An Overview of Dendrimers as Novel Carriers in Drug Delivery

Aravind M¹, Sivaram Kumar P², Arifa Begum SK³*

^1,2Department of Pharmaceutics, Chalapathi Institute of Pharmaceutical Sciences, Lam,

Guntur - 522 034, Andhra Pradesh, India.

³Department of Pharmaceutics, KVSR Siddhartha College of Pharmaceutical Sciences,

Vijayawada - 520 010, Andhra Pradesh, India.

*Corresponding Author E-mail: arifashaik2007@gmail.com

ABSTRACT:

Dendrimers and dendrimer based nanocarriers are gaining much attention in the field of therapeutic drug delivery owing to their advantages such as ease of multifunctionalization, well-defined chemical structure, near-to-monodispersity, as well as multivalency. Dendrimers are used as vectors in gene therapy, solubility enhancers and blood substitutes. Dendrimers have also been investigated as genetic material carriers with potential diagnostic and therapeutic applications. In the current review, an overview of the different types, synthesis methods, unique structural properties, factors affecting properties and applications of dendrimers. Further, the major concerns and future perspectives of the dendrimers have been discussed. The surface-modified dendrimers have been succeeded in their clinical translation and making remarkable progress in the phase of clinical trials. Extensive research is required in order to foster a robust large-scale synthetic method with adequate reproducibility. Significant studies necessarily be carriedout to find the correlation between the degree of surface modification (product quality) and their biological behavior, like pharmacokinetic profiles, therapeutic efficiency, safety and toxicity. In conclusion, dendrimers and dendritic nanoparticles have prospective insight in the arena of health sector in the forthcoming years.

KEYWORDS: Dendrimer, PAMAM, divergent, convergent, nanocarriers.

INTRODUCTION: 

Synthesis of the first dendrimers through divergent methods was carried out by Fritz Vögtle in 1978, R. G. Denkewalter in 1981 at Allied Corporation, Donald Tomalia in 1983 and 1985 at Dow Chemical, and George Newkome in 1985. In 1990, Jean Fréchet implemented a convergent synthetic process. Polyamidoamines were the first synthesized dendrimers (PAMAM). At the same time, the Newkome group announced independently the synthesis of related macromolecules called 'arborols' ^1,2.

Dendrimers are repetitively branched molecules consisting of a core attached to a monomer assembly, where a diameter in the 2 to 10 nm range contributes to a monodisperse, tree-like, star-shaped.

Dendrimer comes from the word 'Dendron' in Greek, meaning a tree. 'Arborols' (from the Latin word 'arbor') also means a tree and 'Cascade molecule' is the synonym for dendrimer.

A dendron normally comprises a single category called the focal point, which is chemically addressable (branching points)^3,4. Dendrimers are comprised of an initiator center, made up of repeating modules, radically attached to the inner core, internal layers (generations), external (terminal functionality) attached to the outermost interior generations as depicted in Figure 1.

Figure 1: Dendrimer – basic structure

Structure of Dendrimer:

The core part of dendrimer is made with single atoms such as nitrogen, carbon  and  other chemical reaction elements.

Components:

Pincer and Shell:

Variable number of pincers are produced in the outer shell of dendrimers by the last focal point headed before the surface of dendrimer⁵. Shell is the homo-structural spatial segment between focal point. Outer shell is the space between last external branching point and the surface. Inner shells are interior parts of dendrimer.

Generation number:

It is the number of focal points in the dendrimer that are counted from centre to surface of dendrimer. When moving from center to periphery, a dendrimer with 5 focal points is represented as dendrimer of 5^th generation and abbreviated as G5-dendrimer. Ex: A fifth era polypropylene imine (PPI) is truncated to a G5-PPI dendrimers. Center of dendrimer is signified as generation zero (G0), i.e., there are no focal points in core structure, as hydrogen substituents are not considered as focal points. Intermediates produced during synthesis of dendrimer are known as half-generations. Ex: PAMAM dendrimers terminated with carboxylic acid.

End-group:

The end groups are commonly referred to as dendrimer or terminal surface group.  Dendrimers terminated with amine end-groups are represented as amino-terminated dendrimers. Solubility of dendrimer in solvent is based on end group⁶.

Table 1: Different types of dendrimers with their use^7,8

S. No.	Type of dendrimer	Example	Use
1	PAMAM dendrimer	Dendritech^TM	Material science, biomedicine   computer toners
2	PAMAMOS dendrimer	SARSOX	Nano-lithography, electronics, photonics, Chemical catalysis Precursor for honeycomb like network preparations
3	PPI dendrimer	Asramol by DSM	Material science and biology
4	Tecto dendrimer	Stratus^® CS Acute Care^TM, Starburst^®, Mercapto	Diseased cell recognition, diseased state drug delivery diagnosis, reporting location to outcome of therapy
5	Chiral dendrimer	Chiral dendrimers derived from pentaerythritol	Biomedical applications, chiral hosts for enantiomeric resolutions and as chiral catalysts for asymmetric synthesis
6	Hybrid dendrimer	Hybrid dendritic linear polymer, polysilsesquioxanes	Biomedicals, molecular electronics, nanophotonics, sensing
7	Liquid crystalline dendrimer	Mesogen functionalized carbosilane dendrimers	Science and engineering
8	Amphiphilic dendrimer	SuperFect, hydra amphiphiles and bola-amphiphiles	Structure-directing agent, use as polar part, cell and gene transfection
9	Micellar dendrimer	Beclomethasone dipropionate, NX-200, Magnevist^®	Biological and medical applications, drug delivery, imaging agent
10	Multiple antigen peptide dendrimer	VivaGel	In vaccines and diagnostic research, biological applications
11	Fréchet type dendrimer	Dendron azides, Priostar^TM	Drug carrier, purifiers, organic synthesis, detecting agent, drug delivery

Table 2: Different types of dendrimers and their methods of synthesis^9,10

S. No.	Type of dendrimer	Structure	Synthesis
1	PAMAMOS dendrimer	End group: Hydrophobic organosilicon (OS) Interior part: Hydrophilic, nucleophilic polyamidoamine	Convergent and divergent
2	PPI dendrimer	End group: Primary amines Interior part: Numerous tertiary trispropylene amines. Commercially available up to G5.	Divergent
3	Tecto dendrimer	Composed of a core dendrimer with multiple dendrimers at its periphery	Divergent
4	Chiral dendrimer	Chirality is based on construction ofconstitutionally variable but chemically similar branches to a chiral core	Convergent
5	Hybrid dendrimer	These are hybrids (block or graft polymers) of dendritic and linear polymers obtained by complete mono functionalization of peripheral amines of a “zero-generation”	Divergent
6	Liquid crystalline dendrimer	A highly-branched oligomer or polymer of dendritic structure containing mesogenic groups that can display mesophase ehaviour	Divergent
7	Amphiphilic dendrimer	Unsymmetical globular dendrimers built with two segregated sites of chain end. One half is electron donating and the other half is electron withdrawing	Divergent
8	Micellar dendrimer	Unimolecular micelles of watersoluble hyper-branched polyphenylenes	Divergent
9	Multiple antigen peptide dendrimer	Dendron-like molecular construct based upon a polylysine skeleton. Lysine with its alkyl amino side-chain serves as a good monomer for the introduction of numerous of branching points	Convergent
10	Frechet type dendrimer	Dendrimers having carboxylic acid groups as surface groups and containing poly-benzyl ether hyperbranched skeleton	Convergent

Comparative Study of Dendrimer Structure and Synthesis:^7,8

Dendrimers can be synthesized either by convergent or divergent methods as represented in Table 2. Each dendrimer has interior and end groups in its structure.

Properties of Dendrimers:

Cytotoxicity:

The cytotoxicity of dendrimer depends on its size, shape and immunogenicity. It relies on center of dendrimer however, influenced by useful gathering present on surface of dendrimer having amino (-NH₂) bunch at surface shows cytotoxic property yet this additionally rely on generation of dendrimer and fixation. Higher generation dendrimers being the most harmful.

Size and Shape:

The size of dendrimers is in nano range. Dendrimers, in contrast to conventional linear polymers, exhibit certain substantially improved physicochemical characteristics due to their molecular architecture. Dendrimer form depends on dendrimer generation. Lower generation - Elliptical form of open planer, higher generation - spherical compact form ¹¹.

Immunogenicity:

Small functional groups or polyethylene glycol modified dendrimer surfaces become nonimmunogenic or less immunogenic.

Rheological property:

A non-linear relationship exists between molecular weight and viscosity in case of dendrimers in contrast to linear polymers in which viscosity increases with increase in molecular weight. The greater the intrinsic molecular weight of dendrimer, the greater is the viscosity upto 4^th generation dendrimers. Further, in case of 5^th generation dendrimers, the viscosity decreases.

Solubility:

The solubility of dendrimers depend on the functional group present on their surface. The surface hydrophilic and hydrophobic groups are soluble in polar and                   non-polar solvents, respectively.

Monodispersity:

Random structure and greater size variability are precisely regulated by dendrimer synthesis, which in turn minimizes size variation. A dendrimer is synthesized from a high monodispersity convergent system than other approaches. Dendrimer monodispersity is characterized by analytical techniques such as mass spectroscopy, size exclusion chromatography, high-performance liquid chromatography, transmission electron microscopy and gel electrophoresis¹².

Factors Affecting Dendrimer Properties:

Effect of pH:

The interior of the dendrimer becomes gradually hollow at a low pH conditions (pH<4). With the increase in generation type of dendrimer, repulsion increases between positively charged amines on both dendrimer surface and tertiary amines in the interior. The dendrimer contracts at higher pH (pH>10) as the molecule load becomes neutral, resulting in a more spherical (globular) shape where the minimum repulsive forces exists between dendrimer arms and groups of surface¹³.

Effect of salt:

Higher salt concentrations play a significant role in case of charged PPI dendrimers. Further, presence of salts may facilitate conformation of a contracted dendrimer, with extensive back-folding similar to the conditions when poor solvation occurs or pH increases. In order to reduce charge repulsion within the system, the repulsive forces between charged dendrimer segments influence to an extended conformation¹⁴.

Effect of solvent:

A very significant parameter to solvate the dendrimer is the solvation capacity of the solvent. With reduced solvent quality, dendrimers of all generations typically demonstrate a greater degree of back-folding. The arms of dendrimer induce greater molecular density over the dendrimer surface.

Effect of concentration of dendrimer:

Small-angle X-ray scattering (SAXS) experiments carried out in a polar solvent such as methanol on PPI dendrimers (G4, G5) exhibit that the molecular conformation of dendrimers is gradually contracted with the increase in dendrimer concentration. The repulsive forces between dendrimer molecules can be reduced by such molecular contractions which further improves the capacity of dendrimers to display a closer intermolecular packing¹⁵. Effect of synthesis method over the properties of dendrimers have been elaborated in Table 3.

Table3: Methods of synthesis for dendrimers^16–20

Method of synthesis	Characteristics	Merits	Demerits
Divergent method	Dendrimer formation starts from the core	A large quantity of dendrimer was produced by this method	To prevent problems during synthesis largequantity of reagent is required. Product purification is a very tedious task
Convergent method	Dendrimer formation starts from surface	Defects in final structure are fewer and product is easily purified	Due to steric hinderance higher generationdendrimer cannot be formed.
Double exponential and mixed method	Both divergent and convergent methods can be used	Rapid growth technique for linear polymers and fast method	--
Hyper cores and branched monomers growth	Involves the pre-assembly of oligomeric species that can be linked together in order to form dendrimers	Fewer steps and higher yield	--

Table 4: Different types of dendrimer formulations along with their composition

S. No.	Drug	Therapeutic category	Type of dendrimer	Composition	Reference
1	Dexamethasone (Dex)	Diabetic retinopathy	PAMAM	Dex : PAMAM (1:5), methanol  and  water	(29)
2	Beclomethasone dipropionate (BDP)	Asthma	PAMAM (G4)	Methanolic dendrimer solution, BDP (10% w/w), phosphate buffer (pH 7.4), cellulose acetate membrane – 0.45 µm	(30)
3	Methylprednisolone (Nasal delivery)	Asthma	PAMAM (G4-OH)	Glutaric acid, Dicyclohexylcarbodiimide, 4-dimethyl aminopyridine, Dimethyl sulfoxide, Methylprednisolone, PAMAM (G4-OH), N-hydroxy benzotriazole	(31)
4	Acetazolamide	Glaucoma	PPI (G5)	PPI dendrimer aqueous solution, Acetazolamide aqueous solution	(32)
5	Enoxaparin	Deep vein thrombosis	PAMAM (0.5% G3)	Enoxaparin – dendrimer solution with saline, final enoxaparin sodium content	(8)
6	Cisplatin	Ovarian cancer	PAMAM	Cisplatin, Aqueous PAMAM dendrimer	(33)
7	Melphalan	Cancer	FPPI	Melphalan, FPPI (G3, G4, G5)	(34)
8	Dithranol  (Microsponge gel based )	Psoriasis	PAMAM (G4)	Dithranol, ethyl cellulose, polyvinyl alcohol, dichloromethane, sodium metabisulphite, distilled water, drug:polymer, carbopol 934, triethanolamine, NaOH 2% w/v to adjust pH 6.8	(35)
9	Chloroquine phosphate	Malaria	PPI (G4)	L-lysine. Dioxane, NaOH, Di-tertiary butyl pyrocarbonate, ethyl acetate. KHSO4, Na2SO4	(36)
10	Indomethacin (Transdermal delivery)	Analgesic, Anti-inflammatory	PAMAM (G4.5)	Indomethacin, methanolic solution of dendrimer	(37)

Dendrimers serve as vectors in gene therapy, solubility enhancers and blood substitutes. PAMAM dendrimers have been investigated as genetic material carriers. Dendrimers have potential diagnostic and therapeutic applications. Dendrimers are widely used in pharmaceutical drug delivery systems as depicted in Table 4.

Marketed dendrimers with their applications^27,28

Examples:

a. Vivagel^® is multiple antigen type of dendrimer used in HIV prevention.

b. Priofect^TM is an amphiphilic type of dendrimer applied in gene transfection.

c. An Alert ticket^TM is a PAMAM type of dendrimer has application in anthrax detection.

d. Stratus CS^® is a tecto type of dendrimer used as a cardiac marker.

e. Priofect™ and Priostar™ are tecto type of dendrimers used as targeted diagnostic and therapeutic delivery for cancer cells.

Applications of Dendrimers as Nanocarriers in Therapeutics:

Entrapment of poorly aqueous soluble molecules is facilitated by the distinctive structural design of dendrimers builds pockets or internal void volume and further improves their hydrophilicity³⁸. Therefore, superior loading efficienes have been shown by higher generation dendrimers (G4 and greater) with higher internal volumes. Greater generation dendrimers do possess more densely packed surfacesin comparison to their minor counterparts, which pose difficulty in drug release, ensuing high drug encapsulation efficiencies as well as retention^39,40. Unrestrained burst release of the encapsulated drug in physiological media appears unavoidable eventhough improved core enclosure increases encapsulation of drug^41,42.

Antimicrobial drug delivery:

Dendrimer-based nanomaterials have exhibited the ability to enhance aqueous solubility, bioavailability as well as efficacy of antimicrobial class of drugs^43-45. Dendrimers demonstrate effective antimicrobial activities devoid of carrying traditional antimicrobial drugs after performing suitable surface modifications.

Cancer-targeted drug delivery:

It is the majorly investigated prospective biomedical application for dendrimers as well as dendritic nanoparticles. Dendrimer based nanocarriers be able to target cancers similar to other nanocarriers, primarily through two approaches namely passive  and ligand-mediated tumor targeting⁴⁶. Dendrimers might facilitate selective delivery of chemotherapeutic agents for cancer treatmentas well as contrast agents for imaging and cancer diagnosis^47,48.

Vaccination:

Initially dendrimer-based immune-stimulatory system was developed by the scientist Tam, utilizing a a multiple antigenic peptide system⁴⁹ and it was constructed from a PPI dendron scaffold which exhibits multiple copies of the peptide antigens. The multiple antigenic peptide systems were found to be stable at the pH ranges between 2 to 9 and might be stored as a freeze dried powder, offering them a substantial benefit in comparison to whole pathogen vaccine preparations or recombinant proteins which need cold storage conditions⁵⁰. Due to the ease of synthesis as well as simple design, the multiple antigenic peptide system has been extensively explored for the delivery of vaccines against numerous diseases such as malaria^51-53, AIDS⁵⁴ and influenza⁵⁵.

Gene delivery:

PAMAM and PPI dendrimers can able to undergo complexation with polyanionic nucleic acids via electrostatic interactions, producing stable dendriplexes.

Oral drug delivery:

Oral delivery is the highly preferred route of drug administration due to its non-invasive nature, but it has not been extensively used as nanocarriers due to their rapid degradation and poor gastrointestinal absorption⁵⁶.

Transdermal drug delivery:

Dendrimers also serve as skin permeation enhancers for delivery of drugs through transdermal route. In the review of literature, it was revealed that PAMAM dendrimers of diflunisal, ketoprofen and indomethacin exhibited skin permeation enhancement by four folds^57,58. The extent of skin permeation enhancement was mainly based upon the surface charges of dendrimers.

Concerns and Future Perspective:

Positively surface charged dendrimer based materials are found to be generally toxic, hence their toxicities must be carefully monitored and controlled^59,60. Fast systemic clearance of dendrimers delays their application in field of drug delivery. G2 to G4 dendrimers show rapid renal clearance by renal filtration because of their relatively smaller size, where as higher generation dendrimers, are easily recognized as well as eliminated by reticuloendothelial system⁶¹. In summary, latest developments in dendrimer chemistry has simplified the methods their synthesis, which may enhance the reproducibility and scalability of dendrimer-based materials. Further, proper changes in surface charges were found to decrease dendrimer toxicity. Based on the obtained results, it was revealed that the concerns of dendrimers as nanocarriers are adaptable. Eventhough, such concerns impede their advancement in the clinical translation.

CONCLUSION:

The advantages of dendrimers, like ease of multifunctionalization, well-defined chemical structure, near-to-monodispersity, and multivalency, have led to several novel dendrimer-based formulations to troubleshoot the drawbacks in the fields of therapeutic delivery. Surface-modified dendrimers have been succeeded in their clinical translation and making remarkable progress in the phase of clinical trials. Further, extensive researchis required in order to foster a robust large-scale synthetic method with adequate reproducibility. Significant studies necessarily be carriedout to find the correlation between degree of surface modification (product quality) and their biological behavior, like pharmacokinetic profiles, therapeutic efficiency, safety  and toxicity. In conclusion, dendrimers  and  dendritic nanoparticles have prospective insight in the arena of health sector in forthcoming years.

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Received on 16.03.2021            Modified on 11.04.2022

Accepted on 26.10.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(4):2051-2056.

DOI: 10.52711/0974-360X.2023.00337