Corrigendum Corrigendum to “Applications of Dendrimers in Drug Delivery Agents, Diagnosis, Therapy, and Detection”

[28] V. Gajbhiye, V. K. Palanirajan, R. K. Tekade and N. K. Jain, “Dendrimers as therapeutic agents: a systematic review,” Journal of Pharmacy and Pharmacology, vol. 61, pp 989-1003, 2009. [39] J. M. Oliveira, A. J. Salgado, N. Sousa, J. F. Mano and R. L. Reis, “Dendrimers and derivatives as a potential therapeutic tool in regenerative medicine strategies – a review,” Progress in Polymer Sciences, vol. 35, no. 9, pp. 1163-1194, 2010. [102] D. Astruc, E. Boisselier and C. Ornelas, “Dendrimers Designed for Functions: From Physical, Photophysical, and Supramolecular Properties to Applications in Sensing, Catalysis, Molecular Electronics, Photonics, and Nanomedicine,” Chemical Reviews, vol. 110, pp. 1857-1959, 2010. [105] S. Svenson, “Dendrimers,” In Kirk-Othmer Encyclopedia of Chemical Technology. Copyright John Wiley & Sons, Inc., vol. 26, pp. 786-812, 2006. [112] N. Joshi and M. Grinstaff, “Applications of dendrimers in tissue engineering,” Current Topics in Medicinal Chemistry, vol. 8, no. 14, pp. 1225-1236, 2008. Abstract


Introduction
Dendrimers, also known as cascade polymers, are tridimensional structures that were first reported by Gajbhiye et al. in 2009 [2]. These unimolecular micelles were also the basis for polypropylene imine (PPI) dendrimers, constructed by Oliveira et al. and Astruc et al. in 2010 [3][4]. In 2006, Svenson also reported a very interesting type of dendrimer prepared from a mixture of amines and amides, which are known as poly(amido amines) or PAMAM dendrimers [5]. Several dendrimers were reported in the 1980s and 1990s, and in general terms, these molecules are widely known as tree-, branch-, arborol-or cascade-shaped polymers.
The dendritic branching leads to semiglobular and globular configurations with a large number of terminal functional groups that define their reactivity and interaction with the molecular environment. The central core, on the other hand, could be a single atom or molecule with multiple branching peripheral groups from which the hyperbranching building blocks are sequentially connected. This region around the central dendrimer unit is characterized not only by empty spaces in which small organic and/or inorganic molecules can be located but also by chemical functionalities responsible for a variety of supramolecular interactions that can be exploited to form an interesting and potentially important array of weak complexes.
As previously mentioned, the particular structure and space configuration of dendrimers give rise to different physicochemical characteristics that can be used to define and exploit internal as well as external interactions with other organic and/or inorganic molecules. In fact, the branching structure that characterizes dendrimer molecules (with diameters < 10 nm) resembles, from a generic point of view, not only the shape of some proteins and biomolecules (biomimics) but also their ability to interact with other organic molecules by encapsulation to increase their solubility, disperse active molecules, and enhance the administration and transport properties in a given medium, as well as by other different mechanisms, or to improve pharmaceutical activity to treat memory impairment, inflammatory diseases, microbial infections, and cancer.
In this review, we study the applications of dendrimers as protein mimics, delivery agents for drugs, and anticancer or antiviral therapeutics. In addition, we discuss the use of dendrimers in biomedical diagnostic applications such as modified electrodes.

Dendrimers as Possible Globular Protein Mimics
Considering the particular internal and external structure and morphology of dendrimers, these molecules can be used for biomimetic studies to better understand the function and dynamics of some biological systems. In this regard, PAMAM dendrimers have been used as molecular structure analogs of insulin (generation 3.0 with a diameter of 3 nm), cytochrome C (generation 4.0 with a diameter of 4 nm), and hemoglobin (generation 5.0 with a diameter of 5.5 nm, with an ammonia functional group in the central core). Although dendrimers are similar to some important proteins and, as has been pointed out, can be used to mimic these biomolecules and gain a better understanding of their structure-activity relationship, it is also true that there are important differences between proteins and dendrimers and that these must be taken into account so that a proper comparison can be made. As opposed to proteins whose structure (and function) usually obeys a weak balance of supramolecular interactions that are asymmetric in different directions, dendrimers are similar to unimolecular covalent micelles that are characterized by a large resistance to environmental changes such as alterations in temperature, light, and pH. Therefore, the stability of the internal and external complexation suites is far greater than that in proteins (see, for example, Figure 1). The next sections show examples of mimetic applications of dendrimers.

Dendrimers Mimicking Proteins Involved in Angiogenesis.
Dendrimers have been prepared and used to mimic the protein region involved in the angiogenesis inhibition of b-FGF in endothelial cells (Figure 2(a)) so that antitumor processes can be better understood. In vitro and in vivo studies (Figure 2(b)) have been carried out to prevent the growth and metastasis of tumors.

Dendrimers as Drug Delivery Agents
Due to their physicochemical structure, internal void regions, and external or peripheral surface functional groups, dendrimers have been widely studied as drug delivery agents. Furthermore, due to the sequential nature of the most common synthetic procedures, controllable structure, size, internal and terminal functional groups, permeability, hydrodynamic volume, molecular weight, molecular geometry, and variation in the internal and external charge can be designed and incorporated into the final dendrimer structure. With all these characteristics, dendrimers have been used to retain drugs, enzymes, antibodies, and other bioactive agents (Figure 4).

Dendrimers in Drug
Administration. One interesting approach for the development of drug delivery dendrimers was a report on the use of PAMAM dendrimer generation 3.0 and 3.0-lauroyl to study their effect on the transport of 2 Journal of Nanomaterials propranolol to the adenocarcinoma cell line CaCo-2. This phenomenon involves endocytosis-mediated transepithelial transport ( Figure 5) to increase drug solubility and bypass drug efflux transporters, improving the drug bioavailability. PAMAM dendrimers have also been used as drug carriers of ketoprofen and camptothecin. The corresponding studies in vitro and in vivo showed that the dendrimer molecules were capable of increasing the solubility of the drug in water and eliminating the negative effect in the gastrointestinal tract. In the case of the PAMAM dendrimer-ketoprofen complex, a favorable effect was also found in terms of anti-inflammatory, antipyretic, and analgesic properties. On the other hand, in the case of the PAMAM dendrimer-camptothecin complex, promising results were found in anticancer therapy (including lung, prostate, breast, colon, stomach, bladder, and ovarian cancer as well as melanoma). In addition, PAMAM dendrimer generation 3.5-SN38 (7-ethyl-10hydroxy-camptothecin) without and with CaCo-2 monolayers or PAMAM dendrimer generation 3.5-glycine-SN38 has shown interesting properties in terms of stability in the gastric and intestinal region by oral administration, without cytotoxicity, targeting the treatment of colorectal hepatic metastasis.

Dendrimers as Carriers or Scaffolds for Diagnosis and Therapy
Dendrimers have a number of advantages for use as carriers or scaffolds for diagnosis and therapy. For example, the amphiphilic property and interior cavities of dendrimers can be used to encapsulate hydrophobic or hydrophilic drugs depending on the dendrimer components. In addition, the generation-size linear correlation of dendrimers implies that they can be used as suitably sized molecules for specific biomedical applications.

Dendrimers as Anticancer Drug
Carriers. The most promising uses of dendrimers are as drug carriers due to their globular shape and their combined hydrophobic and hydrophilic character. In this way, properly positioned functional groups in the internal or peripherical zone can retain organic and inorganic compounds by means of dynamic supramolecular interactions, such as those found in DNA (for gene delivery), cisplatin (anticancer drug), and silver salts (antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli bacteria).

Dendrimers as MRI Contrast
Agents. Magnetic resonance imaging (MRI) is widely used to obtain tridimensional images in vivo without ionizing radiation. Using a gadolinium chelate contrast agent, superparamagnetic iron oxide particles and hepatobiliary contrast agents are administered before the scan. Among the main properties that are required for contrast agents, the need to diffuse rapidly from blood vessels into the interstitial space and to be efficiently excreted from the body without accumulation are two of the most important. In this regard, Gd(III)-2-(4-isothiocyanato-benzyl)-6-methyl-(DTPA)-PAMAM dendrimers have been found to be suitable for in vivo experiments with rats.  Figure 1: Representation of G2.0 PAMAM with 16 terminal amine groups. 3 Journal of Nanomaterials of living tissue for organs, which can in turn be used in transplant procedures [6]. To do so, biocompatible matrices are necessary to support or encapsulate cellular material so that the living cells can have access to nutrients and eliminate metabolic waste. Among the natural polymers that have been explored for tissue regeneration, collagen, fibrin, hyaluronic acid, chondroitin sulfate, alginate, dextran, and chitosan stand out as the most popular materials due to their biocompatible nature and their availability. On the other hand, in the case of synthetic polymers, both linear and three-dimensional polymers are studied. To this end, linear polymeric chains such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(caprolactone) (PCL), and poly(ethylene glycol) (PEG) have been explored.    5 Journal of Nanomaterials (AIDS) vaccine, there are some interesting reports involving dendrimers. Among these, studies involving a major antigenic peptide (MAP) with glycoprotein gp120 of the human immunodeficiency virus (HIV) sequence conjugated to a lysine dendrimer or a peptide-succinyl-maltose-prolinepoly(lysine) dendrimer can be readily found. Therefore, the inclusion of dendrimers in these vaccines should increase their water solubility and decrease cell toxicity and antigenicity. Other antigen-related studies involving dendrimer molecules report the use of polyacrylate dendritic polymers to eliminate infection with Streptococcus pyogenes, commonly known as group A Streptococcus (GAS), in rheumatic fever and heart disease (RHD), antigen peptide of P. yoelii by polyclonal antibodies, MAP-containing Plasmodium falciparum T-and B-cell stimulatory peptides, and MAP-sensitized dendritic cells and P815 cell lysis by pRL1a-specific B-24 CTL.

Dendrimers in Modified Electrodes
In clinical chemistry, the food industry, and different sectors of the environmental field, there is an increasing need for efficient, cost-competitive, and reliable electrochemical sensors. In this regard, surface modification of conductor electrodes serving as supporting substrates is by far the most common approach; in particular, the layer-by-layer (LBL) assembly method is one of the most important for the design and construction of bioelectrochemical detectors using organic or inorganic molecules such as proteins, DNA, viruses, dendrimers, and nanoparticles with unique properties. In the particular case of dendrimers, their unique supramolecular properties have been used in LBL electrochemical sensors to detect and quantify molecules of biological importance. Using specific physicochemical properties such as encapsulation capacity, molecular control, hydrophobicity/hydrophilicity biocompatibility, controlled diffusion, and electron transfer kinetic effects, dendrimers are currently positioned as an important class of surface modification compounds for the design and construction of electrochemical sensors.

Electrochemical Detection in Medical Diagnosis.
Detection and quantification in medical diagnosis can be made using optical, electrochemical, or piezoelectric transduction techniques. The electrochemical method in comparison with other techniques usually shows high sensitivity, low cost, and compatibility with microfabrication technology. Good examples of this approach involving dendrimer molecules are gold electrodes modified with ferrocenyl-tethered poly(amido amine) dendrimers linked to carboxylic or aminoterminated self-assembled monolayers (NPs, Figure 6).

Electrochemical Detection of H 2 O 2 .
Another interesting type of sensor that has been studied using dendrimers consists of modified surfaces to detect H 2 O 2 . In this way, cystamine-modified gold substrates were used to attach PAMAM dendrimer generation 4.0 through glutaraldehyde cross-linking. The effect of the dendrimer structure and terminal functional groups in the presence of horseradish peroxidase increased the sensitivity of the system for the detection of H 2 O 2 .  Journal of Nanomaterials

Electrochemical Detection of Glutamate.
For the electrochemical detection of glutamate, an amperometric biosensor based on the self-assembly of glutamate dehydrogenase (GLDH) and poly(amido amine) dendrimer-encapsulated platinum nanoparticles (Pt-DENs) on multiwalled carbon nanotubes (CNTs). The (GLDH/Pt-DENs)n/CNTs/Ppy hybrid film obtained by electropolymerization of pyrrole on glassy carbon electrodes resulted in a substrate capable of detecting glutamate.

Electrochemical Detection of Dopamine.
Another interesting example is the amperometric detection of dopamine in urine samples using glassy carbon electrodes modified with hydroxyl-terminated PAMAM dendrimer generation 4.0 containing different metallic nanoparticles (Figure 7). The resulting surface-attached nanocomposite was coupled to a high-performance liquid chromatography (HPLC) system, showing good sensing performance and no matrix effects. Similar electrochemical detection has been reported for platinumcontaining dendrimers, Pt-DENs, coupled to a flow injection amperometric (FIA) detector.

Conclusion
As has been mentioned several times in this work, there are important specific features of dendrimer molecules that make them an interesting class of compounds. The branched structure, internal void regions, and supramolecular internal and external capabilities of these unimolecular covalent micelles make them attractive as drug delivery agents, porous polymeric environments for controlled transport processes, and surface-attached films for biosensor applications.

Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.