Dendrimers as drug delivery systems; the benefits and challenges – Journal of Advanced Chemical and Pharmaceutical Materials

Simin Sharifi ¹, Sepideh Zununi Vahed ², Azin Jahangiri ^3*

¹Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

²Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

³Department of Pharmaceutics, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.

Abstract

Dendrimers as nanostructured macromolecules have ideal capabilities in capturing and/or conjugating the high molecular weight different cargos by host-guest connections as well as covalent bonding, respectively. Besides, dendrimers are recognized for their distinct buildings, flexibility in drug delivery, and great functionality whose possessions resemble with biomolecules. Dendrimers can be used to deliver nucleic acid-based drugs such as siRNA, shRNA and miRNA alongside chemotherapeutic agents into cells with no damaging or deactivating effects on the DNA. For selective targeting of drugs into cancer cells, dendrimers can be functionalized with targeting ligands such as antibodies and folic acid. The aim of the current review paper is to present an outline of dendrimers as drug delivery structures and the benefits and challenges.

Keywords: Cancer, Dendrimer, Drug delivery

Introduction

The medicine-based on nanotechnology, nanomedicine, offers a new route and a strong procedure of drug therapy that can progress drug performance and overcome restrictions [1-4]. Nowadays, nanotechnology offers methodologies to produce different compounds with an extensive variety of applications, from simple nanoparticles (NPs) to more complex buildings of biological and inorganic macromolecules [5-8]. Multi-functional structures in nanometric range may convert to the basis of medicine in the near future. Nanotechnology plays serious role in cancer treatment due to the application of different nano-vectors such as dendrimers, micelles, liposomes, carbon nanotubes (CNTs), metal NPs, synthetic and natural polymer NPs, and polymer–drug conjugates [9-11].

Dendrimers are unique nanoarchitecture structures with excellent characteristics such as nanometric size, a spherical 3D form, and monodispersed unimicellar nature. The other properties like drug encapsulation, solubilizing together with passive targeting also contribute to the curing usage of dendrimers [12]. According to recent reports, dendrimer-based combination chemotherapy (DCC) is a novel approach in targeted drug delivery into cancer cells [13]. DCC strategies involve co-delivery of two chemotherapeutic medications, the chemotherapeutic drug with anti-tumor metals and molecular agents, as well as co-delivery with dendrimer-coated magnetic NPs and combination of photodynamic treatment and chemotherapy. The aim of the current review paper is to present an outline of dendrimers as drug delivery schemes as well as the benefits and challenges. The search process was performed using internet databases mainly PubMed and included in vitro and in vivo reports using MeSH keywords to recognize related available literature in English.

2. Properties of dendrimers

Dendrimers are one of the best-recognized NPs due to unique properties like symmetrical structure, spherical shape, monodispersed, and branched structure. There are three main parts in the structure of a dendrimer; a central core, branches, and functional end groups on the surface. All three parts have reported showing critical functions, influencing the size, shape as well as the other features of the dendrimers [14]. The generation of a dendrimers denotes to the number of repeated branching series that are formed throughout its preparation. For instance, if the branching is done onto the core molecule 3 times, the prepared dendrimer is a third-generation kind (G3) [15]. Figure 1 shows a G4 dendrimers structure with different types of targeting ligands in different sections of dendrimer.

Figure 1. Main parts in the structure of a dendrimer.

Many advantages of dendrimers have been recognized compared to other polymeric architectural systems. The features of branched macromolecules in dendrimers are completely different from current linear polymeric materials [16]. Such differences are typically owing to the synthesis approaches. The traditional polymerization method generally produces polydisperse structures with different molecular weights, while dendrimers producing methods are able to generate homogeneous structures with uniform molecular weight [17]. Because of the spherical form as well as interior cavities, dendrimers are known as “host-guest” molecules, that they can display great encapsulation capabilities with the ability to deliver several compounds in their interior. Host–guest structures are composed of 2 or more molecules/ions that are kept together in inimitable structural connections. The forces other than full covalent bonds are involved among them.

Different possessions of the dendrimers are subject to surface terminal groups. The high number of surface functional groups has reported being responsible for high solubility as well as the permeability of dendrimers [18]. Sometimes, the terminal groups are extremely reactive and then may need to further alterations. Post-modification of the surface of the macromolecule is performed either to vary the physicochemical possessions or to make a specific activity like catalytic or therapeutic [19].

3. Type of dendrimers

Dendrimers can be classified based on their shape, internal cavities, generation, and end functional groups. Some types of main dendrimers are classified in Table 1.

Type of dendrimer	Main points	References
PAMAM (Poly Amido Amine) Dendrimer	· Synthesized through the divergent procedure. · Ammonia or ethylenediamine are used as initiator core. · Condensation of DNA followed by transfection owing to possess a positive surface. · A diamine like ethylenediamine as the core of PAMAM reacted with methyl acrylate, and then another ethylenediamine to form the generation-0 (G-0) PAMAM.	[20] [21]
PPI (Poly Propylene Imine) Dendrimer	· Amine terminated hyper-branched macromolecules. · Synthesized by divergent approach. · 1, 4-diaminobutane is used as dendrimer core. · Some other molecules with primary or secondary amine groups may also be utilized as core in their synthesis.	[22, 23]
Liquid crystalline (LC) dendrimers	· Consist of mesogenic LC monomers. · Usually designed by rod-like (calamitic) or disk-like (discotic) molecules. · The lack of mesomorphism is observed for the fifth-generation dendrimer due to its inability to reorganize into a cylindrical shape.	[16, 24]
Core Shell (tecto) dendrimers	· Possess a well-ordered structure due to controlled covalent bond of building blocks. · Composed of a core dendrimer that may or may not contain a cargo. · Have simple synthesis procedure.	[16, 25-27]
Chiral Dendrimer	· Have different construction of constitutionally but are chemically similar with a chiral core. · Chiral, non-racemic dendrimer that have ideal stereochemistry are proper for applications in asymmetric catalysis and chiral molecular recognition.	[16, 28]
	·	[16, 29, 30]
Hybrid dendrimers	· Combination of dendritic and linear polymers in hybrid block or graft copolymer systems. · are applied as surface active agents, compatibilizers or adhesives, or hybrid dendritic linear polymers owing to the small dendrimer segment coupled to multiple reactive chain ends provides an opportunity to use them. · Can produced from various polymers with dendrimers generated the compact, rigid, uniformly shaped globular dendritic hybrids. ·	[31]

4. Drug delivery systems based on dendrimers

An extremely branched building can be used as an appropriate targeted drug delivery carrier by attaching different ligands [32]. Outstanding possessions of dendrimers are responsible for their great advantages comparing to other delivery systems. The three-dimensional construction alongside with different terminal groups as well as many internal hollows let dendrimers to transport different cargoes. These cargoes can be captured within the scaffold or attached to the surface of dendrimers. These structures are known by high loading efficiency as well as stability in the path of intracellular transportation. According to literature, dendrimers can progress drug’s solubility, spread the cargo’s blood circulation time through decreasing their removal, preserve drug concentrations higher than the minimal therapeutic dose in the plasma, and protect them from probable environmental damages. Dendrimers as systems proper for drug delivery can apply to avoid the resistance mechanisms and simplify the carriage of the drug directly to target cells without involving normal cells [33].

From some point of view, dendrimers are different compared to conventional polymers; they are in nano-metric size and spherical shape that own a high grade in the uniformity of molecular structure and tolerate of high surface modifications [34]. A large drug capturing can also confer by the unique structural configuration of dendrimers. Such a cargo loading may perform through numerous methods such as surface adsorption (that benefit from ionic interactions), entrapment within microcavities, or direct covalent bonding to the surface functional groups. These outstanding possessions convert dendrimers to an ideal system for the simultaneous delivery of hydrophobic and hydrophilic drugs [33]. The potential applications of dendrimers in medicine have made considerable attention in this regard. As an instance, there are many alterations of dendrimers’s exterior groups which permit to attain antibody or peptide conjugates with or to form dendritic boxes that capture guest molecules [30,32]. Poly (amidoamine), or PAMAM, is possibly the most famous dendrimer.

5. Challenges of using dendrimers in drug delivery

Some properties of surface groups such as charge affect the cytotoxic action of dendrimers. Irrespective of surface composition and molecular structure, cationic dendrimers are more cytotoxic and hemolytic than anionic and neutral dendrimers, owing to their non-specific affinity to cell membranes with a negative charge. Their toxic effect is generation-dependent and increases with some surface groups [33] while neutral and negatively charged dendrimers do not show cytotoxic effect in vitro. To aid diagnostic and therapeutic uses, it is required to decrease the toxicity of positively charged dendrimers. To this end, some chemical alterations of terminal groups have been presented which improve the targeting potential, meaningfully extend blood half-life, improve bio-distribution and biocompatibility design of dendrimers [34].

Conclusion

Outstanding possessions of dendrimers like their size, shape, diverging ability, and their surface modifiability convert these compounds to an ideal vehicle in different medical fields such as drug/gene delivery. These possessions present the dendrimers as smart selections for drug delivery. The unique properties of dendrimers have confirmed vast flexibilities in diversity of applications. However, more researches are required to identify their absorption or uptake mechanisms through biological membranes as well as in vivo stability.

Acknowledgments

The authors state that there is no financial support for this study.

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HOW TO CITE

Sharifi, S., Zununi Vahed, S., & Jahangiri, A. (2019). Dendrimers as drug delivery systems; the benefits and challenges. Journal of Advanced Chemical and Pharmaceutical Materials (JACPM), 2(2), 119-123. Retrieved from http://advchempharm.ir/journal/index.php/JACPM/article/view/84

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