and chemical properties compared to traditional linear polymers. A number of significant properties of dendrimers are: (1) monodispersity; (2) nano-size and shape; (3) biocompatibility; (4) periphery charge; (5) dendrimer-membrane interaction; and (6) pharmacokinetics [13–17].
Types of dendrimers
A quick growth of dendritic new carrier has been probable because of recent advances in synthetic chemistry and characterization methods. Also a variety of dendritic scaffolds has become accessible with defined nanoscopic size and plenty numbers of functional end groups .
Nowadays there are more than fifty families of dendrimers each with unique properties that are undergoing investigation for use in a diversity of different biomedical applications . Dendritic polymers are similar to proteins, enzymes, and viruses, and are simply functionalized. Dendrimers and other molecules can either be linked to the rim or can be encapsulated in their internal holes. Current medicine uses a diversity of this material as potential blood substitutes, for example polyamidoamine (PAMAM) dendrimers . For instance, phosphorus-containing dendrimers have demonstrated antiprion activity and can potentially be used as inductors for gene therapy Boronated starburst PAMAM dendrimer-monoclonal. Antibody immune compounds as potentially effective anticancer reagent containing boron neutron capture were used [21, 22].
Multifunctional end groups and occurrence of various internal cavities cause to be dendrimers appropriate for possible pharmaceutical uses counting a variety of therapeutic and biomedical applications [23–25].
Dendrimers and various routes of drug delivery. Nano scale materials have unique properties, such as structural uniformity, efficient membrane transport, high purity, high drug pay load, good colloidal, targeting potential, and shelf stability. Because of these unique features, dendrimers are one of the talented technologies of recent times and have served as an exceptional platform to reach the development as new drug delivery scaffolds; for instance, PAMAM dendrimers have carried the antitumor drug methotrexate and fluorescein for tracking [26–28]. The best dendrimer must have a low molecular weight to be effortlessly filtered by the kidneys . Due to the unique characteristics of dendrimers, such as well-defined size, shape, molecular weight and monodispersity, these molecules have wide applications in drug delivery [30, 31]. Drug molecules can be physically trapped inside the dendrimers or be adsorbed on the dendrimer surfaces using electrostatic interaction, hydrogen bonding, or van der Waals force. Drug molecules can also be covalently attached on the dendrimer surfaces to provide dendrimer-drug conjugates .
Oral drug delivery. Among the various routes of drug delivery, the oral route is may be the one mostly favored by patients and clinicians. For several available and novel drugs for example peptidomimetics, therapeutic peptides, oligonucleotides and other cases, oral bioavailability is in the most of cases below passable levels. To control this problem and to guaranty an adequate high oral absorption, the use of effective oral drug delivery systems is significant . An effective oral macromolecular drug carrier should have the capability to prevent the drugs from degrading. They might decrease non-specific interactions with food proteins and let increased absorption through the intestinal epithelium. The potential use of PAMAM dendrimers as oral drug delivery carriers have been demonstrated by several studies [34–44]. In a study that was done by Kitchens et al.  it was demonstrated that transepithelial transport and microvascular extravasation of PAMAM dendrimers are dependent upon their structural properties such as molecular geometry, molecular size, and surface chemistry. These consequences indicate that by optimizing factors such as the size and surface charge of PAMAM dendrimers, it is possible to expand oral drug delivery systems based on these carriers.
Ocular drug delivery. Dendrimers have attracted remarkable attention as ocular drug delivery systems, because of their tailorable structure, well-defined size and potentially favorable ocular biodistribution . Surface-modified PAMAM dendrimers with carboxylic or hydroxyl surface groups, have been reported in increasing residence time and improving bioavailability of pilocarpine in the eye . Conjugating of dendrimers with polyethylene glycol (PEG), create hydrogels that have applications including cartilage tissue production and for sealing ophthalmic injuries [48, 49]. Consequently, the improvement of ocular drug delivery by dendrimers may be a promising method for clinical applications.
Transdermal drug delivery. Drug delivery via the skin to get a systemic effect of drug is generally known as transdermal drug delivery . The permeability of dendrimers via the skin is determined by physicochemical parameters such as surface charge, molecular weight, generation size, composition and concentration [51, 52]. Dendrimers have been demonstrated to be effective as transdermal drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs), antimicrobial, antiviral, anticancer or antihypertensive drugs. Yiyun et al.  and other researchers have shown that PAMAM dendrimers can considerably increase transdermal delivery of diflunisal and ketoprofen, two model NSAIDs [53, 54]. Encapsulation of cisplatin, a platinum based anticancer drug into PAMAM dendrimers gave conjugates that presented higher accumulation in solid tumors, slower release, and lower toxicity compared to drug [55, 56].
Targeted drug delivery. Targeted drug delivery is a technique of delivering a therapeutic agent to a specific cell type or tissue in a site-specific manner. Dendrimers have been studied as one kind of vehicle for application in targeted drug delivery [1, 2, 57, 58]. Targeted delivery of chemotherapeutics to tumor cells decreased side effects compared to systemic delivery . Patri et al.  reported the synthesis of generation 5 PAMAM dendrimer conjugated with folic acid for the targeted delivery of methotrexate.
Magnetic resonance imaging (MRI). Recently the use of dendrimers as a new class of macromolecular MRI contrast agents has been explored. The most generally used MRI contrast agents are gadolinium-based contrast agents [59, 60]. The covalent attachment of Gd(III) complexes to PAMAM dendrimers to generate unique macromolecular contrast agents for MRI have been reported by several research groups. Kojima et al.  have prepared fully PEGylated PAMAM dendrimers loaded with Gd-diethylenetriamine pentaacetic acid (DTPA). For conjugation of Gd-DTPA to the side chain, Lysine (Lys) was attached before the PEG modification . Their results showed that PEGylation of a Gd-labeled PAMAM dendrimer decrease the relaxivity and plasma clearance, and variations susceptibility to temperature. Even though PEGylation decreases relaxivity by reducing access to water, by using a bigger dendrimer (G5 vs G4) this effect can be improved with intrinsic higher relaxivities because of slower molecular tumbling rates. The calculation of PEG to a dendrimer increased retention in the vascular pool, a feature that could be useful for vascular imaging in cancer, atherosclerosis, and inflammatory disorders, as well as for improving drug delivery .
Photodynamic therapy (PDT). PDT is a talented approach to treat certain kinds of cancer. PDT was planned as a helpful oncology tool more than 30 years ago, but it has restrictions. The success of PDT depends mostly on photosensitizers and improvement of an effective second generation is continuing. PDT is a hopeful treatment methodology whereby diseased cells and tissues are destroyed by reactive oxygen species by using a combination of light and photosensitizers. Dendrimers possess architecture appropriate for incorporating particular functional moieties and are a hopeful venue for further researches [63, 64].
Delivery of bioactive. The core and the interior branches of a dendrimer can be synthetic or based on natural peptide or saccharide structures. When adorned with peptide or carbohydrate ligands throughout surface functional groups, dendrimers are endowed with the bioactivity to mediate the interaction with cell surface receptors. Bioactive dendrimers can attach with particular receptors on cell membrane [65–70]. When linking peptides or carbohydrates, the general ligation strategies can be applied directly to generating bioactive dendrimer conjugates. However, there are at least two factors characteristically related with the ligation of dendrimer scaffolds: one of them is the type and generation of dendrimer trellis that would ascertain the shape and size of final products and another one is the number of peripheral branches and modification level that could affect the multivalent spatial arrangement and receptor binding properties of bioactive ligands .
Dendrimers in gene delivery. Dendrimers can be used as a transporter in gene therapy. For instance, PAMAM dendrimers have terminal amino groups which interact with phosphate group of nucleic acid. As a result PAMAM dendrimers have been tested as a genetic material vector . Dendrimers were discovered in 1970 by Tomalia and co-workers . The first article using the term “dendrimer” and describing in detail the preparation of poly(PAMAM) dendrimers was presented in 1984. They are polymeric symmetric monodisperse complexes that comprise of well-defined branches around a small molecule, called core. Dendrimers of lower generations (0, 1, and 2) have highly asymmetric shape and have more open structures as compared to higher generation [73–75]. Dendrimers become densely packed as they extend out to the periphery, which forms a closed membrane-like structure . Dendritic copolymers are a specific group of dendrimers, two different types of copolymers were recognized: Segment-block dendrimers are obtained by attaching different wedges to one polyfunctional core molecule. Layer-block dendrimers consist of concentric spheres of differing chemistry .
DNA molecules are well suited for these purposes because of their unique molecular detection features. Linear DNA chains can assemble into a range of non-linear structures: branching of the double helix is induced by breaking the run of the complementarity of the part strands. Dendrimers with arms terminating in oligonucleotides of the same or of different sequences could be used to build cages, cryptands, tubes, nets, scaffolds and other more complex three-dimensional (3-D) structures [76–80]. An important characteristic of nucleic acids is the sharp melting transition of the base-paired double strand. It is important to know how dendrimerisation affects this behavior in order to understand how branched nucleic acids may be used as molecular building blocks .
Recognition features ability to deliver pieces of DNA to the required parts of a cell includes many challenges. 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 [82, 83]. Apart from small drug particles dendrimers are thoroughly examined for the delivery of DNA. PAMAM dendrimers, and polycationic molecules can form complexes with DNA through sequence-independent electrostatic interaction between anionic phosphate groups of nucleic acid and cationic primary amino surface groups. These opposite charges neutralize; therefore, the net charge modifications result in changes of physicochemical and biological properties. The nature of “dendriplexes” are affected not only by concentration of the DNA phosphate groups and dendrimers surface amino groups, also by the shape of dendritic polymers and solvent’s properties such as pH, salt concentration, buffer strength and the dynamics of mixing [84–87].
Targeted delivery of dicer-substrate siRNAs. Small interfering RNAs (siRNA) are talented as new therapeutic agents, given that convenient delivery systems that are available. Dendrimers, a particular group of synthetic macromolecules, demonstrate an exciting delivery platform by virtue of their well-defined dendritic structure and unique multivalency and cooperativity limited within a nanosized volume. Significant interest has been considered to capitalize on dendrimer nanocarriers for the delivery of the emerging RNA interference (RNAi) based nucleic acid drugs [88, 89]. The delivery of RNAi therapeutics should be not only efficient but also targeted in the right site in order to achieve higher efficacy and less toxicity.
Cancer therapy. During the past few years there has been considerable advancement in the application of biocompatible dendrimers for cancer treatment, including their use as drug delivery systems for chemotherapeutic agents such as cisplatin and doxorubicin . The necessity for using of biodegradable dendrimers appeared as a strategy to generate the desired large molecular weight carriers which lead to high retention and accumulation in tumor tissue, while permitting rapid and safe omission of dendrimer fragments into the urine to prevent nonspecific toxicity . Lee et al.  synthesized biodegradable cationic G3 dendrons and G2 dendrimers by the convergent synthetic method and introduced them as candidates for biomedical applications. Because of excellent properties of PEGylated dendrimers, such as tunable pharmacokinetics and ability to carry multiple copies of bioactive molecules, these materials are attractive for many biological applications. The fast and efficient synthesis of a robust and biodegradable PEGylated dendrimer based on a polyester-polyamide hybrid core is demonstrate by Frechet, Szoka and co-workers .
Role of dendrimers in advanced drug delivery and biomedical applications is briefly reviewed. Dendrimers are known as extremely defined artificial macromolecules, which are characterized by a combination of a high number of functional groups and a condensed molecular structure. Pharmacokinetic property is one of the most important aspects in the successful applications of dendrimers, for example, imaging, drug delivery, PDT, etc. The variety of potential applications of dendrimers in medicine results in increasing attention in this area.
The authors thank the Department of Medical Nanotechnology, Faculty of Advanced Medical Science of Tabriz University, for all support provided. This work is funded by a 2017 grant by the Drug Applied Research Center, Tabriz University of Medical Sciences.
conflict of interest
The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.
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