Prajapati et al Asian Journal of Dental and Health Sciences. 2021; 1(1):1-9 [1] AJDHS.COM Available online at ajdhs.com Asian Journal of Dental and Health Sciences Open Access to Pharmaceutical and Medical Research Copyright © 2021 The Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited Dendrimers as Drug Delivery Carriers in the Dentistry Sunil Kumar Prajapati1*, Vijay Kumar Tilak2, Ram Chand Dhakar3 , Krishan Kumar Verma4*, Vikrant Saluja5, R. Jayakumararaj 6, Rajeshwar Kamal Kant Arya7, Manas Kumar Das8, Soumya Das9 1 Professor, Institute of Pharmacy, Bundelkhand University, Jhansi, India 2 Apex Professional University, Pasighat, Arunachal Pradesh-791102, India 3 Hospital Pharmacy, SRG Hospital & Medical College Jhalawar, Rajasthan, India-326001 4 Professor, Lloyd School of Pharmacy, Plot No 3, Knowledge Park-1, Greater Noida, U.P., India-201308 5 Associate Professor, Faculty of Pharmaceutical Sciences, PCTE Group of Institutes, Ludhiana, India 6 PG Department of Botany, Government Arts College, Melur – 625106, Madurai District, TN, India 7 Assistant Professor, Deparment of Pharma sciences, Kumaun University Nainital, India 8 Director, Orlean Collge of Pharmacy, 42-Knowledge Park-3, Greater Noida, U.P., India-201308 9 Associate Professor, NIET (Pharmacy Institute), 19-Knowledge Park-2, Greater Noida, U.P., India-201308 Article Info: _________________________________________ Article History: Received 03 Nov 2021 Reviewed 11 Dec 2021 Accepted 19 Dec 2021 Published 25 Dec 2021 _________________________________________ Cite this article as: Prajapati SK, Tilak VK, Dhakar RC, Verma KK, Saluja V, R Jayakumararaj, Arya RKK, , Das MK, Das S, Dendrimers as Drug Delivery Carriers in the Dentistry, Asian Journal of Dental and Health Sciences. 2021; 1(1):1-9 DOI: http://dx.doi.org/10.22270/ajdhs.v1i1.3 Abstract ___________________________________________________________________________________________________________________ This review gives concise information about the application of dendrimers as drug delivery carrier in the field of drug delivery. Due to their unique architecture these have improved physical and chemical properties. Due to their terminal groups these show high solubility, miscibility and reactivity. Dendrimers have well defined size, shape, molecular weight and monodispersity. These properties make the dendrimers a suitable carrier in drug delivery application. Dendrimers are unimolecular miceller in nature and due to this enhances the solubility of poorly soluble drugs. Their compatibility with DNA, heparin and polyanions make them more versatile. Dendrimers, also referred as modern day polymers, they offer much more good properties than the conventional polymers. Due to their multivalent and mono disperse character dendrimers have stimulated wide interest in the field of chemistry biology, drug delivery, gene therapy and chemotherapy. Self-assembly produces a faster means of generating nanoscopic functional and structural systems. But their actual utility in drug delivery can be assessed only after deep understanding of factors affecting their properties and their behaviour in vivo. Keywords: Dendrimers, Drug targeting, nanoscale carriers. *Address for Correspondence: Dr. Sunil Kumar Prajapati, Professor, Institute of Pharmacy, Bundelkhand University, Jhansi Email:drsunilprajapati@gmail.com Introduction Dendrimers are class of well-defined hyper branched synthetic polymer systems, which can be conjugated to various chemical species, such as detection agents, imaging agents, targeting components, biomolecules, pharmaceutical/ therapeutic agents, radio ligands, affinity ligands, for various bioanalytical applications1. The term “Dendrimer” arise from two Greek words; “Dendron” meaning tree and “Meros” meaning part. A typical dendrimer structure consists of three basic components: a multi-functional central core moiety where other molecules can be trapped 2, 3, branched units that emanates from the central core and external capping�groups. The highly regular branching units are organized in layers called “generations”, and represent the repeating monomer unit of these synthetic macromolecules 4. Therefore, dendrimers can be synthesized from simple branched monomer units, in a precise and controlled fashion from trunk to branch and to leaf “surface groups”. The three-dimensional structure of dendrimers gives them a variety of unique properties, such as nanoscaled globular shape, well- defined functional groups at the periphery, hydrophobic or hydrophilic cavities in the interior and extremely low polydispersity 5, and thus a wide range of potential applications. The precise control over the distribution of drugs is highly valuable to abolish the typical drawbacks of traditional medicine. In recent years, improved pharmacokinetics, biodistribution and controlled release of the drug to the specific targeted site has been achieved with polymer based drug delivery6 Unlike traditional polymers, dendrimers have received considerable attention in biological applications due to their high water solubility,7 biocompatibility,8 polyvalency9 and precise molecular weight.4 These Open Access Review Article DOI: http://dx.doi.org/10.22270/ajdhs.v1i1.3 http://jddtonline.info/ https://orcid.org/0000-0001-8250-8489 http://dx.doi.org/10.22270/ajdhs.v1i1.3 mailto:drsunilprajapati@gmail.com http://dx.doi.org/10.22270/ajdhs.v1i1.3 Prajapati et al Asian Journal of Dental and Health Sciences. 2021; 1(1):1-9 [2] AJDHS.COM features make them an ideal carrier for drug delivery and targeting applications. For investigating dendrimers as drug delivery vehicles, their biopermeability across the biological membranes should be considered. Figure 1: Schematic representation of the Dendrimer Structure1 Table 1: Various Dendrimer based marketed products for drug delivery, therapy and diagnosis Name of Product Type Company Use Ref Priostar PEHAM/PEA Starpharma Targeted diagnostic and therapeutic delivery for cancer 10, 11 Starburst PAMAM Dow chemical Targeted diagnostic and therapeutic delivery for cancer 12 Stratus CS PAMAM Dade Behring Cardiac marker 13 Astramol® PPI Starpharma - 14 Taxotere ND Sanofi Aventis Anticancer drug delivery - SuperFect PAMAM Qiagen Gene transfection 15,16 Alert ticket PAMAM US Army Research Lab. Anthrax detection 17 ND: not define, PEHAM: Poly (etherhydroxylamine), PEA: Poly (esteramine), PAMAM: Polyamidoamine, PPI: Poly (propylene imine), HIV: Human immunodeficiency virus, STDs: Sexually transmitted diseases Application of Dendrimers in Drug delivery for dentistry The development of dendrimer based efficient drug delivery systems has attracted a great deal of attention over the last few years. Unlike traditional polymers, dendrimers can be obtained in precise molecular weights even at high generations, which as previously highlighted can provide a reproducible pharmacokinetic behavior. This feature makes them ideal candidates for drug delivery applications. 18, 19 PAMAM dendrimers loaded with calcium and phosphate ions and have been used experimentally to prevent tooth decay. The loaded PAMAM dendrimer was effective for prolonged release of calcium and phosphate at low pH, with neutralization of the acidic environment and inhibition of dental caries..20 Many potential uses of dendrimer hydrogels (DH) as a drug delivery system in periodontics and implants dentistry as they allow clinicians to customize drug release kinetics, mechanical properties, and in-situ gelling for specific clinical applications. 21 Dendrimer-based dental composites have attracted attention because of the higher cross-link density, decreased water sorption and solubility, improved mechanical properties, and higher resin melting temperature. 22, 23 Triclosan, an effective antimicrobial agent encapsulated into the PAMAM dendrimer resulted in the solubilization of TCN, thus slow release of the drug and improved efficacy. 24 PAMAM dendrimer loaded with different metronidazole concentrations showed prolonged release of the drug, thus proved to be a suitable vehicle for the delivery of antimicrobial drugs at the target site. Hence, it has a relevant application in periodontal therapy. 25 Prajapati et al Asian Journal of Dental and Health Sciences. 2021; 1(1):1-9 [3] AJDHS.COM Table 1: Reported work on dendrimers as drug delivery carrier in dentistry18 Source Type of Dendrime r Generation Objective Methodical approach Outcome Ref (Dodiuk -Kenig et al., 2004) PAMAM dendrimer - To check the adhesive properties of hyper-branched and dendritic polymers in acrylate-based dental composite Commercial hyper- branched polyesteramide, two dendripolyamides and PAMAM dendrimer  Compressive strength of dental composite with 0.3 wt% hyper- branched polyesteramide improved the from 253 ± 20MPa to 386 ± 20MPa  The same composite showed reduction in linear shrinkage from 2.4 ± 0.2% to 1.5 ± 0.2 %  Improved bond durability and shear bond strength with the above composition 26 (Paul et al., 2006) Methyl methacryla te dendrimer - To enhance the composite properties in dental additive Highly branched, globular 2,3- dihydroxybenzyl motif to achieve multi-methacrylate dendritic additive  Compared to control, addition of 0.5% multi-methacrylate dendritic additive showed 21–35% increase in flexural strength  Flexural strength increased with higher molecular weight dendrimers  Increase in additive concentration could not have positive effect on flexural strength 27 (Gardin er et al., 2008) PAMAM dendrimer G3 Incorporation of triclosan in dendrimer to enhance solubility π-π stacking between G3 dendrimer and the amino acid, phenylalanine to enhance solubility  Solubilization of triclosan increased with increasing concentration of dendrimer due to ionisation effect  Solubility of triclosan showed to improve with π-π stacking between dendrimer and phenylalanine at 1:21 ratio  The increase in solubility could to reflected by change in pH 24 (Kim et al., PAMAM dendrimer G5 Modified G5 dendrimer could G5 dendrimer with RGD ligand  Western blot analysis suggested increase in 28 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib78 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib80 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib95 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib108 Prajapati et al Asian Journal of Dental and Health Sciences. 2021; 1(1):1-9 [4] AJDHS.COM 2010) bind to dental pulp cell to increase odontogenic potential vascular endothelial growth factor, matrix extracellular phosphoglyco- protein, dentin sialoprotein and matrix protein through JNK pathway  Application of G5- RGD showed enhanced mineralization as evidenced by Von Kossa assay (Eichler et al., 2011) PAMAM dendrimer G5 PAMAM dendrimer could modify adsorption/desorp tion behaviour of human saliva compared to self- assembled monolayers grafted surface Surface of the periodontitis model grafted with PAMAM-NH2  Covalently bound PAMAM depicted decreased adherence of Streptococcus gordonii in absence of saliva  Same approach of repelling bacteria was observed even after saliva conditioning  Substitution of PAMAM lowers the amount of absorbed protein 29 (Li et al., 2013) PAMAM dendrimer G3 and G4 Restorative substitution with PAMAM in human hard tissues to mimic the functions of noncollagenous proteins to promote mineralization Carboxyl (-COOH) terminated G3 and G4 PAMAM dendrimers to substitute noncollagenous proteins on dentine surface  Monodispersed characteristics and steric hindrance property were reported advantageous  Bioinspired mineralization process in dentine environment was facilitated by G4 dendrimer  Dendritic structure could be a potential restorative material for biomineralized hard tissue 30 Dung Th et al. 2013 PAMAM dendrimer G5 To study the sustained release of metronidazole an antibacterial and antiprotozoal drug A series of dendrimer G5- pluronic F127 nanofilms (at 1:10, 1:20 and 1:30 mole ratios), loaded with various percent of metronidazole Dendrimers showed prolonged release of the drug, thus proved to be a suitable vehicle for the delivery of antimicrobial drugs at the target site. 25 (Bengazi et al., 2014) Methyl methacryla te - To investigate the degree of utilization of The commercial dendrimers of different methyl  Following heat induced polymerization, there 31 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib112 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib113 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib105 Prajapati et al Asian Journal of Dental and Health Sciences. 2021; 1(1):1-9 [5] AJDHS.COM dendrimer methyl methacrylate monomers in different dendrimer conjugated resins methacrylate units (12 in D12 and 24 in D24) were incorporated in dental resin were 65% and 62% degree of conversion for D12 and D24, respectively  Residual monomer contents were 1.0% and 1.5%, respectively for D12 and D24  Following photo polymerization, degree of conversion decreased with increase in methyl methacrylate proportion and thus increase in residual monomer content  Heat induced polymerization method was suggested as best method with degree of conversion and residual monomers (Galli et al., 2014) Poly(epsilo n-lysine) dendron G3 Dendritic approach to titanium surfaces could improve differentiation of osteoblastic cells and the activation of Wnt/b-catenin signalling Phosphoserine- tethered poly(epsilon-lysine) dendrons in endosseous implants  Dendrons showed increased expression of two osteoblastic markers, alkaline phosphatase and osteocalcin in primary bone marrow cells and murine osteoblastic MC3T3 cells  Osteoclastogenesis opposing protein osteoprotegerin was found to get expressed significantly higher  Wnt target genes, Wisp-2 and b-catenin were also showed increased expression 32 (Lin et al., 2017) PAMAM dendrimer - Application of dendrimer functionalized with nano- hydroxyapatite in dentin tubule occlusion Modification of nano- hydroxyapatite with COOH-terminated PAMAM dendrimer  Dendrimer functionalized nano- hydroxyapatite found to crosslink with collagen fibres  Therefore, effective dental tubule occlusion reported  Superior value of microhardness was observed with modified nano- 33 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib106 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib74 Prajapati et al Asian Journal of Dental and Health Sciences. 2021; 1(1):1-9 [6] AJDHS.COM hydroxyapatite (Tao et al., 2017) PAMAM dendrimer G4 Determination of dentin remineralization extent with PAMAM dendrimer PAMAM-OH, PAMAM-COOH, PAMAM-NH2 coated dentin  Dentin coated with PAMAM containing different functional groups showed increased hardness of dentin, reduced loss of mineral and lesion depth, with higher remineralization capability  Lower mineral loss and lesion depth with higher dentin tubule blocking effect was shown by PAMAM- COOH, PAMAM- NH2 than PAMAM-OH  Effects of PAMAM- COOH, PAMAM- NH2 dentin remineralization were comparable 34 (Xiao et al., 2017) PAMAM dendrimer G3 Development of bioactive multifunctional composite (BMC) via nanopar ticles of amorphous calcium phosphate, 2- methacryloyl- oxyethyl phosphoryl- choline, dimethylamino- hexadecyl methacrylate and silver nanoparticles for class V restoration Investigation of BMC with PAMAM dendrimer on remineralization of demineralized root dentin in a cyclic artificial saliva/lactic acid environment for the first time BMC complex mixture with nanoparticles of amorphous calcium phosphate, 2- methacryloyl- oxyethyl phosphoryl-choline, dimethylamino- hexadecyl methacrylate and silver nanoparticles And BMC with PAMAM dendrimer  PAMAM with BMC showed superior dentin mineralization characteristics  The hardness of the dentin increased enough to match healthy root dentin  PAMAM with BMC induced complete and effective root dentin remineralization in an acid challenge environment 35 (Ge et al., 2017) PAMAM dendrimer G3 The anti-caries effect and mechanical properties of the modified adhesive in biofilm regulation and remineralization PAMAM and dimethylaminodode cyl methacrylate in biofilm adhesive  Addition of PAMAM and dimethylaminododec yl methacrylate in adhesive showed no adverse effecton dentin bond strength 36 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib75 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib76 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820096/#bib77 Prajapati et al Asian Journal of Dental and Health Sciences. 2021; 1(1):1-9 [7] AJDHS.COM capabilities  The modified adhesive with 1% PAMAM and 5% dimethylaminododec yl methacrylate showed anti-biofilm properties and developed a healthier biofilm to reduce the chances of dental caries  Remineralization capabilities of the modified adhesive was found to have similarity with 1% PAMAM modified adhesive El-Aziz Khater et al 2018 PAMAM dendrimer to evaluate the remineralizing effect of PAMAM dendrimer, Gluteraldehyde and their combination on demineralized dentin luteraldehyde was applied to the demineralized dentin, Group (III), (n=10): a combination of PAMAM dendrimer and Gluteraldehyde All treatment materials used were effective in increasing dentin microhardness and produced micromorphological changes of the dentin surface in 37 K. Liang et al 2019 PAMAM dendrimer Ca Delivery to prevent tooth decay dendrimers loaded with calcium and phosphate ions  The loaded PAMAM dendrimer was effective for prolonged release of calcium and phosphate at low pH, with neutralization of the acidic environment and inhibition of dental caries 20 Nicholas Yesbeck 2021 PAMAM dendrimer G5 to prolong the release kinetics of antibiotics Dendrimer hydrogels were synthesized from PAMAM and PEG diacrylate to contain Cefazolin  Dendrimer hydrogels is a promising platform for long-term release of cefazolin in-vitro 21 Ramyaa Shri K et al 2021 PAMAM dendrimer To develop PAMAM dendrimer to enhance the antibacterial activity Entrapping dexamethasone into the dendrimer's cavities was done to ensure a slow release of the drug  PAMAM dendrimer's functionalization to silver nanoparticles to protect the nanoparticles from aggregating and reducing its cytotoxicity without affecting the antibacterial properties 22 Conclusion PAMAM dendrimer has shown to have marked prospective to be used as biomimetic biomaterial for remineralisation of enamel.18 Addition of dendrimers has shown significant enhancement of mechanical properties of adhesive systems and reduction in polymerization shrinkage of dental composites. 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