Surface-Engineered Dendrimers in Gene Delivery - American

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Surface-Engineered Dendrimers in Gene Delivery Jiepin Yang, Qiang Zhang, Hong Chang, and Yiyun Cheng* Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China production problems, and high cost of manufacture.6 On the basis of these disadvantages, researchers are developing alternatives to viral vectors in an effort to circumvent the safety and production problems. A variety of nonviral vectors, including polymers,7−10 liposomes and exosomes,2,11−14 peptides and proteins,15,16 and nanoparticles, were developed.17−20 Among these vectors, polymers are particularly attractive due to their diversity in terms of polymer structure, composition, and properties.6 They have the following advantages when acting as gene vectors: lack of immunogenicity, facile synthesis, flexibility, degradability, environmental stability, and being easily modified with functional ligands.21−23 Numerous cationic polymers, including polyethylenimine CONTENTS (PEI),3,24−26 chitosan,27 poly-L-lysine (PLL),28 dendrimers,29,30 poly(N,N-dimethylaminoethyl methacrylate) (PDMAE1. Dendrimers and Gene Delivery A MA),31,32 poly(β-amino ester),33,34 and diethylaminoethyl2. Surface-Engineered Dendrimers in Gene Delivery C dextran (DEAE-dextran),35 were developed as vectors for the 2.1. Lipid-Modified Dendrimers C delivery of DNA and small interfering RNA (siRNA), and 2.2. Fluorinated Dendrimers E several of them even approach the efficacy of viruses, indicating 2.3. Amino Acid-Modified Dendrimers G that polymeric gene vectors are promising tools in clinical gene 2.4. Saccharide-Modified Dendrimers H therapy.36−38 2.5. Protein- and Peptide-Modified Dendrimers J Dendrimers are a class of highly structurally controlled, 2.6. Polymer-Modified Dendrimers L dendritic polymers built up from branched repeat units called 2.7. Nanoparticle-Modified Dendrimers L “branch cell monomers”.39−42 More random dendritic/hyper2.8. Cationic-Moiety-Modified Dendrimers N branched polymers were first envisioned theoretically by 2.9. Other Ligand-Modified Dendrimers P Flory.43 Initial synthesis of low molecular weight branched 2.9.1. Hormone-Modified Dendrimers P precursors (i.e., cascade molecules) by Voegtle and co-workers 2.9.2. Folic Acid-Modified Dendrimers P preceded the systematic synthesis of high molecular weight 2.9.3. Photosensitizer-Modified Dendrimers P structurally controlled dendrimers.44 Dendrimers were first 2.9.4. Fluorophore-Modified Dendrimers P synthesized using a divergent strategy by the groups of 2.9.5. Aminoglycoside-Modified Dendrimers P Denkewalter,45,46 Tomalia,47,48 and Newkome,49 as described 3. Conclusions and Perspectives P extensively elsewhere. In 1990, a convergent synthetic approach Author Information P was introduced by Hawker and Frechet to synthesize Corresponding Author P dendrimers.50 Since then, the popularity of dendrimers then Author Contributions P greatly increased and many new dendrimers were reported, Notes P using both divergent and convergent methods.51 The Biographies Q commercialization of dendrimers was realized in 1993, when Acknowledgments Q Meijer and co-workers described the kilogram-scale synthesis of Abbreviations Used Q dendrimers.52 Dendrimers consist of three parts from the References R interior to the surface: a central core, repeated units, and surface functionalities.39 They are synthesized in an iterative sequence of reaction steps by convergent or divergent 1. DENDRIMERS AND GENE DELIVERY 53−58 During dendrimer synthesis, each successive methods. Gene therapy represents a promising option for the treatment reaction step leads to an additional generation of branching, of diseases such as inherited disorders, viral infections, and 1−3 and the number of repeated cycles is defined as the dendrimer cancers. A major obstacle to clinical gene therapy is the lack generation (denoted as G). These versatile polymers have of safe and efficient gene vectors.4−6 Current gene vectors can steadily grown in popularity in miscellaneous fields, ranging be divided into viral and nonviral vectors. Viral vectors such as from polymer chemistry to nanomedicine and biomateriretroviruses and adenoviruses have attracted significant attention due to their dramatic efficacies for both in vitro and in vivo gene delivery, but they are associated with safety Received: December 9, 2014 concerns (e.g., immunotoxicity and genotoxicity), large-scale © XXXX American Chemical Society

A

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Figure 1. Structures of cationic PAMAM, PPI, triazine, carbosilane, PETIM, phosphorus, PLL, and viologen dendrimers used as nonviral gene vectors.

als.53,55,59−75 Dendrimers have unique architecture, nanoscale size, and a high density of surface functionalities.39 Cationic dendrimers have a well-defined number of amine groups on the surface. They can efficiently condense nucleic acids into small nanoparticles by ionic interactions and protect them from enzymatic degradation.76−82 The formed nanoparticles are internalized by cells via several endocytic pathways.6 The internalized nanoparticles mainly localized within acidic vehicles such as endosomes and lysosomes. The high density of tertiary amine groups within the interior of dendrimers gives them strong pH buffering ability (pKa ∼ 6.0), which facilitates efficient endosomal escape of dendrimer/DNA polyplexes from the endocytic pathway through the possible proton-sponge mechanism.29,83 Owing to these properties, dendrimers are considered as a new class of polymeric gene vectors. Up to now, dendrimers including poly(amidoamine) (PAMAM) dendrimer,84,85 poly(prophylenimine) (PPI) dendrimer,86 triazine dendrimer,87,88 carbosilane dendrimer,89 poly(ether imine) (PETIM) dendrimer,90−92 phosphorus dendrimer,93−95 PLL dendrimer,96 and viologen dendrimers97 were explored as gene vectors (Figure 1). Among these dendrimers, PAMAM and PPI dendrimers are the most-investigated ones in gene delivery.98−106 PAMAM dendrimers were first proposed as nonviral gene vectors in 1993 by Haensler and Szoka.98 These cationic polymers can efficiently induce the expressions of luciferase and β-galactosidase reporter genes in adherent and suspension cell cultures. Generation 6 (G6; the definition of dendrimer generation in this review is in accordance with the generation definition initially applied for PAMAM dendrimers by Tomalia et al.) PAMAM dendrimer shows maximal gene transfection among G1−G10 PAMAM dendrimers. Partially degraded PAMAM dendrimers prepared by heat treatment of the dendrimer in solvolytic solvents show much higher transfection efficacy (>50-fold) than untreated dendrimers.107 Baker and colleagues found that cationic PAMAM dendrimers are not

only able to effectively deliver plasmid DNA but also antisense oligonucleotides (asODN).108 The transfection efficacy of PAMAM dendrimers in certain cell lines is increased in the presence of DEAE-dextran or lysomotrophic agents such as chloroquine.99 A G9 PAMAM dendrimer was successfully used as an effective vector for in vivo pulmonary gene delivery via intravenous administration.109 The degraded PAMAM dendrimer based material SuperFect is now available on the market as a gene transfection reagent.110−112 PPI dendrimers are another type of dendrimer intensively explored in biomedical applications.113 The interactions of PPI dendrimers with DNA were reported by Kabanov et al. in 1999.114 Since that, PPI dendrimers have been widely explored as potential in vitro and in vivo gene vehicles.115−118 However, the performances of dendrimers as well as current dendrimer-based products in gene transfection are less than ideal. These materials are usually hampered by moderate transfection efficacy and serious cytotoxicity.110,119 Gene transfection is like a relay race in which multiple barriers, such as polyplex instability, insufficient cellular uptake and endosomal escape, difficulty in DNA unpacking, and DNA degradation by cytosolic nuclease, prevent efficient gene transfection.6,29,76,120 To break down these barriers, cationic dendrimers were modified with various functional ligands (Figure 2). The modified ligands include (1) lipids, (2) fluorous compounds, (3) amino acids, (4) saccharides, (5) proteins and peptides, (6) polymers, (7) nanoparticles, and (8) cationic moieties. This critical review focuses on recent advances in the design of surface-engineered dendrimers for efficient and low cytotoxic gene delivery. Mechanisms of the surface-engineered dendrimers in gene delivery are discussed in detail. In addition, the structure−function relationships of the surface-engineered dendrimers in gene delivery are reviewed. B

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Figure 2. Surface-engineered dendrimers in gene delivery.

from the cationic polymers.21 In addition, modification of nanoparticles with lipids or hydrophobic polyelectrolytes leads to specific cellular uptake by endothelial cells via caveolaemediated endocytosis.123 Therefore, lipid modification was widely used to improve the performance of a variety of polymeric gene vectors.21 Several attempts were made to improve the efficacy of cationic dendrimers by joining the cationic nature of dendrimer with the fusogenic property of lipids (Figure 3).124 PAMAM dendrimers conjugated with fatty acids such as lauric acid (1), myristic acid (2), and palmitic acid (3) show much increased gene transfection efficacy on mesenchymal stem cells.124 The presence of lipids significantly increases the cellular uptake of dendrimer/DNA polyplexes, and the cellular uptake level increases in direct proportion to the chain length of the modified lipids (lauric acid < myristic acid < palmitic acid). However, dendrimers modified with longer lipids have difficulty in intracellular DNA release due to stronger associations between lipids, and as a result, dendrimers modified with lauric acid (the shortest lipid) show the highest gene transfection efficacy. Similarly, the transfection efficacy of alkylcarboxylated PPI dendrimer depends much on the chain length of modified lipids (4−6).125 C6- and C16- alkane-modified PPI dendrimers (4, 6) show scarcely improved transfection efficacy compared

2. SURFACE-ENGINEERED DENDRIMERS IN GENE DELIVERY 2.1. Lipid-Modified Dendrimers

Most of the cationic polymers bind nucleic acids via ionic interactions and form nanoscale polyplexes. Excess positive charges on the polyplexes are required for subsequent interaction with anionic glycoproteins and phospholipids on the cell membrane. This interaction facilitates the internalization of polyplexes into cells, either by passive transport caused by membrane destabilization or by endocytosis.76 However, excess positive charges on the polyplex may lead to increased cytotoxicity.9 Hydrophobic interaction also plays a crucial role in the cellular uptake and endosomal escape of polyplexes.21 Cell membranes as well as intracellular vesicles consist of phospholipids. Lipids such as fatty acids and cholesterol have strong fusogenic activity; as a result, lipidbased gene vectors such as Lipofectamine, Lipofectin, and Lipofectam show high transfection efficacy in a variety of cell lines. Direct conjugation of lipids to nucleic acids such as siRNA allows efficient gene delivery.121 Balancing the cationic charge and lipid content of a polymeric gene vector improves both cellular uptake and endosomal escape of the polyplexes.122 Lipid modification also has beneficial effects on polyplex stability, serum stability, and intracellular DNA dissociation C

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Figure 3. Structures of lipid-modified PAMAM or PPI dendrimers.

Figure 4. Structures of PAMAM-dendron-bearing lipids.

to unmodified PPI dendrimer, while C10-alkane-modified dendrimer (5) shows a much improved transfection efficacy. In a separate study, modification of a much shorter lipid (C6 alkane, 7) on a triazine dendrimer efficiently improves its siRNA transfection efficacy, and the improved gene-silencing efficacy was attributed to facilitated endosomal escape, favorable intracellular siRNA distribution, and smaller polyplex size.87 Similarly, unsaturated C18-alkane-modified PLL dendrimer (8) shows efficient RNA interference in vivo without apparent toxicity.126 Among the lipid-modified dendrimers, we cannot conclude which chain length or number of conjugated lipids is the best choice for efficient DNA or siRNA delivery, because the answer depends on dendrimer generation, dendrimer species, and even the linkage bond. Lipid modification on dendrimers may also generate polymeric micelles in aqueous solutions, which allows the codelivery of anticancer drugs and therapeutic genes. 1,2Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)−poly-

ethylene glycol (PEG) was conjugated to PAMAM dendrimer (9), and the conjugate assembles into micelles below 100 nm.127 DOPE−PEG-modified dendrimer shows significant improvement of both doxorubicin-loading capacity and siRNA delivery efficacy. Such a polymeric gene vector can be used for the treatment of multidrug resistance (MDR) by codelivering anticancer drugs and a siRNA that silences MDRrelated genes. In dendrimer-based gene delivery systems, there is a correlation between transfection efficacy and cytotoxicity of the cationic dendrimers. High-generation dendrimers show relatively high transfection efficacy but severe cytotoxicity, and on the contrary, low-generation dendrimers have minimal toxicity but extremely low transfection efficacy. Therefore, there is an urgent need to generate highly efficient gene vectors based on low-generation dendrimers. Lipid modification can realize this goal. Lipid-modified low-generation dendrimer behaves like a lipid gene vector rather than a polymeric vector. For example, D

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Figure 5. Structures of fluorinated PAMAM dendrimers.

Figure 6. Comparison of fluorinated PAMAM dendrimers with other transfection reagents on gene transfection efficacy. (a) Transfection efficacies of fluorinated PAMAM dendrimers and Lipofectamine 2000 on five cell lines. Diamonds in part a represent cell viability (%). (b) Transfection efficacies of fluorinated PAMAM dendrimers and several transfection reagents on HeLa cells. Squares in part b represent mean fluorescence intensity. Reprinted with permission from ref 119. Copyright 2014 Nature Publishing Group.

2.2. Fluorinated Dendrimers

G2 PAMAM dendrimers modified with several lipid moieties including alkyl chains (C4, C12, saturated and unsaturated C18, 10−13) and cholesterol (14) show efficient transfection efficacy.128 A saturated C18 alkyl chain modified G2 PAMAM dendrimer (12) shows the highest transfection efficacy, which is about 3-fold higher than that of Lipofectamine 2000. Besides lipid chain length, the linkage bond between lipid and dendrimer also significantly influences the transfection efficacy. The lipid-modified low-generation dendrimers show excellent serum-resistance, low cytotoxicity, and efficient transfection on several eukaryotic cell lines, such as Neuro-2A and RAW 264.7 cells. One may ask whether the cytotoxicity of cationic dendrimers is increased or decreased after lipid modification. The answer to this question is still unclear but should depend on a list of parameters such as lipid chain length, modification degree, dendrimer generation, and species. The reported materials show low cytotoxicity on the transfected cells under their transfection conditions. It is worth noting that modification of lipids to the core of low-generation PAMAM dendrons also generates materials (15−17) with promising transfection efficacy (Figure 4). These lipid−dendron conjugates form micelles in aqueous solutions and show efficient DNA and siRNA delivery.129−133 We focus on surface-engineered dendrimers in this review, and therefore, these examples are not discussed in detail.

Perfluoroalkyl substances have unique properties compared to traditional lipids. These compounds are both hydrophobic and lipophobic, but they prefer to associate with other fluorous compounds.134 Fluorination has become a promising tool in medicinal chemistry, and nearly 25% of the drugs on the market containing fluorine atoms in their chemical structures.135 These drugs show improved stability, therapeutic efficacy, and/or pharmacokinetic behavior after fluorination.136 Fluorination even improves the stability of proteins without altering their biological functions.137,138 Fluorous compounds have a high affinity for cell surfaces and intracellular vesicles and are able to incorporate into these membranes, which ensures efficient cellular uptake of fluorinated materials.139 In addition, fluorinated biomaterials show excellent biocompatibility and are able to support the growth and differentiation of stem cells.140 Due to these properties, fluoroalkylated gene vectors may have unexpected performance in gene delivery. Fluorinated liposomes show improved transfection efficacy as compared to nonfluorinated liposomes.141,142 However, the fluorinated cationic lipids must be typically coformulated with a helper lipid, and only a moderate increase in transfection efficacy is achieved. In a recent study, Cheng and co-workers modified PAMAM dendrimers with perfluoroalkyl acids including trifluoroacetic acid (18), pentafluoropropionic acid (19), E

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Figure 7. Gene transfection mechanism of dendrimers, with emphasis on the benefits brought by fluorinated dendrimers.

heptafluorobutyric acid (20), and perfluorobutanesulfonic acid (21) via a facile route (Figure 5).119 Fluorination dramatically improves the transfection efficacy of PAMAM dendrimers. Among these fluorinated dendrimers, the heptafluorobutyric acid-modified dendrimer G5-F768 (an average number of 68 heptafluorobutyric acids conjugated on each G5 PAMAM dendrimer) shows the highest transfection efficacy (>90%) on a list of commonly used cell lines, which is superior to commercial transfection reagents such as Lipofectamine 2000 and SuperFect (Figure 6). The improved transfection efficacy of cationic PAMAM dendrimers after fluorination is attributed to increased cellular uptake, serum stability, endosomal escape, and easier intracellular DNA disassociation from the polymer (Figure 7). Not limited to PAMAM dendrimers, fluorination also effectively improves the transfection efficacy of PPI dendrimers (Figure 8),143 suggesting that the fluorination strategy can be developed as a versatile route to improve the transfection efficacy of dendrimer-based gene vectors. Most of the polymeric gene vectors effectively deliver nucleic acid at high polymer/DNA charge ratios (or nitrogen to phosphorus ratios, N/P ratios) to maintain high cellular uptake and stability of the prepared polyplexes. However, excess positive charges on the polyplexes may result in increased cytotoxicity on the transfected cells.9 Therefore, the need to prepare polymeric gene vectors that work well at low charge densities is urgent.8 A fluorinated dendrimer that has a low surface energy due to high affinity fluorous−fluorous interactions thus may assemble into nano- or microaggregates,144 which behaves like a lipid gene vector. Therefore, fluorinated dendrimer binds nucleic acid in the form of polymeric aggregates rather a single polymer. Fluorinated dendrimers such as G5-F768 achieve optimal gene transfection at extremely low positive-to-negative charge ratios or N/P ratios (1.5:1 to 2:1).119 Surprisingly, fluorinated dendrimers

Figure 8. Comparison of fluorinated PPI dendrimers with other transfection reagents on gene transfection efficacy in HEK293 cells. Diamonds represent the mean fluorescence intensity. Reprinted with permission from ref 143. Copyright 2014 Elsevier Ltd.

even show moderate transfection efficacy (above 50%) at N/P ratios below 1:1. Transfection at a low N/P ratio ensures excellent biocompatibility on the transfected cells. As perfluoroalkyls are both hydrophobic and lipophobic, the fluorinated dendrimers should be inert to serum proteins and lipids. Indeed, the fluorinated dendrimers exhibit excellent serum-resistance in gene delivery. For example, G5-F768 maintains efficient gene transfection even in the presence of 50% serum, while Lipofectamine 2000 fails to transfect the same cells in the presence of 30% serum (Figure 9). The excellent serum-resistance of fluorinated dendrimers allows efficient in vivo gene therapy. Besides perfluoroalkylation, Wang and Cheng et al. proved that fluorinated PAMAM or PPI F

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Fect, and PolyFect). Finally, fluorine can be used as a highly sensitive probe in nuclear magnetic resonance (83% of the sensitivity of hydrogen).144−148 Therefore, the fluorinated dendrimers have potential to track and uncover in vitro and in vivo gene delivery by magnetic resonance imaging (MRI). In a word, fluorination on dendrimers generates highly efficient, low cytotoxic, and multifunctional gene vectors. 2.3. Amino Acid-Modified Dendrimers

Common amino acids have the same fundamental structure, differing only in their residues. They can be sorted into different families, such as cationic, anionic, or neutral amino acids and hydrophilic or hydrophobic amino acids. The amino acid residues such as guanidine and imidazole play essential roles in the gene delivery processes. For example, arginine-rich or histidine-rich peptides and cationic poly(amino acids) such as PLL were directly used as gene vectors.149,150 Anionic poly(amino acids) such as poly(γ-glutamic acid) (PGA) can efficiently tailor the transfection efficacy of cationic polymers such as chitosan by forming a ternary complex.151 In addition, the introduction of amino acid moieties to cationic polymers can improve the physicochemical properties of the polymers, such as solubility and mucoadhesiveness.27 Cationic polymers can be modified with amino acids via a facile condensation reaction, and the diversity of amino acid residues perfectly meets our need to modulate the transfection efficacy of cationic polymers. Conjugation of cationic amino acids such as arginine and lysine to PAMAM dendrimers can improve the transfection efficacy of unmodified dendrimers (Figure 10).152−154 Arginine and lysine have two positively charged groups in their structures and their modifications significantly increase the charge density on dendrimer surface (27−31), which facilitates DNA condensation and is beneficial for polyplex stability. Besides the charge density effect, the positive charge of the guanidinium group in arginine is delocalized on three nitrogen atoms; thus, guanidinium shows better interaction with phosphates in DNA than localized cations such as ammonium.155 In addition, the guanidinium group in arginine has a strong affinity for cell membranes through ionic pairing and hydrogen bonding.156,157 On the basis of these reasons,

Figure 9. Serum-resistance abilities of fluorinated PAMAM dendrimer G5-F768 and Lipofectamine 2000 on gene transfection in HeLa cells. Diamonds in part b represent mean fluorescence intensity. The scale bar in part a is 200 μm. Reprinted with permission from ref 119. Copyright 2014 Nature Publishing Group.

dendrimers synthesized by different routes display promising transfection efficacy. For example, PAMAM dendrimers modified with fluoroaromatics (22−26) show a much improved transfection efficacy than unmodified ones.23 The efficacy of fluorinated dendrimer increases in direct proportion to the number of fluorine atoms on the aromatic rings. The most efficient dendrimer conjugated with 2,3,5,6-tetrafluoro-p-toluic acid (24) has transfection efficacy superior to that of three commercial transfection reagents (Lipofectamine 2000, Super-

Figure 10. Structures of amino acid-modified PAMAM dendrimers. G

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Figure 11. Structures of multiple-functionalized dendronized polymers (35) and PAMAM dendrimers (36, 37) with amino acids.

dendrimer surface will decrease the solubility of the yielded conjugates. Therefore, the conjugation degree should be carefully chosen to realize efficient and low cytotoxic gene delivery. As mentioned above, there are multiple barriers existing in the gene delivery process, and single functionalization cannot overcome all the barriers at once. A solution to this problem is multiple functionalization of dendrimers with several amino acids (Figure 11). A recent study found that dual functionalization of a reduction-sensitive dendronized polymer with histidine and phenylalanine or tyrosine can significantly improve its siRNA interference efficacy (35).183 Dual functionalization of PAMAM dendrimer with arginine and histidine also achieves efficient gene delivery (36).184,185 A combination of arginine, histidine, and phenylalanine on PAMAM dendrimer surface (37) generates a synergistic effect in gene delivery (Figure 12).186 This combination strategy provides a rational, versatile, and practical approach to optimizing the performance of dendrimers in gene delivery.

arginine- and lysine-modified dendrimers were widely used as efficient vectors for DNA and siRNA during the past decade.152,153,158−174 The efficacy of arginine- and lysinemodified dendrimers depends much on the dendrimer species. For example, arginine-modified PAMAM dendrimers are more efficient in gene transfection than lysine-modified ones,152,153 while lysine-modified PPI dendrimers are more efficient than arginine-modified ones.166,167 The linkage between amino acid and dendrimer also plays a critical role in gene delivery. Arginine−PAMAM dendrimer (29) and lysine−PAMAM dendrimer (30) conjugates with degradable ester bonds are more efficient and biocompatible than those with nondegradable amide bonds (27, 28).153 The arginine-modified PAMAM dendrimers are even able to efficiently transfect hardto-transfect cells such as human umbilical vein endothelial cells (HUVECs) and primary cortical cultures.153,159,165,171 Histidine modification is also able to improve the transfection efficacy of cationic PAMAM dendrimers (32).175 The imidazole group with a pKa value around 6.0 in histidine is protonable under mildly acidic conditions. As a result, incorporation of histidine to dendrimer increases the pHbuffering capacity of dendrimers, which facilitates the endosomal escape process. The histidine-modified dendrimers are serum-resistant due to the inert nature of the imidazole group.175 Histidine modification also decreases the cytotoxicity of cationic PAMAM dendrimers. It is worth noting that guanidinium- and imidazolium-modified dendrimers also show improved transfection efficacy,176−179 and the mechanisms of these polymers are the same as those of arginine- and histidinemodified dendrimers, respectively.180 Another approach to improve the transfection efficacy of a cationic polymer is tailoring the balance of charge and hydrophobic contents in the polymer.21 This hydrophobic effect on improving gene transfection efficacy is also discussed in section 2.1.124 Modification of PAMAM dendrimers with hydrophobic amino acids such as phenylalanine (33) and leucine (34) can improve the cellular uptake of dendrimer/ DNA polyplexes and thereby increases their transfection efficacy.181,182 However, modification of hydrophobic amino acids also brings extra cytotoxicity to the transfected cells, and an excess amount of hydrophobic amino acids modifying the

2.4. Saccharide-Modified Dendrimers

Cyclodextrins (CDs) are cyclic oligosaccharides of six, seven, and eight glucopyranose units linked by R-1,4 linkages, which are called α-, β-, and γ-CD, respectively.187,188 The internal cavities of CDs can encapsulate a wide range of size-matched hydrophobic guest molecules.189−191 For example, CDs can sufficiently bind cholesterol, cholic acid, and other lipid molecules located on cell membranes. 192 As a result, conjugation of CDs to a polymer improves its affinity for cell membranes.193 In addition, conjugation of CDs improves the solubility, stability, and biocompatibility of cationic polymers, which were reported to have non-negligible cytotoxicity in gene delivery.194 Pioneering research found that conjugation of one α-, β-, or γ-CD to a G2 PAMAM dendrimer (38-40) significantly improves its transfection efficacy on NIH3T3 cells and RAW264.7 cells (Figure 13).195 Among the conjugates, G2−α-CD (38) is the most potent vector to transfect both cell lines, which is about 100-fold more efficient than G2 PAMAM dendrimer alone and a mixture of G2 PAMAM dendrimer and α-CD. Moreover, the efficacy of G2−α-CD on H

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the cells is superior to the commercial transfection reagent Lipofectin. The improved transfection efficacy of dendrimer after α-CD conjugation is attributed to improved cellular uptake of dendrimer/DNA polyplexes as well as their altered intracellular trafficking behaviors. Uekama and co-workers further optimized the transfection efficacy of PAMAM dendrimer−CD conjugates by choosing proper dendrimer generations and α-CD conjugation degrees.196,197 G3−α-CD conjugate with an average number of 2.4 α-CD molecules conjugated on each G3 PAMAM dendrimer shows the highest transfection efficacy both in vitro and in vivo. β-CD-modified dendrimers (39) also show high efficacy in DNA and siRNA delivery.198−200 A recent study reported that a PAMAM dendrimer modified with three β-CD molecules can be simultaneously loaded with siRNA and retinotic acid (Figure 14).201 The compound retinotic acid is loaded within β-CD via hydrophobic interactions, forming an inclusion structure with the polymeric vector. The siRNA and retinotic acid loaded within the dendrimer−β-CD conjugate generate a synergistic enhancement in stem cell differentiation, ensuring long-term cell growth and survival. It is known that sugars can be internalized inside cells by receptor-mediated endocytosis. For example, mannose receptors are overexpressing on macrophages and dendritic cells. Asialoglycoprotein receptors are primarily expressed on hepacytes. Mannose receptors specifically bind mannose, while asialoglycoprotein receptors bind galactose and lactose. Modification of these saccharides to dendrimers allows cellspecific gene delivery. Galactose- (41) and N-acetylgalactosamine-modified (42) PAMAM or PPI dendrimers show selective DNA and siRNA delivery into hepacytes such as HepG2 cells.202−204 The luciferase activity transfected by a PPI

Figure 12. Synergistic effect of arginine, histidine, and phenylalanine on PAMAM dendrimer surface on gene transfection efficacy. Reprinted with permission from ref 186. Copyright 2014 Elsevier Ltd.

Figure 13. Structures of saccharide-modified PAMAM dendrimers. I

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For example, epidermal growth factor receptors (EGFR) are highly expressed in a wide variety of cancer cells. The binding of EGF to EGFR triggers fast internalization of EGFconjugated dendrimers by the cancer cells. As a result, EGF modification improves the efficacy by 10-fold compared to the EGF-free vector in a liver cancer cell line.215 Similarly, antibody-modified PAMAM dendrimer exhibits much higher cellular uptake and more efficient Bcl-2 gene silencing (an antiapoptotic gene) in cancer cells compared to unmodified dendrimers.216 When PAMAM dendrimer was linked with an antibody against P- and E-selectin expressed on activated endothelial cells, the conjugate can be used in targeted gene delivery for the treatment of inflammatory or cardiovascular diseases.217 Since transferrin receptors are highly expressing on prostate cancer cells, transferrin-conjugated PPI dendrimers were used as vectors for the delivery of plasmids encoding tumor necrosis factor α (TNFα), TNF-related apoptosisinducing ligand (TRAIL), interleukin 12 (IL12), or p73 (a protein that induces cell cycle arrest or apoptosis) to prostate cancer in vitro and in vivo.218−220 Gene therapy mediated by these transferrin-conjugated materials effectively inhibits tumor growth and thus prolongs the survival period of animals. Among the therapeutic plasmids, TNFα plasmid is the most effective one using the conjugate as a targeted vector, which inhibits tumor by 60% for PC-3 prostate tumors and 50% for DU145 prostate tumors.220 The blood−brain barrier (BBB) is a highly selective permeability barrier that hinders the delivery of therapeutic agents to the brain.221−223 Receptor-mediated endocytosis is one of the major strategies to penetrate the BBB.224 It is reported that there is a high density of transferrin receptors on the surface of brain capillary endothelial cells.225 Therefore, conjugation of transferrin to gene carriers may improve the expressions of target gene in the brain during gene therapy. As expected, conjugation of transferrin or lactoferrin to PAMAM dendrimers significantly improves their gene transfection efficacy in the brain.226−228 Besides proteins, some peptides also help the dendrimer/DNA polyplexes to penetrate the BBB (Table 1). These peptides include a 29 amino acid peptide derived from rabies virus glycoprotein (RVG29, which specifically binds to nicotinic acetylcholine receptor on neuronal cells),229 a 30 amino acid peptide derived from leptin (which specifically binds to leptin receptor overexpressed on

Figure 14. Cyclodextrin-modified PAMAM dendrimer in the codelivery of siRNA and small molecules to neural stem cells to enhance differentiation into neurons. Reproduced with permission from ref 201. Copyright 2013 American Chemical Society.

dendrimer conjugated with three galactose molecules is 4 orders of magnitude higher in liver than in other organs such as lung, heart, spleen, and kidney. Pretreatment of the mice with asialofetuin, a natural ligand for asiaologlycoprotein receptors, effectively inhibits the glactosylated-dendrimer-mediated gene transfection in liver. Similarly, mannosylation significantly improves the transfection efficacy of a PAMAM dendrimer in macrophages.203 CDs and targeting saccharides show a synergistic effect in gene delivery. G2− and G3−α-CD conjugates were further modified with mannose (43),205,206 fructose (44),207 lactose (45),208−210 or galactose (46)211 moieties to achieve cellspecific DNA and siRNA delivery. Further information on these CD-functionalized dendrimers and dual-functionalized dendrimers is available in review articles by Arima et al.212−214 2.5. Protein- and Peptide-Modified Dendrimers

A major approach for targeted gene delivery is to target the gene carrier to a cell-specific receptor through ligand−receptor or antibody−antigen recognitions. Besides saccharides described in section 2.4, proteins and peptides were widely used as targeting ligands. These ligands were conjugated to dendrimers for cancer-targeted or site-specific gene delivery. Table 1. Peptide-Modified Dendrimers Used in Gene Delivery peptide

peptide sequence

receptor

RVG29 leptin30 angiopeptide

YTIWMPENPRPGTPCDIFTNSRGKRASNG YQQVLTSLPSQNVLQIANDLENLRDLLHLL TFFYGGSRGKRNNFKTEEY

nicotinic acetylcholine receptor leptin receptor LRP1

T7 chlorotoxin

HAIYPRH MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR

RGD

RGD

transferrin receptors membrane-bound matrix metalloproteinase-2 endopeptidase intergrin

LHRH MSC binding peptide pHLIP

QHWSYKCLRP SGHQLLLNKMPNGGGSC

LHRH receptor 

AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTCG



TAT R9 NLS

CGRKKRRQRRRK RRRRRRRRR PKKKRKV

   J

goal

ref

brain targeting brain targeting brain and glioma targeting brain targeting glioma targeting

229 230 232

cancer and MSC targeting cancer targeting MSC targeting

236, 238, 239 237 235

tumor acidity targeting cell penetrating cell penetrating nuclear targeting

244

233 231

248 246 247

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Figure 15. Structures of polymer-modified PAMAM or PPI dendrimers.

of the mice better than the commercial drug temozolomide.232 Compared with targeting proteins, the peptides conjugated on dendrimers maintain high binding affinity with the receptors, reduce spatial hindrance on the dendrimer surface, and improve stability of vectors during gene delivery. Besides brain-targeting peptides, other peptides with high affinity for specific cells, such as peptides with high affinity for mesenchymal stem cells (MSCs),235 RGD (a three amino acid peptide that specifically binds to integrin on cancer cells or MSCs),236 and luteinizing hormone-releasing hormone (LHRH) peptide (LHRH receptors are overexpressed on various cancer cells),237 were conjugated on PAMAM or PPI dendrimer surface for targeted gene delivery.236−239 The above examples of protein/peptide-targeted gene delivery actively target on the basis of receptor-mediated endocytosis. We can also achieve cancer-targeted gene delivery by a passive targeting

cells located in the hypothalamus and other parts of the brain),230 the 36 amino acid peptide chlorotoxin (which specifically binds to receptors up-regulated on glioma cells),231 the 19 amino acid peptide angiopep-2 [which targets lowdensity lipoprotein receptor-related protein-1 (LRP1) that is highly expressed in the central nervous system],232 and the 7 amino acid peptide T7 (which specifically binds to transferrin receptors).233,234 These modifications efficiently improve the penetration ability of PAMAM dendrimers across the BBB and gene expressions in the brain. For example, LRP1 is highly expressed on brain capillary endothelial cells as well as glial cells; therefore, the angiopep-2-conjugated PAMAM dendrimer can realize a dual-targeting function during gene delivery (penetrating across BBB and further targeting glioma tumors in the brain). Treatment of brain-tumor-bearing mice with the TRAIL-loaded vector efficiently prolonged the survival period K

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obtained when PEG chains were modified on a PAMAM dendrimer through an acid-cleavable hydrazone linkage.261 Such a design strategy bestows on the PEGylated dendrimers a degradable property in gene delivery. Gene therapy in mucosal tissues is typically limited by protective mucus layers that serve as the body’s first line of defense on the surface of eyes, lungs, and gastrointestinal and cervicovaginal tracts. For efficient gene delivery to the mucosal tissues, the polyplex should be able to penetrate across the mucus layer and be inert to the mucus constituents. A recent study shows that this goal can be achieved by conjugating a cationic PAMAM dendrimer with a high density of PEG chains.254 A single-site of the dendrimer was functionalized with another cationic polymer such as PAMAM dendrimer or PEI. The yielded polymer has excellent biocompatibility and high ability to condense plasmid DNA to penetrate human cystic fibrosis sputum. Such a PEGylated dendrimer has potential applications in clinical gene therapy for the treatment of mucosal diseases.254 Besides PEG, other polymers, such as hyaluronic acid (48),262,263 chitosan (49),264 PLL (50),265 Pluronic P123 (51),266 PEI (52),267−270 PEG−PLL (53),271 PEG−PEI (54),272 PGA−PEI (55),273 poly(N,N-di(2-aminoethyl)aminoethyl glutamine) (PAGA, 56)274 and arginine-grafted bioreducible poly(disulfide amine) (ABP, 57),275−277 were grafted on cationic PAMAM or PPI dendrimers to optimize the performance of dendrimers in gene delivery. Dendrimers modified with PLL, Pluronic P123, PEI, PAGA, and PGA− PEI show improved transfection efficacy and better serum resistance. The ones modified with ABP exhibit reductionresponsive properties in gene delivery.275,276 Hyaluronic acid modification allows cell-specific gene delivery.262,263 Hyaluronic acid is a natural linear polymer.278 Its receptors such as CD44 are overexpressed on cancer cells such as MCF-7 and MDAMB-231 cells.279,280 The hyaluronic acid-modified PAMAM dendrimers efficiently deliver siRNA to drug-resistant MCF-7 cells and knock down the expression of major vault protein (MVP), which is involved in drug resistance of human breast cancer cells.263 Codelivery of doxorubicin and MVP siRNA by the hyaluronic acid-modified PAMAM dendrimer overcomes the drug resistance and kills the cancer cells effectively.

strategy. It is known that most tumors exhibit a more acidic extracellular microenvironment (pH 6.5−6.8) compared to normal tissues.240 The tumor extracellular acidity is ubiquitous in solid tumors, regardless of cancer type; thus, it can serve as a general biomarker to design tumor-targeted gene delivery systems. The tumor extracellular acidity can activate a pH (low) insertion peptide (pHLIP), followed by its endocytosis.241−243 Therefore, conjugation of pHLIP to a PAMAM dendrimer allows specific gene transfection in tumor rather than in normal tissues.244 The gene transfection efficacy of a material depends on multiple steps, such as endocytosis and nuclear entry. Conjugation of a polymeric vector with a cell-penetrating peptide or a nuclear localization signal (NLS) peptide may optimize intracellular trafficking of the polyplex, thus improving its transfection efficacy.245−247 For example, two types of cellpenetrating peptide [oligoarginine (R9) and transactivator of transcription (TAT)] were conjugated to a PAMAM dendrimer.246 R9-conjugated PAMAM dendrimer loaded with siRNA significantly improves cardiac function recovery in a cardiovascular disease model, while the TAT-conjugated dendrimer is less effective in siRNA delivery. Dual functionalization of a PLL dendrimer with TAT peptide and NLS peptide also significantly improves its transfection efficacy.247 However, in a separate study, TAT functionalization failed to improve the efficacy of a PAMAM dendrimer on the delivery of asODN and siRNA.248 The distinct results are probably attributed to different dendrimer scaffolds and different numbers of peptides modified on dendrimer. Further structure−function relationships of these peptide-functionalized dendrimers in gene delivery should be investigated. 2.6. Polymer-Modified Dendrimers

Polymer modification may also increase the transfection efficacy while the cytotoxicity of cationic dendrimers is reduced (Figure 15). PEG is the most-investigated polymer in improving the performance of dendrimers in gene delivery. Use of dendrimers in clinical gene therapy is limited due to their inherent cytotoxicity. PEGylation of dendrimers (47) significantly reduces their cytotoxicity.249,250 In addition, cationic dendrimers and their polyplexes are rapidly cleared by the reticuloendotherial systems when administrated via intravenous route. PEGylation of dendrimers can increase the serum stability and blood circulation time of the polyplexes, which is essential for in vivo applications.246,251−253 However, a high degree of PEGylation of dendrimers reduces the number of positive charges available for DNA condensation. Lessefficient DNA compaction may lead to relatively large polyplex size and inferior protection of the bound nucleic acids. As a result, PEGylation may decrease the cellular uptake and transfection efficacy of cationic dendrimers.249,254,255 Similar phenomenon is observed for acetylated PAMAM dendrimers.249,256,257 The degree of PEGylation is an important parameter to optimize the materials. After carefully choosing the PEGylation degree and the dendrimer scaffold, PEGylated dendrimers may achieve win−win results on transfection efficacy and biocompatibility.258−260 For example, 8% PEGylation on G5 or G6 PAMAM dendrimer yields improved transfection efficacy and reduced toxicity and hemolytic activity.260 Not limited to DNA delivery, the PEGylated (8%) PAMAM dendrimers show high efficacy in intramuscular gene silencing,258 being superior to unmodified dendrimers and comparable to Lipofectamine 2000. Similar results were

2.7. Nanoparticle-Modified Dendrimers

Nanoparticles such as carbon nanotubes, graphene, quantum dots, gold nanoparticles, magnetic nanoparticles, upconversion nanoparticles, and silicon nanomaterials are widely used in the diagnosis and treatment of many diseases.281−286 These materials have unique properties, such as photothermal activity (carbon nanotubes, graphene and gold nanorods),287−289 magnetic properties (Fe3O4 nanoparticles),281 and fluorescent properties (quantum dots and upconversion nanoparticles).285,286 Dendrimer can be easily grafted with these nanostructures to prepare multifunctional materials with reduced cytotoxicity compared to unmodified dendrimers (Figure 16).72 These multifunctional materials show great promise in gene delivery. For example, PAMAM dendrimers were functionalized with multiwalled carbon nanotubes or carbon nanohorns for efficient DNA, siRNA, and asODN delivery.290−293 Similarly, PAMAM dendrimers were modified with gold nanorods and the conjugates were used to deliver short hairpin RNA (shRNA) into MCF-7 cells.294 The gold nanorods have an absorbance peak around 800 nm that can be used to monitor L

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particles but are not included in the yielding polyplexes. The polyplexes efficiently deliver siRNA into cancer cells and silence their target mRNAs. The efficacy of mRNA silencing by the low-generation-dendrimer-stabilized gold nanoparticles is superior to that of high-generation dendrimers. In addition, PAMAM-dendrimer-encapsulated gold nanoparticles also show much improved gene transfection efficacy on several cell lines and reduced cytotoxicity on the transfected cells.296−298 PAMAM or PPI dendrimers were functionalized with magnetic Fe3O4 nanoparticles or bacterial magnetic nanoparticles for asODN and siRNA delivery.299−301 The materials and their complexes with asODN enter into cancer cells within 15 min and cause remarkable down-regulation of survivin gene and protein, efficiently inhibiting the growth of cancer cells.299 These materials allow targeted gene delivery by an external magnetic field and tracking the distribution of gene materials by MRI. Similarly, PAMAM dendrimers modified with Fe3O4 nanoworm were used for siRNA delivery.302 The combination of PAMAM dendrimer and Fe3O4 nanoworm significantly improves their abilities for endosomal escape. The conjugate

Figure 16. Structures of nanoparticle-modified dendrimers. (a) PAMAM-dendrimer-conjugated carbon nanotube, (b) PAMAMdendrimer-conjugated gold nanoparticle, and (c) PAMAM-dendrimer-conjugated quantum dot. Reproduced with permission from ref 72. Copyright 2011 Royal Society of Chemistry.

their positions in cancer cells and to enhance the gene transfection efficacy via near-infrared light irradiation. Such materials can kill cancer cells by a combination of gene therapy and photothermal ablation. PPI dendrimers were used to prepare dendrimer-stabilized gold nanoparticles.295 The gold nanoparticles facilitate lowgeneration PPI dendrimers to package siRNA into nano-

Figure 17. Structures of cationic-moiety-modified dendrimers. M

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Figure 18. “Odd−even” effect of oligoamines in gene delivery. Oligoamines modified with even-numbered aminoethylene units show higher buffering capacity than those with odd-numbered aminoethylene units. Reproduced with permission from ref 306. Copyright 2011 American Chemical Society.

and high activity in destabilizing membrane integrity selectively at endosomal pH. Similarly, PAMAM dendrimer modified with diethylenetriamine (even-numbered aminoethylene, 59) shows significantly higher transfection efficacy than those modified with oligoamines having odd-numbered aminoethylene (58) or even-numbered aminopropylene units (60).307 Among these oligoamine-modified dendrimers, minimal difference in the oligoamines may remarkably influence the transfection efficacy. This odd−even effect of oligoamines also works on other types of dendritic polymers, such as polyglycerol and Newkome-type “arborol”.308−310 Modifications of polyglycerol with oligoamines such as spermidine (62), spermine (63), and pentaethylenehexamine (64) failed to increase the transfection efficacy of an amine-terminated polyglycerol on the delivery of siRNA.308,309 Therefore, we can design efficient oligoaminebased gene vectors according to this odd−even law. Tertiary-amine- and quaternary-ammonium-modified dendrimers (65−69) were used as carriers for in vitro and in vivo gene delivery.89,311−320 For example, quaternized carbosilane dendrimers successfully deliver asODNs and siRNA into a list of cells relevant to HIV pathology, such as peripheral blood mononuclear cells, lymphocytes, primary macrophages, dendritic cells, and immortalized adherent cells.89,315,316 The quaternized carbosilane dendrimer complexed with asODNs efficiently reduces HIV replication in these cells. In addition, the dendrimer complexed with siRNA inhibits cyclooxygenase 2 gene expression in HIV-infected nervous system cells.316 Quaternized carbosilane dendrimer presents safety properties during gene delivery; e.g., it decreases the release of TNF and IL12 by macrophages as well as the phagocytosis activity of macrophages, while it does not induce proliferation of the CD4-T lymphocytes.89 Similarly, quaternized phosphorus dendrimers successfully deliver siRNA into peripheral blood mononuclear cells and efficiently knock down the NEF, an HIV-1 auxiliary gene in the cells, with very low cytotoxicity.321 Treatment of HIV-infected peripheral blood mononuclear cells with the phosphorus dendrimer/siNEF complex significantly reduced viral replication. These low-toxicity dendrimers might

delivers siRNA against EGFR, reducing the EGFR protein levels in human glioblastoma cells by 70−80%, which is 2.5-fold more efficient than Lipofectamine 2000. In addition, the conjugate efficiently suppresses EGFR expressions in glioblastoma in vivo. Besides, PAMAM dendrimers were modified with MnO nanorods,303 mesoporous silica nanoparticles,304 and biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles305 for gene delivery. These materials show high transfection efficacy and minimal cytotoxicity on the transfected cells. The nanoparticle-modified dendrimers will play an important role in combination therapy (gene therapy, chemotherapy, photothermal therapy, etc.) for the treatment of cancers in future studies. 2.8. Cationic-Moiety-Modified Dendrimers

Cationic dendrimers usually have primary amine groups on their surface. These dendrimers can be further functionalized with other cationic moieties, such as oligoamine, tertiary amine, quaternary ammonium, imidazolium, guanidium, and phosphonium (Figure 17). Conjugation of dendrimers with oligoamines (58−64) significantly increases the charge density on the dendrimer. However, the transfection efficacy of the oligoamine-modified dendrimers is not always in proportion with the length of the modified oligoamines. This is because the transfection efficacy of a cationic polymer depends on multiple parameters. Grafting cationic dendrimers with longer oligoamines is beneficial for DNA condensation, but it might be harmful for DNA unpacking in the cytoplasm after endosomal escape. In addition, pH buffering capacity of these modified oligoamines should be considered. For example, there is an odd−even effect on gene transfection efficacy of oligoamines grafted on the polymers. The oligoamines with even-numbered repeating aminoethylene units (59) show significantly higher transfection efficacy than those with odd-numbered aminoethylene units (58) when grafted on a linear polymer.306 This odd−even effect agreed well with the buffering capacity of these oligoamines (Figure 18). Oligoamines modified with evennumbered aminoethylene units have high buffering capacity N

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Figure 19. Other ligand-modified PAMAM dendrimers in gene delivery.

Dendrimers were also modified with guanidium and imidazolium (70) for improved transfection efficacy,176−179 and the mechanisms are similar to those of arginine- and histidine-modified dendrimers, respectively, as discussed in section 2.3. Phosphonium-modified polymer is a more efficient and safer alternative to the ammonium-modified vector in gene delivery.326 In a recent study, triphenylphosphonium-modified PAMAM dendrimers (71) show high transfection efficacy and low cytotoxicity.83 The efficacy of the triphenylphosphoniummodified dendrimers is superior to that of amine-terminated dendrimer and SuperFect and is comparable to that of Lipofectamine 2000. The high transfection efficacy is attributed to the mitochondria-targeting ability of triphenylphosphonium-

be developed as promising gene vectors in the treatment of HIV infection. It is worth noting that interior-quaternized PAMAM or PPI dendrimers are also able to efficiently bind DNA and siRNA and deliver the nucleic acids into cells.322−324 Interior-quaternized viologen dendrimers with ethyl or thymine as the surface capping group were reported with high transfection efficacy in U2OS cells.97 These materials can also be used as chemokine receptor CXCR4 antagonists.325 Using a TNFα plasmid, the viologen dendrimers successfully prevent CXCR4-mediated cancer cell invasion and facilitates TNFαmediated cancer cell killing. Since this review article focuses on surface-engineered dendrimers in gene delivery, these examples are not discussed in detail. O

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drimers due to the hydrophobic effect and fusogenic property of the lipids. Fluorination improves the cellular uptake, serum resistance, endosomal escape, and intracellular DNA release profiles of dendrimers. The fluorinated dendrimers can achieve efficient gene transfection at extremely low N/P ratios, thus reducing the cytotoxicity of dendrimers on the transfected cells. Due to the hydrogen bonds between fluorine atoms and water molecules, the fluorinated dendrimers show excellent aqueous solubility. Amino acid modification improves different steps in gene delivery; e.g., arginine modification improves DNA- and membrane-binding affinity, histidine modification facilitates endosomal escape due to increased pH buffering capacity, and phenylalanine modification improves cellular uptake due to the hydrophobic effect. Cyclodextrin modification improves the transfection efficacy of dendrimers by increasing their affinity for cell membranes. Saccharide, protein, and peptide modifications improve the transfection efficacy of dendrimers on specific cell lines or in specific tissues/organs in vivo. Polymer modification increases the biocompatibility, flexibility, blood circulation time, and transfection efficacy of cationic dendrimers. Nanoparticle modification endows the dendrimers with new functions and altered intracellular trafficking. Oligoamine modification improves DNA binding capacity and sometimes the pH buffering capacity of cationic dendrimers. Quaternary ammonium modification reduces the cytotoxicity of amine-terminated dendrimers on the transfected cells. These surface-engineered dendrimers provide helpful insights into the design of efficient and biocompatible gene vectors. The current surface-engineered dendrimers in this review article were investigated on different cell lines by different researchers. Their transfection efficacies cannot be directly compared. The structure−function relationships of these surface-engineered dendrimers still need in-depth investigations. Perhaps, one may prepare a library of surface-engineered dendrimers using the same dendrimer scaffold, carefully optimize the number of ligands conjugated on the dendrimers, and screen the highly efficient ones for gene delivery, especially for siRNA delivery. Of course, there are multiple barriers in the gene transfection process, and single functionalization on a dendrimer cannot overcome all the barriers. We need to clearly understand the exact mechanism for each modified ligand and synthesize dual-, triple-, or multiple-functionalized dendrimers with ligands to optimize the performance of the surfaceengineered dendrimers.

modified dendrimers, which facilitates endosomal escape and membrane disruption during intracellular trafficking. 2.9. Other Ligand-Modified Dendrimers

2.9.1. Hormone-Modified Dendrimers. PAMAM dendrimers modified with dexamethasone (72), a hydrophobic glucocorticoid, show high transfection efficacy in HEK293 and Neuro-2A cells (2−4 orders of magnitude higher than unmodified dendrimers) (Figure 19).327 Besides, the conjugates allow efficient nuclear translocation and even show higher antiinflammatory activity than free dexamethasone.328 This modification strategy allows us to design efficient polymeric gene vectors with nuclear targeting and anti-inflammatory properties. Similarly, modification of dendrimer with triamcinolone acetonide (73), a glucocorticoid with nuclear targeting property, significantly improves the transfection efficacy of dendrimers.329 2.9.2. Folic Acid-Modified Dendrimers. Folic acid receptors are overexpressed on a list of cancer cells. Modification of PAMAM dendrimers with folic acid (74) improves the transfection efficacy of dendrimers on specific cell lines. For example, folic acid-modified PAMAM dendrimer allows efficient DNA and siRNA delivery in folic acid receptor overexpressing cells such as KB cells.330,331 2.9.3. Photosensitizer-Modified Dendrimers. Photosensitizing compounds such as porphyrin were conjugated on the surface of PAMAM dendrimers (75).332 The conjugates show significantly improved transfection efficacy upon laser exposure, which is due to the breakdown of endosomal and lysosomal membranes by photoactivation of porphyrin localized on the membranes of these organelles.333−335 In addition, the photosensitizing compounds conjugated on dendrimer can also be used to monitor the intracellular localization of the gene vector in cells via its fluorescent property.332 2.9.4. Fluorophore-Modified Dendrimers. PAMAM dendrimers modified with a fluorescent dye, Oregon Green 488, allow visualization of the vector during gene transfection (76).336 Surprisingly, the fluorophore-modified dendrimer shows much higher transfection efficacy compared to unmodified dendrimer, which is comparable to three commercial transfection reagents, including SuperFect, Lipofectin, and Lipofectamine. The unexpected high transfection efficacy of fluorophore-modified dendrimer is attributed to hydrophobic effect of the fluorescent dye. 2.9.5. Aminoglycoside-Modified Dendrimers. Aminoglycosides are a class of small molecular antibiotics with natural affinity for DNA and siRNA. These compounds are able to mediate the cellular uptake of macromolecules depending on the valency of the transporter. Conjugation of aminoglycosides such as neamine (77), paromomycin (78), and neomycin (79) to a PAMAM dendrimer significantly improves its transfection efficacy.337 In addition, the aminoglycoside-modified dendrimers may also act as antibacterial reagents.

AUTHOR INFORMATION 3. CONCLUSIONS AND PERSPECTIVES Dendrimers were modified with lipids, fluorous compounds, amino acids, saccharides, proteins and peptides, polymers, nanoparticles, and cationic moieties to optimize their transfection efficacy and biocompatibility. These surface-engineered dendrimers show promising potential for in vitro and in vivo gene delivery. Lipid functionalization improves the cellular uptake and membrane-disrupting activity of cationic den-

Corresponding Author

*E-mail: [email protected]. Author Contributions

J.Y. and Q.Z. contributed equally to this review. Notes

The authors declare no competing financial interest. P

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Biographies

Hong Chang obtained her Bachelor’s degree from Liaoning Normal University. Currently, she is a Ph.D. candidate at the School of Life Sciences, East China Normal University, supervised by Y.C. Her research interest is focused on dendrimer-based gene delivery systems.

Jiepin Yang obtained her Bachelor’s degree from the Department of Horticulture, China Agricultural University, and her Ph.D. degree from the School of Life Sciences, University of Science and Technology of China. She is now a lecturer in the School of Life Sciences, East China Normal University. Her research interest is focused on the development of smart biomaterials for drug and gene delivery.

Yiyun Cheng is a full professor of biomedical engineering at School of Life Sciences, East China Normal University. He received his Ph.D. from University of Science and Technology of China and was a postdoctoral fellow at Washington University in St. Louis, MO. He was recognized with the following awards: Excellent Young Scholars of NSF, Shanghai Dawn Scholar, Shanghai Rising Stars, and New Century Excellent Talents in the Universities of Ministry of Education, China. He was the Regional Editor of Current Drug Discovery Technologies and an Editorial Board Member of Letters in Drug Design & Discovery and was invited to be a reviewer for more than 100 international journals. He has published more than 80 peer-reviewed papers in journals such as Nature Materials, Nature Communications, Chemical Reviews, Chemical Society Reviews, and Journal of the American Chemical Society, and his work has been cited more than 2000 times by other research groups. His research interests are focused on the biomedical applications of dendrimers and other dendritic polymers.

ACKNOWLEDGMENTS Financial supports from the National Natural Science Foundation of China (No. 21322405 and No. 21474030) and the Shanghai Municipal Science and Technology Commission (13QA1401500 and 148014518) are greatly appreciated.

Qiang Zhang is an associate professor of biomedical engineering at School of Life Sciences, East China Normal University. He received his B.S. in material physics in 2005 and his Ph.D. in biochemistry and molecular biology (with Prof. Longping Wen) in 2011 from University of Science and Technology of China. He studied as a visiting scholar in Biomedical Engineering at Washington University in St. Louis, MO (with Prof. Younan Xia), from 2008 to 2010, and worked with Prof. Dong Qin at Georgia Institute of Technology as a postdoctoral research associate, from 2012 to 2013. His research interests focus on controlled synthesis of nanomaterials and their applications in cancer diagnosis, imaging, and therapy.

ABBREVIATIONS USED ABP arginine-grafted bioreducible poly(disulfide amine) asODN antisense oligodeoxynucleotide BBB blood−brain barrier CD cyclodextrin DEAE-dextran diethylaminoethyl-dextran DOPE 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine EGFR epidermal growth factor receptor IL12 interleukin 12 LHRH luteinizing hormone-releasing hormone LRP1 low density lipoprotein receptor-related protein-1 MDR multidrug resistance MSCs mesenchymal stem cells MVP major vault protein NLS nuclear localization signal NMR magnetic resonance imaging N/P nitrogen to phosphorus ratio OEI oligoethylenimine Q

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Chemical Reviews PAGA PAMAM PDMAEMA PEG PEI PETIM PGA pHLIP PLGA PLL PPI RVG shRNA siRNA TAT TRAIL TNFα

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poly(N,N-di(2-aminoethyl) aminoethyl glutamine) poly(amidoamine) poly(N,N-dimethylaminoethyl methacrylate) polyethylene glycol polyethylenimine poly(ether imine) poly(γ-glutamic acid) pH (low) insertion peptide poly(lactic-co-glycolic acid) poly-L-lysine poly(prophylenimine) rabies virus glycoprotein short hairpin RNA small interfering RNA transactivator of transcription tumor necrosis factor related apoptosis-inducing ligand tumor necrosis factor α

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