Skip to Main contentScienceDirectJournals BooksRegisterSign in Sign inRegisterJournals BooksHelpPoly[2 (Dimethylamino)ethyl Methacrylate]PAMAM bearing tertiary amino groups in their interior exhibit the proton sponge effect, fulfilling to a significant extent the criteria for gene transfection of cells.From: Progress in Molecular Biology and Translational Science, 2011Related terms:PolymerNanoparticleDNACopolymerPolyamidoaminePolyethyleneimineGenetic TransfectionMicelleAmineMethacrylic AcidView all TopicsDownload as PDFSet alertAbout this pageThe Application, Neurotoxicity, and Related Mechanism of Cationic Polymers∗Y. Li, D. Ju, in Neurotoxicity of Nanomaterials and Nanomedicine, 20172.1.8 PAMAM DendrimersPAMAM dendrimers are commercially available macromolecules that can be used as gene transfer vectors for plasmid DNA, antisense oligonucleotides, and siRNA (Eichman et al., 2000).Choi et al. (2004) presented l-arginine-grafted-PAMAM dendrimers, a novel three-dimensional artificial protein and gene delivery vector. By introducing arginine residues to the dendritic surfaces, gene delivery potency of l-arginine-grafted PAMAM dendrimers was significantly increased by improving cell penetration and internalization mechanisms when compared with native PAMAM or PEI. Imamura et al. (2014) developed a ternary complex of plasmid DNA electrostatically assembled with PAMAM dendrimers and chondroitin sulfate for effective and secure gene delivery. Perez et al. (2009) screened the formation of complexes between ethylendiamine core PAMAM dendrimers and a short interfering RNA, and found that the complex combined with siEGFP and PAMAM dendrimers G7 produced highest suppression of EGFP expression in the cells, although it induced less protection of siRNA against RNase A degradation.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B978012804598500012XGene Delivery Using Chemical MethodsJigar Lalani, Ambikanandan Misra, in Challenges in Delivery of Therapeutic Genomics and Proteomics, 20114.2.1.4 Poly[2-(Dimethyalamino)Ethyl Methacrylate]Hennink et al. have synthesized and evaluated poly[2-(dimethylamino)ethyl methacrylate] (pDMAEMA) for gene transfer (Fig. 4.5) [76–78]. pDMAEMA is a water-soluble cationic polymer, capable of forming compact complexes by electrostatic interaction with DNA [77]. The size of the complex depends on molecular weight. High-molecular-weight pDMAEMA (ϱ300 kDa) was capable of condensing DNA effectively into particles of 150–200 nm, whereas low-molecular-weight pDMAEMA forms larger particles of size 0.5–1.0 μm. It was demonstrated that at pDMAEMA–plasmid ratios above 1 (w/w) and at low ionic strengths, small and stable polyplexes were formed. At ratios below 1, aggregation occurred, irrespective of the other parameters investigated. Low ionic strength favors the formation of small polyplexes because polymer–DNA interaction increases with decrease in ionic strength.Figure 4.5. Chemical structure of pDMAEMA.It was suggested that at the most optimal pDMAEMA–DNA ratio (3–4 w/w), 1–2% of COS-7 cells were transfected, which was eightfold greater than the efficiency of PLL–plasmid complexes having the same zeta potential (30–45 mV) and particle size (100–200 nm) [76]. In another study, pDMAEMA–DNA complex exhibited maximum in vitro cell transfection efficiency when cell viability was only 40–70% [79]. The transfection efficiency increased with the molecular weight of pDMAEMA. A copolymer of DMAEM with 20 mol% methyl methacrylate (MMA) demonstrated reduced transfection efficiency and increased cytotoxicity compared to the pDMAEMA homopolymer. Nevertheless, polyplexes of plasmid and copolymers with low content (20 mol%) of a hydrophilic comonomer (either N-vinyl-pyrrolidone [NVP] or ethoxytriethylene glycol methacrylate [triEGMA]) revealed comparable cytotoxicity and transfection efficiency to the pDMAEMA homopolymer of comparable molecular weight (around 100,000 Da) [80]. The 48 mol% content of triEGMA copolymer showed both reduced transfection efficiency and reduced cytotoxicity, whereas 54 mol% of NVP copolymer demonstrated enhanced transfection efficiency and decreased cytotoxicity compared to the pDMAEMA homopolymer. This demonstrated role of charge density of pDMAEMA polymers as an important parameter for optimizing the efficacy–toxicity ratio. Nevertheless, a high-molecular-weight pDMAEMA (mol. wt 10,000 Da) is still better in mediating transfection.Poly[2-(trimethylamino)ethyl methacrylate] (pTMAEMA), a quaternary ammonium analogue of p(DMAEMA), did not possess the inherent property of endosomal escape, in contrast to the buffering effect for endosomal escape possessed by pDMAEMA [81]. However, pTMAEMA exhibited higher affinity for DNA compared to pDMAEMA, as observed in the complex dissociation studies using poly(aspartic acid) [82].In vitro transfection efficiency for pDMAEMA–DNA complexes was not affected by the presence of 2% serum. However, the particle size of pDMAEMA–DNA complexes increased to greater than 600 nm [76]. The particle formation of 600 nm size is a possible indication of aggregation with negatively charged serum proteins. The DNA complexed to pDMAEMA may be displaced by serum proteins. Also, systemic administration of pDMAEMA polyplexes demonstrated aggregate formation of positively charged polyplexes with blood components.Cell trafficking experiments demonstrated that endosomal escape is a limiting bottleneck for pDMAEMA copolymers. To overcome the problem of endosomal escape, new polymer pDAMA, with two tertiary amine groups in each monomeric unit, poly(2-methyl-acrylic acid 2-[(2-(dimethylamino)-ethyl)-methyl-amino]-ethyl ester) was synthesized [83]. pDAMA has two pKa; one pKa of 5 provides endosomal buffering and the other pKa of 9 is responsible for cationic charge. pDAMA has a low toxicity but also very low transfection activity.The addition of functional group poly-N-(2-hydroxypropyl)methacrylamide (pHPMA) to cationic-hydrophilic block copolymers was believed to prolong circulation time by providing steric stabilization and minimizing interactions with cells and proteins [23]. pHPMA was copolymerized with poly(trimethylammonioethyl methacrylate chloride) (pTMAEM). Although pHPMA–pTMAEM–DNA complexes give monodisperse particles of 70 nm size, the complexes failed in the heparin challenge test. These results were indicative of lack of stability in circulation when exposed to blood proteins.Biodistribution studies after IV administration of positively charged pDMAEMA–[32P]–DNA polyplexes showed that it was primarily distributed to the lungs, and 80% of the injected IV dose was recovered from the lungs within minutes. Although these present pDMAEMA systems demonstrated positive result in some studies, the stability and toxicity issues are of major concern and must be addressed effectively before establishing pDMAEMA as an efficient vector for gene delivery.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123849649000049Micelle-Based Drug Delivery for Brain TumorsAvinash Gothwal, ... Umesh Gupta, in Nanotechnology-Based Targeted Drug Delivery Systems for Brain Tumors, 201811.5.3 MiscellaneousPolymeric micelles were also used as nonviral vectors for the delivery of genes to the brain. Phage-displayed TGN peptides conjugated poly(2-(dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) diblock copolymer was synthesized in order to prepare TGN-MPEG-PDEMAEMA polymeric micelles like polyplexes for efficient gene delivery to the brain. The authors claimed that TGN-modified polyplex has more transfection efficiency than unmodified polyplex (Qian et al., 2013). The intranasal route of administration for antiviral drug-loaded polymeric micelles was effectively explored. Polymeric micelles composed of poly(ethylene oxide)–poly(propylene oxide) loaded with efavirenz were administered by the intranasal route and it was found that the drug concentration was fourfold higher than administration by the intravenous system. The researchers explained that size is not the only parameter which governs absorption in nasal mucosa, but that nanocarrier composition also plays a significant role (Chiappetta, Hocht, Opezzo, Sosnik, 2013). Interestingly, TAT peptide-tagged PEG-cholesterol (TAT-PEG-b-Col) polymeric micelles were loaded with ciprofloxacin and delivered the drug efficiently. The authors claimed that TAT facilitates the cellular uptake of the drug in astrocytes (Liu et al., 2008). Similarly, angiopep-2 modification on amphotericin B-loaded PE-PEG polymeric micelles enhanced the capability of carrying amphotericin B to the brain, with reduced cytoxicity and hemolysis (Shao et al., 2010). In the extended work, efficacy against intracranial fungal infection was investigated and the brain fungal burden was found to be reduced significantly, with decreased histopathological severity and prolonged median survival time (Matsumura, 2008) (Table 11.1).Table 11.1. Different Constructed Micelles With Anticancer Drugs for Glioblastoma TherapyPolymeric MicelleCopolymerDrugSizeLoading EfficiencyCell LinesReferences–Chitosan mPEGRetinoic acid50–200 nm80% w/wU87MGJeong et al. (2006)CS-SACS-SADOX22 nm10.65%C6Xie et al. (2012)p-HA-PEG-DSPE/DTX micellesp-HA-PEG-DSPEDTX18±3 nm7.7%±1.2%BCECs/U87MGZhang et al. (2013)DTX-PLA-PEG/c(RGDyK)PLA-PEGDTX118.4±1.630%U87MG/9LLi et al. (2014)HA-SbQ cross-linked micellesHA-SbQPTX83–125 nm35.1%BMM/U87Saito and Tominaga (2016)Cholesterol polyoxyethylene sorbitol oleate micellesCholesterol polyoxyethylene sorbitol oleatePTX17020U87C. Li et al. (2015), J. Li et al. (2015)CD-PEG-DOX8Choline derivatives-PEGDOX3032.3%U87C. Li et al. (2015), J. Li et al. (2015)cRGD-RCCMsPEG-PCLDOX50 nm18%U87MGFang et al. (2017)View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128122181000117Mechanism, current challenges and new approaches for non viral gene deliveryB. Thapa, R. Narain, in Polymers and Nanomaterials for Gene Therapy, 20161.2.3.3 PolymethacrylatePolymethacrylate is a vinyl-based polymer that binds with DNA due to its inherent cationic charge. These polymers have been used in gene delivery in vitro as well as in vivo models. Poly[2-(dimethylamino) ethyl methacrylate] (PDMAEMA) of molecular weight more than 300 kDa offered the highest transfection efficiency along with tolerable toxicity [5]. The ability of PDMAEMA/DNA polyplexes to destabilize endosomes and dissociate from DNA, in cytosol contributed to transfection efficiency [64]. Intravenous injection of PDMAEMA/DNA polyplexes into mice was found to accumulate in lung due to formation of aggregate that facilitate uptake in lung tissue [5]. Methacrylate polyplexes were shown to uptake via both clathrin and caveolae-dependent pathways [65]. Recently, biodegradable methacrylamide has been synthesized for gene delivery purposes. PDMAEMA has been modified to improve gene delivery efficiency and reduce cytotoxicity. Incorporation of guanidinium side group improved transfection efficiency of PDMAEMA polymer [66]. Copolymer of PDMAEMA with ethoxytriethyl glycol methacrylate (triEGMA) or N-vinyl-pyrrolidone (NVP) showed reduced toxicity and PDMAEMA-NVP exhibited enhanced transfection [5]. Incorporation of tumor-targeting Fabʹ fragment of mAB 323/A3 onto lipid-coated PDMAEMA polyplex as well as folate-conjugated PDMAEMA polyplex showed significantly higher transfection efficiency in human carcinoma (OVCAR-3) [5]. Methacrylate-based polymer with carbonate functionality (pHPMA-DMAE) was synthesized that release DNA at pH7.0 while complexing at pH 5.0 and transfection efficiency was improved in presence of INF-7 [67]. In addition, conjugation of poly(hydroxylethyl methacrylate-co-hydroxylethyl methacrylate propargyl alcohol) onto PDMAEMA create brush copolymer, resulting in reduced toxicity and enhanced transfection in the presence of INF-7 [5].View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780081005200000011Gene Delivery into Cells and TissuesCraig L. Duvall, ... Jeffrey M. Davidson, in Principles of Tissue Engineering (Fourth Edition), 2014Synthetic polymersA variety of natural and synthetic polymers have been developed for nucleic acid delivery systems. The literature on the design and utilization of standard synthetic polycations, such as polyethylenimene (PEI), poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA), and cationic dendrimers, biodegradable synthetic polycations such as poly(beta-amino esters) (PBAE), glycopolymers, and peptide/protein-based polymers is briefly surveyed herein.The earliest polymeric approaches to nonviral gene therapy employed cationic, amine-rich polymers such as PEI, PDMAEMA, and the cationic poly(amido amine) (PAMAM) dendrimers (Fig. 35.4). PEI is commonly used in both in its linear and branched forms for DNA plasmid delivery, whereas PDMAEMA is typically utilized as a linear homopolymer or as a diblock polymer with PEG or other compositions (e.g., see discussion below on pH-responsive, endosomolytic micelles with a PDMAEMA corona). Dendrimers such as PAMAM have more complex ’tree-like’ architectures that form spherical, monodisperse macromolecules. These branched structures are synthesized either from the central core towards the periphery (divergent synthesis) or starting from the outermost residues (convergent synthesis). Commonly used, commercial PAMAM forms spherical polymers with good aqueous solubility because of its highly charged, exposed surface groups, which include abundant primary amines for convenient functionalization [127].FIGURE 35.4. Polycationic polymers for nanoparticle production.(a) PEI (branched and linear), (b) PAMAM dendrimers and (c) PDMAEMA are representative polycationic polymers that have been thoroughly studied for polyplex formation and delivery of nucleic acids.The amines can serve three primary functions in these systems: nucleic acid packaging, enhanced cell uptake, and endosome escape. By mixing with polycations in aqueous solutions, DNA and siRNA, with their negatively charged, phosphate-containing backbone, can be electrostatically condensed into particles, termed polyplexes. Typically, an excess of the polycation is used during polyplex formation, yielding particles with an overall net positive charge. The positive surface charge of the polyplexes increases interaction with negatively charged cell membranes, a process that is likely mediated through anionic, heparan sulfate proteoglycans anchored on the cell surface [128]. This binding enhances their endocytotic cell uptake. Following endocytosis, these polyplexes are capable of mediating endosomal escape through the osmotic disruption (e.g., the hypothesized ’proton sponge effect’) [129].Cationic polymers composed of secondary and tertiary amines, which enable endolysosomal escape through the proton sponge mechanism, have been shown to efficiently transfect nucleic acids into cells [130]. Although these net cationic polyplexes can effectively delivery nucleic acids in vitro, they can cause cytotoxicity, and they have a limited biodistribution profile if delivered intravenously. This is because the cationic surface charge of these polyplexes causes aggregation with serum proteins and red blood cells. These non-specific interactions can cause disproportionate biodistribution to the capillary beds of the lungs, very short circulation times, and acute toxicity [131]. Thus, many recent strategies have focused on decreasing the cytotoxicity and improving steric stabilization of cationic polyplexes. As discussed above, the incorporation of poly(ethylene glycol) (PEG) onto the polyplex surface is an important design aspect for reducing the positive surface charge, improving biodistribution, and decreasing acute toxicity [132,133]. More recently, a number of groups have also pursued bioreducible polycation variants that are degraded by the reducing environment in the cell, and consideration of this design parameter has yielded polyplexes with lower cytotoxicity and higher transfection efficiency [134,135].Micelles formed from synthetic polymers represent another promising category of nucleic acid carriers [136]. In the area of nucleic acid delivery, the Kataoka group has focused on micelles driven by electrostatic interactions, or polyion complex (PIC) micelles [137]. These nanovehicles typically self-assemble after mixing of nucleic acids with diblock polymers, consisting of PEG and a polycationic segment such as poly(Lys). This class of carriers has been shown to achieve gene silencing in vitro, and recently, a variant composed of a diblock polymer consisting of PEG, poly(Lys) and cyclic Arg-Gly-Asp (RGD) targeting peptides was found to efficiently achieve gene silencing and reduced tumor mass following delivery of anti-angiogenic siRNA [138].More traditionally, micelles are defined as core-shell self-assemblies of amphiphilic diblock polymers into morphologies where a more hydrophobic block forms the micelle core, and a more hydrophilic block forms the corona. This class of micelles, which self-assemble into NPs in aqueous solutions even in the absence of added nucleic acid, has recently shown great promise [139–141]. One recent example of a micelle-forming polymer is composed of a block of poly(DMAEMA) and a second block that consists of a random terpolymer of 50% butyl methacrylate (BMA), 25% DMAEMA, and 25% propylacrylic acid (PAA) (Fig 35.4). When a concentrated stock solution of this polymer in ethanol is added dropwise into an excess of phosphate-buffered saline (PBS), the polymer self-assembles into micellar NPs of approximately 50 nm in diameter, with the poly(BMA-co-DMAEMA-co-PAA) terpolymer block in the particle core. The 50 mol% of the hydrophobic BMA drives self-assembly, and electrostatic interactions between PAA and DMAEMA also help to stabilize the micelles near physiologic pH. The homopolymer block of DMAEMA forms the micelle corona and provides a cationic surface that can be used to electrostatically condense siRNA into serum stable siRNA-NPs, sometimes referred to as micelleplexes (Fig. 35.5a). DMAEMA and PAA monomers both contain protonatable groups (tertiary amine and carboxylic acid, respectively) with pK values approximately equal to physiologic pH. The net charge of the anionic PAA and cationic DMAEMA is relatively balanced at physiologic pH, which stabilizes the micelle core. However, due to concurrent protonation of DMAEMA and PAA, the core-forming terpolymer block acquires a net positive charge when it enters the acidic endo-lysosomal pathway. This causes a shift to a net cationic state that electrostatically destabilizes the micelle core, exposing the terpolymer block, and activating its membrane disruptive activity (Fig. 35.5b). This terpolymer composition has been fine-tuned for intracellular delivery based on the BMA content [140] so that this pH-driven transition occurs in environments representative of the early and late endosomal compartments.FIGURE 35.5. siRNA-NPs.(a) Diblock copolymer (i) composition and (ii) scheme for self-assembly/siRNA loading. (b) These siRNA-NPs are designed to respond to the more acidic pH in the endo-lysosomal pathways following endocytotic uptake. This triggers endosomal membrane disruptive activity and mediates siRNA delivery into the cytosol. (c) Environmentally activated siRNA-NP with MMP-removable PEG surface layer and (d) concept for MMP-dependent PEG removal and cell uptake.The micelles in Fig. 35.5a have a cationic surface charge that is not amenable to effective intravenous delivery because, as described for PEI and PDMAEMA homopolymers, particles with cationic surfaces have short circulation times. As discussed above, reversible PEGylation can be utilized to create more stealthy cationic carriers in the circulation while maintaining key, underlying functionalities. For example, a variant of this micelle has been created with a PEG corona that can be removed by naturally occurring proteases for ’proximity activated targeting’ (PAT) [27,142–145] (Fig. 35.5c). The intact PEG corona reduces non-specific binding and uptake in the circulation, while high MMP activity at the pathological site releases the corona and triggers activation of the underlying siRNA-NP (Fig. 35.5d).Evidence suggesting that toxicity profiles are improved with biodegradable versions of traditional polycations has spurred the development of new and better optimized biodegradable polymer chemistries. PBAEs are one very promising class of biodegradable polycationic nucleic acid carriers that have been shown to be superior to in vitro transfection reagents such as Lipofectamine 2000 [146,147]. A key characteristic of PBAEs is that they are amenable to parallel, high throughput synthesis for simultaneous screening of large numbers of polymer variants. Using this approach, PBAE compositions have been identified with transfection activity superior to other nonviral agents and that rival the performance of viral vectors in some applications [148,149]. Conveniently, poly(β-amino ester)-based carriers rapidly hydrolyze and degrade into low molecular weight diols and bis(β-amino acids) in response to the pH drop that occurs during endosomal/lysosomal trafficking, which both facilitates nucleic acid release and makes them less cytotoxic than polymers like PEI [146]. Other promising, new biodegradable, polycationic materials in development have shown very promising preclinical data (i.e., poly(amine-co-esters) [150]), supporting the concept that polymeric nonviral vectors will continue to advance nearer to clinical reality.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123983589000355Biocompatibility, Surface Engineering, and Delivery of Drugs, Genes and Other MoleculesS.G. Spain, ... C. Alexander, in Comprehensive Biomaterials, 20114.424.3.4.1.3 Amino-functionalized methacrylates and methacrylamides(Meth)acrylate and (meth)acrylamide polymers have attracted attention as gene delivery vectors due to their biocompatibility, relative ease of synthesis, and availability of functional monomers with different positive charge-bearing moieties. Cationized polymers previously tested as gene delivery include poly[2-(dimethylamino)-ethyl methacrylate] (p[DMAEMA]); poly[3-(dimethylamino)-propyl methacrylate] (poly[DMAPMA]); poly[2-(dimethylamino)-ethyl methacrylamide] (p[DMAEMAm]); poly[3-(dimethylamino) propyl methacrylamide] (p[DMAPMAm]); poly[2-(trimethylamino) ethyl methacrylate chloride] (p[TMAEMA]); poly[2-(diethylamino)ethyl methacrylate], (p[DEAEMA]); and poly[2-(dimethylamino)ethyl acrylate], (p[DMAEA]). Of these, p[DMAEMA] has been shown to have the best transfection efficiency.160 p[DMAEMA] is a water-soluble synthetic polycation that can strongly bind nucleic acids through electrostatic interactions forming small and compact particles. However, p[DMAEMA]/DNA ratio was found to determine both the size and charge of the condensed polyplexes. Moreover, the weakly basic secondary amines in the p[DMAEMA] side chains are partly (∼50%) protonated at physiological pH (pKa ∼7.5), hence are expected to confer some endosomal escape properties through buffering and osmolysis of acidic endosomal vesicles. However, p[DMAEMA] has demonstrated cytotoxic effects, which are thought to be due to late endosome or lysosome bursting, leading to undesired enzymatic activity in the cytosol. The observed p[DMAEMA] cytotoxicity and nonbiodegradability have limited its usage in gene delivery, irrespective of its efficiency to transfect cells (Figure 8).160–162Figure 8. Structures of (meth)acrylate and (meth)acrylamide polymers tested as nucleic acid delivery vectors.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780080552941001331Nanoparticles in Translational Science and MedicineChunxi Liu, Na Zhang, in Progress in Molecular Biology and Translational Science, 20113 DendrimersCompared to conventional polyamine transfection agents, a variety of positively charged dendrimers that have the advantages of low toxicity, high transfection, and ease of manufacturing have been investigated extensively for their ability as effective gene vectors. Dendrimers have a unique highly branched molecular architecture that is globular and possess repeating units emanating from a central core.100 This defined structure, the inner cavities to encapsulate guest molecules, and controllable multivalent functionalities in their inner or outer part (the chapter by Imae and Tsai in this volume) make dendrimers attractive for gene and drug delivery.101 Dendrimers are superior to other systems due to their unique characteristics such as uniformity, monodispersity, and the ability to functionalize their terminal groups with various targeting agents.102 They can be synthesized by convergent or divergent methods and the resulting dendrimers grow in a geometrically progressive fashion (Fig. 11).Fig. 11. General structure of dentrimers.Since Tomalia and coworkers first proposed starburst polyamidoamine (PAMAM) dendrimers for gene delivery,103 a rapid increase of interest in the chemistry of dendrimers has been observed. PAMAM bearing tertiary amino groups in their interior exhibit the proton sponge effect, fulfilling to a significant extent the criteria for gene transfection of cells.104 PAMAM dendrimers with six generations proved to be more efficient in gene delivery than any others and have been commercialized.105 Now, a transfection reagent called SuperFectTM consisting of activated dendrimers (fractured generation-6 PAMAM) is commercially available for in vitro applications. SuperFect can carry a larger amount of genes than viruses. In addition, SuperFect–DNA complexes provide higher stability and more efficient transport of DNA into the nucleus than liposomes. The high transfection efficiency of dendrimers may not only be attributed to their well-defined shape but also to the low pK of the amines. The low pK permits the dendrimers to buffer the pH change in the endosomal compartment.106PAMAM dendrimers are the most commonly encountered due to their high transfection efficiency. However, they are not biodegradable, thus causing significant problems in vivo. Typical approaches to optimize dendritic gene delivery for in vivo use involve the surface modification of PAMAM backbone, either with arginine107 or hydroxyl groups.108 It was reported that PAMAM dendrimers functionalized with L-arginine (PAMAM-Arg) by an ester bond rather than amide bond showed equivalent transfection efficiency to PEI but lower toxicity, which could attributed to the faster degradation of the ester bond avoiding carrier accumulation in the tissue.109 In an attempt to lower the cytotoxicity of PAMAM, PAMAM-OH dendrimers were prepared by hydroxylation of its primary amino groups. The absence of surface primary amino groups in PAMAM-OH renders this polymer nearly neutral, which might be advantageous in terms of cytotoxicity but unable to form complexes with DNA. Therefore, quaternized PAMAM-OH (QPAMAM-OH) has been designed to overcome this problem. Although the transfection efficiency of QPAMAM-OH/DNA polyplexes was lower by one order of magnitude than that of the parent PAMAM, they exhibited significantly reduced cytotoxicity.Other strategies to reduce their toxicity are PEG or targeting ligand modification. The influence of surface modification on the cytotoxicity of PAMAM dendrimers was examined by conjugating PEG2000 to PAMAM, which showed a marked decrease in the cytotoxicity.110 Alternatively, Kim and coworkers have reported that a novel PAMAM-PEG-PAMAM triblock copolymer could form highly water-soluble polyplexes with pDNA and finally achieve high transfection efficiency comparable to that of PEI in 293 cells.111Despite the extensive interest in the pharmaceutical applications of dendrimers, the clinical applicability of a dendrimer-based gene transfection agent is yet to be established and many basic principles of applicability are still highly debated.112 Therefore, dendrimers have a long way to go before they can enter clinical applications. The success of the applications of dentrimers is likely to depend on the continuing development of novel materials for dendrimer synthesis.113 The ability to functionalize the terminal groups and structures offers endless possibilities to solve all the problems. Overall, the reports available to date certainly suggest that dendrimer-based delivery systems hold great promise and potential in gene delivery.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780124160200000139Use of Polymers in Controlled Release of Active AgentsSharad Prakash Pandey, ... Rakesh K. Tekade, in Basic Fundamentals of Drug Delivery, 20194.3.2.8 Poly(methylmethacrylate)Poly(methylmethacrylate) (PMAA) is a nonbiodegradable, low-cost thermopolymer usually prepared by bulk polymerization, emulsion, or suspension type of polymerization of methacrylic acid. In general, it is regarded as the alternate of polycarbonates and is used to prepare household devices. Use of this polymer in the pharmaceutical industry can be divided into two categories. The first category includes its use in orthopedic, dentistry, grafting, ophthalmic delivery, etc., which are mainly intended to be used in a particular local area. The second category consists of nanoparticulate or microparticulate delivery of PMMA (Bettencourt and Almeida, 2015).In the very early phase of development, Buchholz delivered the antibiotics with PMMA in the form of self-setting bone cement to avoid any infection in such condition. Some major categories of medicament that have been used to prepare orthopedic preparation using PMMA are antibiotics (antimicrobial peptides, clindamycin, daptomycin, etc.), antifungals (amphotericin, voriconazole), antineoplastics (cisplatin, doxorubicin, methotrexate, etc.), antioxidants (Vitamin E), local anesthetic agents (bupivacaine, lidocaine), and osteoporotic agents (alendronate, growth factors, etc.). PMMA is also used as a prosthetic material in dental and mandibular corrections and as a permanent implant for intraocular lens after cataract surgery (Ali et al., 2015).In the middle phase, researchers have started to prepare intraocular lenses and dentures. Oxytetracycline, 5-fluorouracil, celecoxib, etc., are a few of the therapeutic agents which have been successfully administered as ocular delivery with PMAA. But in the last few decades, the use of PMMA has opened a new door in the form of nanoparticulate drug delivery but definitely, for this purpose, it has a certain limitation as it is nonbiodegradable in nature.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128179093000042Chain Polymerization of Vinyl MonomersK. Matyjaszewski, J. Spanswick, in Polymer Science: A Comprehensive Reference, 20123.12.11.6.1 Antibacterial surfacesPolymers with quaternary ammonium ions (PQAs) effectively kill cells and spores by disrupting cell membranes. Monomers, such as DMAEMA, 4-vinylpyridine (4-VP), and N-substituted acrylamides, that can be quaternized thereby providing biocidal activity, can be polymerized by ATRP. The corresponding antimicrobial surfaces were prepared by grafting from287,521,583,584 or grafting onto surfaces287,585 and blended with586 or deposited on other polymers.587 Many surfaces have inherent functional groups that can be employed to conduct a ‘grafting from’ reaction; the only requirement is the ability to tether initiators to the target substrate. In the case of paper and glass, this is readily accomplished by reacting surface hydroxyl groups with 2-bromoisobutyryl bromide.588,589 ATRP of DMAEMA followed by quaternization with ethyl bromide provided effective tethered biocidal functionality.85 When paper was treated, the modified surfaces were very effective in killing Escherichia coli (E. coli), reducing the number of cells by 4 orders of magnitude, from 1.6 × 109 to 4.9 × 105, in 1 h. The surface also showed activity against B. subtilis spores. The activity of a biocidal film on a glass surface survived repeated washing with aqueous detergent solution.A nonleachable biocidal polypropylene (PP) surface was created by chemically attaching PQA chains to the surface of PP. A well-defined poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA), a precursor of a PQA, was grown from the surface of PP via ATRP.287 The tertiary amine groups in PDMAEMA were subsequently converted to quaternary ammonium groups in the presence of ethyl bromide. Antibacterial activity test against E. coli indicated that biocidal activity of the resultant surfaces depends on the amount of polymers grafted to the surface and the number of available quaternary ammonium units. Surfaces grafted with relatively high MW polymers (Mn   10 000) showed almost 100% killing efficiency, that is, killing all of the added E. coli (2.9 × 105) in a shaking test, whereas a lower biocidal activity (85%) was observed for the surface grafted with shorter PQA chains (Mn = 1500).287 Introduction of hydrophobic units into a poly(quaternary ammonium) segment led to 100 times enhancement of biocidal activity with a log(kill) of 7.0.590 It is envisioned that such a permanent, nonleaching biocidal surface treatment would find utility in hospitals, cruise ships, food packaging facilities, household items, and military applications.While grafting from is an efficient method of tethering quaternizable polymers to a substrate, a more convenient approach for existing household equipment, and even hospital use, would be a ‘consumer-friendly’ ‘grafting onto’ approach such as spraying a solution of a reactive copolymer onto a surface.Surface plasmon resonance was used to measure binding of proteins from solution to PDMAEMA brushes end-grafted from gold surfaces.591 These brushes displayed a high capacity for electrostatically selective protein uptake. The net negatively charged protein BSA was taken up in amounts that approach its aqueous solubility limit in the case of PDMAEMA brushes at high grafting densities. These are among the highest reported protein binding capacities for ion exchange media. BSA binding scaled linearly with the mass of PDMAEMA grafted per unit area, with a constant ratio of approximately 120 DMAEMA monomer units per bound BSA molecule. The kinetics of BSA uptake in the brush is considerably more rapid than the slow asymptotic approach to adsorption saturation that is often seen for BSA adsorption to a solid surface.592View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780444533494000716Macromolecular Architectures and Soft Nano-ObjectsJ.K. Kallitsis, A.K. Andreopoulou, in Polymer Science: A Comprehensive Reference, 20126.19.4.3 Sensoring Properties of Rod–Coil Block CopolymersAmphiphilic p-conjugated rod–coil block copolymers have attracted great attention for optoelectronic or sensory applications due to their tunable photophysical properties through different morphologies.32,44,183,236,303,304The key advantage of conjugated polymers over organic small molecules is the ease of solution processing, especially using environmentally friendly solvents like water, which enables the fabrication of simple device structures at low cost. Therefore, water-soluble rod–coil conjugated polymers are of special interest. By incorporating the fluorescent PF segment into thermoresponsive block copolymers, the photophysical properties can be changed through the variation of thermomorphic characteristics.44,305,306 Lu et al.35,36 reported conjugated-acidic and conjugated-ionic block copolymers, the two coil segments of which were based on poly(methacrylic acid) and PDMAEMA, respectively. Aggregates in aqueous solutions were demonstrated in both cases. Moreover, excimer formation within PF aggregates was confirmed in conjugated-ionic block copolymers. This was supported by an additional emission band at longer wavelengths and reinforced by strong hydrophobic interactions. It was also shown that the increase in ionic strength of the solution leads to further decrease in quantum efficiency. These water-soluble rod–coil conjugated polymers are also suitable for biosensors as their supramolecular aggregation behaviors can be changed under different conditions. In this area, Kong and Jenekhe46 have synthesized triblock copolymers 21 consisting of a substituted PF and a PBLG.A series of amphiphilic rod–coil diblock copolymers with a PF as the hydrophobic and light-emitting rod and a PNIPAAm as the hydrophilic coil were prepared. PF-b-PNIPAAm was utilized as a nanocarrier to incorporate hydrophobic tetrakis(mesityl)porphyrin (H2(Me3)TPP) within its micelles, enabling an application of the water-insoluble porphyrin into aqueous solution. Efficient fluorescence resonance energy transfer (FRET), up to 98% from PF to H2(Me3)TPP, was observed in the micellar solution. Therefore, not only were the nanostructures and functionalities through the environmental stimuli successfully controlled using the new amphiphilic functional rod–coil diblock copolymers, but also the micelles were applied to encapsulate a porphyrin to enhance the porphyrin’s singlet oxygen generation efficiency through FRET from PF to porphyrin and its derivatives (see Figure 31).307Figure 31. (a) Schematic drawing of the utilization of the block copolymers to incorporate the H2(Me3)TPP into their micellar cores and the enhancement of the singlet oxygen generation through the FRET. (b) A possible mechanism for the formation of micelles in water and invert large compound micelles (LCMs) in THF/toluene. The chain entanglement pathway (1) was used to show the possible LCM formation process.Reprinted with permission from Tian, Y.; Chen, C. Y.; Yip, H. L.; et al. Macromolecules 2010, 43, 282–291, Copyright 2010 American Chemical Society.307PF-b-PDMAEMA rod–coil block copolymers showed a significant variation in their surface structure and photophysical properties with respect to solvent composition (water–THF), temperature, and pH. The surface structures of PF7-b-PDMAEMA45 varied from spheres, to separate cylinders, to bundles of cylinders and finally spiral-shaped micelles as the solvent composition changed. The micellar aggregate of PF7-b-PDMAEMA45 in water showed a reversible change of surface structure from bundles of cylinders to spheres over a heating–cooling cycle. The lower critical solution temperature (LCST) of the PF7-b-PDMAEMA45 decreases with increasing pH, depending on the protonation of the PDMAEMA block. The PL intensity of PF7-b-PDMAEMA45 in water was thermoreversible based on its LCST. The PL characteristics suggested that the new copolymers behaved as an on/off fluorescence indicator of temperature or pH, with a reversible ‘on–off’ profile at an elevated temperature in water. The pH-fluorescence intensity switched from ‘off–on’ to ‘on–off’ profiles as the temperature increased. Therefore, the PF-b-PDMAEMA copolymer has potential applications as a multifunctional sensory material toward solvent, temperature, and pH.44For the thermoresponsive conjugated rod–coil–coil triblock copolymers 55, the LCST increased with an enhanced hydrophilic PHEAA block ratio, since the longer PHEAA segment facilitated the copolymer chains to stretch at an elevated temperature.45 The micelles of PNIPAAm-b-PHEAA with different block ratio changed into spheres, aggregate spheres, vesicles, and worm-like micelles as the temperature was increased, due to the thermally induced variations in the hydrophilic/hydrophobic character of PNIPAAm (Figure 32). However, the micellar morphologies were worm-like, bundles of worm-like, and hollow tubes in the triblock PF-b-PNIPAAm-b-PHEAA, which were probably induced by the p–p interaction among the fluorene segments. These micelle morphologies showed thermoreversibility based on the LCST of the triblock copolymer. Their PL characteristics suggested that the copolymers behaved as an on/off fluorescence indicator of temperature, showing an ‘on–off–on’ profile at an elevated temperature in water at a higher block ratio of PNIPAAm and switching to ‘on–off’ as the block ratio of PNIPAAm decreased. This suggests that the PF-b-PNIPAAm-b-PHEAA copolymers have tunable morphologies and could be potentially used as thermoresponsive sensory materials.Figure 32. Micelle morphologies of PF7-b-PNIPAAm120-b-PHEAA30 in water during a heating–cooling cycle between 25 and 50 °C. TEM images of micelle aggregates in the heating process at (a) 25 °C, (b) 40 °C, and (c) 50 °C, and (d) high-resolution transmission electron microscopy (HRTEM) observation at 50 °C. TEM images of micelle aggregates in the cooling process at (e) 40 °C and (f) 25 °C.Reproduced by permission of The Royal Society of Chemistry, Lin, S. T.; Fuchise, K.; Chen, Y.; et al. Soft Matter 2009, 5, 3761–3770.45View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780444533494001771Recommended publicationsInfo iconAdvances in Medical SciencesJournalUHMWPE Biomaterials Handbook (Third Edition)Book • 2015Polymers and Nanomaterials for Gene TherapyBook • 2016TuberculosisJournalBrowse books and journalsAbout ScienceDirectRemote accessShopping cartAdvertiseContact and supportTerms and conditionsPrivacy policyWe use cookies to help provide and enhance our service and tailor content and ads. 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