Dendrimer nanocomposites in medicine (original) (raw)
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Bioapplications of poly(amidoamine) (PAMAM) dendrimers in nanomedicine
Journal of Nanoparticle Research, 2014
Poly(amidoamine) (PAMAM) dendrimers are a novel class of spherical, well-designed branching polymers with interior cavities and abundant terminal groups on the surface which can form stable complexes with drugs, plasmid DNA, oligonucleotides, and antibodies. Amine-terminated PAMAM dendrimers are able to solubilize different families of hydrophobic drugs, but the cationic charges on dendrimer surface may disturb the cell membrane. Therefore, surface modification by PEGylation, acetylation, glycosylation, and amino acid functionalization is a convenient strategy to neutralize the peripheral amine groups and improve dendrimer biocompatibility. Anticancer agents can be either encapsulated in or conjugated to dendrimer and be delivered to the tumor via enhanced permeability and retention (EPR) effect of the nanoparticle and/or with the help of a targeting moiety such as antibody, peptides, vitamins, and hormones. Biodegradability, non-toxicity, non-immunogenicity, and multifunctionality of PAMAM dendrimer are the key factors which facilitate steady increase of its application in drug delivery, gene transfection, tumor therapy, and diagnostics applications with precision and selectivity. This review deals with the major topics of PAMAM dendrimers including structure, synthesis, toxicity, surface modification, and also possible new applications of these spherical polymers in biomedical fields as dendrimer-based nanomedicine. The core-shell structure for PAMAM dendrimer.
Polyamidoamine dendrimers (PAMAM) are being used as efficient vectors for delivery of nucleic acids to the cells. However, these dendrimers cause a significant amount of cytotoxicity. In order to improve its transfection efficiency and cell viability, surface amine groups of PAMAM were converted into guanidinium (Gn) and tetramethylguanidi-nium (TMG) moieties. These modified PAMAM dendrimers interacted with negatively charged plasmid DNA efficiently and formed stable complexes as revealed by dynamic light scattering analysis. PAMAM/pDNA, PAMAM-TMG/pDNA and PAMAM-Gn/pDNA complexes were found to be in the range of 175-250 nm with zeta potential in the range of +21-37 mV. Further, these modified dendrimers did not display toxicity rather it decreased a bit when tested in HEK293, HeLa and MCF-7 cells. Among these modified dendrimers, PAMAM-Gn/pDNA complex displayed the highest transfection efficiency in both the cell lines HEK293 and MCF-7.
The use of PAMAM dendrimers in the efficient transfer of genetic material into cells
Pharmaceutical Science & Technology Today, 2000
In recent years, the gene therapy field has expanded its search to find a gene delivery vector that achieves high-efficiency, nontoxic transgene expression. Numerous materials have been studied as potential vectors for gene delivery (Box 1) 1-7 with varying results. Polyamidoamine (PAMAM) dendrimers are a relatively new class of nanoscopic, spherical polymers that have captured the interest of researchers in various scientific disciplines over the past few years. This interest was sparked, in part, because of the successful use of PAMAM dendrimers for nonviral gene delivery. PAMAM dendrimers with primary amino surface groups have the inherent ability to associate, condense and efficiently transport DNA into a wide number of cell types, including primary cells, without inducing significant cytotoxicity in vitro 8,9. These dendrimers have also been used as delivery vehicles for oligonucleotides, antisense oligonucleotides and probes for oligonucleotide arrays 9-11. Additionally, experiments in vivo have suggested that efficient gene transfer is possible with PAMAM dendrimers without inducing immunogenicity 12,13. Initial work by Szoka and coworkers with heat-degraded polymers and other research using intact PAMAM dendrimers has produced promising results within the gene delivery field 14. In addition, a significant quantity of information on PAMAM dendrimers has been obtained during the past decade. This information is important for all areas of dendrimer research, but it is just the initial step in a process to optimize PAMAM dendrimers for the delivery of genetic material into cells. Dendrimer synthesis and characterization Tomalia et al. first reported the successful, wellcharacterized synthesis of dendritic polymers in the early 1980s (Ref. 15). Dendrimers are a unique class of synthetic polymers, in which growth emanates from a central (i.e. initiator) core molecule such as ammonia, ethylenediamine, propyldiamine or benzene tricarboxylic acid chloride.The choice of the initiator core is of great importance because it will determine the overall molecular and surface charge density. In the divergent synthesis method, polymer growth emanates in an outward direction from the initiator core by a series of stepwise polymerization reactions that attach layers (i.e. generations) to form the final tree-like structure.The synthesis has been previously described in specific detail 16-18 .
Dendrimers in biomedical applications—reflections on the field
Advanced Drug Delivery Reviews, 2012
The formation of particulate systems with well-defined sizes and shapes is of eminent interest in certain medical applications such as drug delivery, gene transfection, and imaging. The high level of control possible over the architectural design of dendrimers; their size, shape, branching length/density, and their surface functionality, clearly distinguishes these structures as unique and optimum carriers in those applications. The bioactive agents may be encapsulated into the interior of the dendrimers or chemically attached/physically adsorbed onto the dendrimer surface, with the option of tailoring the carrier to the specific needs of the active material and its therapeutic applications. In this regard, the high density of exo-presented surface groups allows attachment of targeting groups or functionality that may modify the solution behavior or toxicity of dendrimers. Quite remarkably, modified dendrimers have been shown to act as nano-drugs against tumors, bacteria, and viruses. Recent successes in simplifying and optimizing the synthesis of dendrimers such as the 'lego' and 'click' approaches, provide a large variety of structures while at the same time reducing the cost of their production. The reflections on biomedical applications of dendrimers given in this review clearly demonstrate the potential of this new fourth major class of polymer architecture and indeed substantiate the high hopes for the future of dendrimers.
Commentary Dendrimers in biomedical applications—reflections on the field B
The formation of particulate systems with well-defined sizes and shapes is of eminent interest in certain medical applications such as drug delivery, gene transfection, and imaging. The high level of control possible over the architectural design of dendrimers; their size, shape, branching length/density, and their surface functionality, clearly distinguishes these structures as unique and optimum carriers in those applications. The bioactive agents may be encapsulated into the interior of the dendrimers or chemically attached/physically adsorbed onto the dendrimer surface, with the option of tailoring the carrier to the specific needs of the active material and its therapeutic applications. In this regard, the high density of exo-presented surface groups allows attachment of targeting groups or functionality that may modify the solution behavior or toxicity of dendrimers. Quite remarkably, modified dendrimers have been shown to act as nano-drugs against tumors, bacteria, and viruses. Recent successes in simplifying and optimizing the synthesis of dendrimers such as the dlegoT and dclickT approaches, provide a large variety of structures while at the same time reducing the cost of their production. The reflections on biomedical applications of dendrimers given in this review clearly demonstrate the potential of this new fourth major class of polymer architecture and indeed substantiate the high hopes for the future of dendrimers. D 2005 Published by Elsevier B.V.
New Advances in General Biomedical Applications of PAMAM Dendrimers
Molecules, 2018
Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named ‘starburst polymers’. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targetin...
Poly(amidoamine) dendrimer complexes as a platform for gene delivery
Expert Opinion on Drug Delivery, 2013
Gene therapy is one of the most effective ways to treat major infectious diseases, cancer, and genetic disorders. It is based on several viral and non-viral systems for nucleic acid delivery. This review discusses and summarizes recent advances in polyamidoamine (PAMAM) dendrimers as effective gene carriers in vitro and in vivo, and their advantages and disadvantages relative to viral vectors and other non-viral systems (liposomes, linear polymers) will be considered. In this regard, dendrimers are nonimmunogenic and have the highest efficiency of transfection among other non-viral systems, and none of the drawbacks characteristic for viral systems. The toxicity of dendrimers both in vitro and in vivo is an important question that has been addressed on many occasions. Several non-toxic and efficient multifunctional dendrimer-based conjugates for gene delivery, along with modifications to improve transfection efficiency whilst decreasing cytotoxicity, are discussed. The conclusion is that dendrimers are promising candidates for gene delivery, but it is early days and further studies are required before using them in human gene therapy.
DENDRIMER: NOVEL STRATEGIES FOR DRUG DELIVERY SYSTEM
The development of novel particulate systems with defined shapes and sizes is of prominent interest in certain therapeutic applications such as drug delivery, gene transfection, diagnostic and imaging. On controlling and designing optimized architectural design of dendrimers; their shape, size, branching pattern length/density, and their surface functionality, clearly discriminate these structures as inimitable and optimal hauler in those applications. Moderately modified dendrimers have been shown to act as nano-drugs adjacent to tumors, viruses and bacteria. Recent triumph in simplifying and optimizing the production of dendrimers make available a large variety of structures while simultaneously reducing the cost of their production. The reflections on biomedical applications of dendrimers given in this review clearly make obvious the impending of this new fourth major class of polymer structural design and undeniably prove the high expectation for the future of dendrimers.
Dendrimer based nanostructures have been increasingly used for delivery of drugs/genes. These nanosystems, as non-viral gene delivery systems, were shown to have relatively high transfection efficiency despite exerting somewhat cytotoxicity. In this current investigation, poly(amido amine) (PAMAM) dendrimers, generation (G) zero to five, PEGylated PAMAM G3 and a new quaternized PAMAM G4 were synthesized and further characterized using FT-IR and 1 H-NMR spectroscopies. The cellular uptakes and toxicity of these nanosystems were investigated using fluorescence microscopy and MTT assay, at which they revealed high internaliza-tion potential with low cytotoxicity in both T47D and MCF-7 cells. To establish a simple detection methodology, a ninhydrin reaction was performed on intact PAMAM full generations as well as PEGylated PAMAM G3 and quaternized PAMAM G4. Impacts of various factors such as reaction time, kinetic, reaction medium, and generation dependency of the reaction of dendrimer...
Journal of Materials Science: Materials in Medicine, 2010
The use of dendrimers as nano-sized excipients/ vectors in biological and pharmaceutical systems is dependent on the investigation of their toxicological profiles in biological media. In this study, a series of mechanistic in vitro structure-associated cell toxicity evaluations was performed on the two generations of an anionic linearglobular dendrimer G1 and G2 (where PEG is the core, and citric acid is the periphery) each of which has a different size, charge, and MW. In vitro cytotoxicity behavior of the dendrimers with the methods like crystal violet staining, methyl thiazolyl tetrazolium (MTT), and lactate dehydrogenase (LDH) assays was analyzed. The cell death mechanisms (apoptosis-necrosis) induced by the dendrimers were also evaluated in HT1080 cell line. The impact of the dendrimers on the release of the pro-inflammatory cytokines like TNF-a (tumor necrosis factor alpha) and IL1-b (interleukin 1 beta) was assessed in THP-1 cell line. Hemolysis assay and coagulation studies such as PT (prothrombin time) and APTT (activated partial thromboplastin time) on human blood samples were conducted to examine the interactions of the dendrimers with such bioenvironments. The results of cell cytotoxicity experiments and the amounts of IL1-b and TNF-a secretions from THP-1 cell line were consistent with the hemoglobin release from the erythrocytes and the results gained from the coagulation studies. In fact, no significant harmful effect was observed for the dendrimers up to the concentration of 0.5 mg/ml. Both apoptosis and necrosis were ascribed to cell death. The G1 with more flexibility, less negative charge, and greater poly dispersity in size versus the G2 displayed more toxicity than the G2 at the concentration of 1 mg/ml and above in most of the experiments. As a whole, these results suggest a biocompatible range for these hybrid structures up to the concentration of 0.5 mg/ml. Therefore, the potentiality for these structures to be employed in the different and numerous realms of nanomedicine will be very great.