Polyamidoamine dendrimers essentially have a central ethylenediamine core with ascending divisions with amide groups which form a wall of the spherical structure and at the surface of each terminal with amine functional groups (Figure 3A). PAMAM dendrimers are good candidates for carrying drugs and peptides because they are biocompatible and have well-defined spherical nanoparticles with bifunctional modifying parts. Dendrimers PAM are used in the nanomedicine platform to maximize the bioavailability of drugs and minimize the number of doses required (Pedziwiatr-Werbicka et al., 2019). However, there are some limitations associated with the use of PAMAM, particularly those with positively charged groups. It leads to the accumulation produces cytotoxicity. PAMAM dendrimers of G5 are mostly considered as a non-toxic (Beezer et al., 2003). To address the aforementioned limitation, the surface is reconfigured with polyethylene glycol (PEG). Compared to “other dendrimers,” PAMAM has the broadest range of applications in therapeutics such as antibacterial, antiviral, antioxidant, and diagnostic agents.

The dendrimer polypropylenimine (PPI) is the first known dendrimer used industrially as a therapeutic agent. There are also other names used for PPI dendrimers which are astramol or butylenediamine (BDA) or “polypropyleneamine” (POPAM) (Noske et al., 2020). These dendrimers mainly consist of butylenediamine as the core and repeat propylenimine branching units via sequential Figure 3B is the reaction of Michael’s addition of acrylonitrile to a primary amino group, followed by hydrogenation of the nitrile groups to form primary amino groups (Sherje et al., 2018). The amino-terminal groups contribute to its solubility in water. PPI Dendrimers are characterized by their ability to improve the water solubility of hydrophobic drugs entrapped in the hydrophobic inner crevices of PPI due to this property. Cell membranes can be destabilized by positively charged PPIs, leading to cell lysis. As a result, PPIs have a lower ability to load drugs than PAMAMs. Furthermore, the PPI/drug complex has lower stability than PPI alone. PEGylation and acetylation of the surface groups are selected. Acetylation is preferred as it is extremely efficient and able to penetrate deeply. Moreover, the steric hindrance of the PEG chain can affect the interaction of the entrapped drug molecules with the surface functional groups (Fant et al., 2010). Diaminoethane or diamino-propane would form the central functional groups in Poly (ethyleneimine) (PEI) dendrimers, a subclass of PPI dendrimers.

Dendrimers containing poly-l-lysine residues such as poly-l-lysine dendrimers (PLL) or dendrigraft poly-l-lysine dendrimers (DGL) also possess lysine residues (Figure 3C). These dendrimers have higher cytocompatibility, lower cytotoxicity, convenient enzymatic degradation and resultant efflux of low molecular products (Ryan et al., 2013). Furthermore, DGL dendrimers have been researched for the use of delivery vectors for siRNAs. “The ability to respond to stimuli on demand by incorporating specific protein sequences into PLL dendrimers is quite tantalizing”. Higher-generation PLL dendrimers have exhibited improved gene transfection efficiency whereas conventional linear poly (lysine) dendrimers have exhibited lower genome transfection efficiency and higher cytotoxicity compared to PLL dendrimers (Byrne et al., 2013).

Carbosilane dendrimers consist of carbon and silicon molecules as building blocks. With the widespread use “of silicon chemistry, a new class of carbosilane dendrimers with hydrophobic scaffolds and superior thermal stability have emerged (Figure 3D) (Uchida et al., 1990). The chemical properties of silicon are utilized in dendrimers preparation because they allow the “nucleophilic molecules to reach the electrophilic silicon (Si+) easily” (Zhou and Roovers, 1993). However, the presence of the C-Si bond in carbosilane dendrimers provides low polarity and high energy which makes them more hydrophobic compared to other dendrimers (Sepúlveda-Crespo et al., 2015). Although they have a hydrophobic endoskeleton, carbosilane dendrimers can be modified to polar molecules by surface chemistry with polar moieties such as Si-H, Si-Cl, Si- CH = CH2, and Si-CH2CH = CH2, allowing the introduction of various other intriguing inorganic, organic, and organometallic substituents. This would lead to increased applications in the pharmaceutical fields. The ability of the generation 2 ammonium-terminating carbosilane dendrimer “has been tested on a variety of cell types including the glial cells, progenitor cells, leukocytes, granulocytes and human peripheral blood mononuclear cells, general pluripotent stem cells, primary cells as well as suspension cells” (Liu et al., 2012).

Cationic dendrimers are dendrimers with cationic phosphorus as the core and decorated surface groups that have been studied in a variety of biological and theragnostic applications due to their special properties (Figure 3E). In phosphorus dendrimers, the “presence of phosphorus at each branch point” and reactive end groups provide a hydrophilic shell and hydrophobic backbone that can affect their internalization into cells. Moreover, they have effects on the growth of cells as well such as neurons, immune and cancer cells (Caminade and Majoral, 2013). Rolland et al. (2008) investigated on phosphorus-terminated dendrimers that could be explored for immunotherapy to target and activate monocytes. Based on the study conducted, such dendritic materials have been shown to be able to affect the aggregation of amyloid oligomers and tau protein in neurodegenerative diseases (Wasiak et al., 2012). Polyphosphorhydrazone (PPH) dendrimers have also shown the ability to deliver antisense siRNAs to target cells (Dzmitruk et al., 2015) and treat HIV infection with gene therapy (Briz et al., 2012).

Peptide “dendrimers are macromolecules which comprise either branched polypeptide core” or radically arranged peripheral polypeptide chain or both (Figure 3F) (Sadler and Tam, 2002). These dendrimers are divided into three categories. The first category is grafted dendrimers with amino acids chain only at their surface. The second category is grafted dendrimers composed entirely of amino acids, while the third category consists of amino acids that branch both in the core and on the surface and have non-peptide branching units. Divergent and convergent techniques are often used to synthesize peptide dendrimers, and with the advent of solid-phase peptide synthesis methods, extensive “libraries of peptide dendrimers can be prepared and tested for desired properties.” Peptide dendrimers are used as surfactants as well as multiple antigen peptides (MAP) (Bruckdorfer et al., 2004), protein analogs (Thompson and Scholz, 2021), drugs, and gene transporters in the biomedical field. They are also used “as contrast agents for magnetic resonance imaging and angiography, fluorescence imaging” and in serum analysis (Choi et al., 2000).

Dendrimers that comprise carbohydrates “moieties such as monosaccharides (glucose, mannose, galactose) (Woller and Cloninger, 2001) and disaccharides (chondroitin sulfate) (Roy and Baek, 2002) ”into their structure are referred as glycodendrimers. Although most of “the researched glycodendrimers have sugar residues on their exterior surfaces, glycodendrimers” with a sugar unit as the central core in which all branches would emerge have been discovered as well. In general, glycodendrimers are classified into three types: “Carbohydrate-centered, carbohydrate-based and carbohydrate-coated dendrimers (Oliveira et al., 2010). There is a potential application for these dendrimers which is site-specific delivery to lectin-rich” tissues. These dendrimers are predicted to have a stronger affinity for lectin-anchored systems than monosaccharide-anchored systems (Mousavifar and Roy, 2021).

Triazine dendrimers are aptly named as they “consist of 1,3,5-triazine rings as branches with amine groups at both ends” (Figure 3G). A study was conducted recently on the siRNA transport ability of a series of “triazine dendrimers with different core structures, generation numbers and surface functions”. Dendrimers with inflexible structures and “arginine-like or hydrophobic terminals had the most efficient siRNA gene repression effects” on Hela cells in an experimental luciferase model (Simanek, 2021). Triazine dendrimers are deemed suitable for various biomedical applications due to their liquid crystalline structure and non-linear optical properties. In one study, triazine dendrimers were evaluated for their potential for drug delivery. The results showed that they are suitable for hydrophobic drugs as solvents and carrier systems and are not toxic to organs at a dose of up to 10 mg/kg via the intraperitoneal route in an animal model. However, these dendrimers should be explored further for various applications with or without surface functionalization by appropriate moieties (Merkel et al., 2010).

Dendritic polyglycerols are hyperbranched structures that are made of glycerol with a wide range of sizes (at the nanoscale) and functional groups at their ends which allow them to interact with different biological receptors (Maršić et al., 2021). Sheikhi Mehrabadi et al. (2015) have developed polyglycerol dendrimers (PG) with a variety of cationic amine end groups, including a star-shaped oligoamine shell (Figure 3H). These dendrimers have a neutral biocompatible aliphatic polyether core, numerous siRNA-binding and complexing amine end groups. PG-PEHA (Polyglycerol-pentaethylene hexamine) was the most efficient at silencing genes, whereas polyglycerol-amine (PG-NH2) was the least effective. “The favorable primary amines at the 1,2-position of PG-NH2” might be the reason for the reported high efficiency in the transfer of siRNA (Sheikhi Mehrabadi et al., 2015). Moreover, PG-NH2 could be used to deliver siRNA in animal models by intravenous injection, resulting in efficient gene silencing with low toxicity. This further indicates the potential utility of the dendrimer for siRNA therapy delivery (Sheikhi Mehrabadi et al., 2015).

Citric acid dendrimers can be good candidates for an efficient drug delivery system as they are relatively stable in water with good drug deposition and release properties (Figure 3I). Namazi et al. prepared β-cyclodextrin (β-CD)-modified citric acid dendrimers with -cyclodextrin (CD) to increase the loading capacity and encapsulation properties of the dendrimers. The results showed that by increasing the number of branches, it had further increased the internal cavity, hence responsible for the resulting loading potential (Namazi and Hamrahloo, 2011). Similarly, Namazi and his colleagues prepared dendrimers with PEG as the central core and repeating citric acid units as surface functionalized groups (Namazi et al., 2011). In the viability assay, the viability of HT1080 cells which were exposed to the PEG-citric acid dendrimer was found to be more than 80% up to 2 days at a high concentration of 1 mg mL-1. In other toxicity tests, the dendrimers were shown to be extremely safe. The tests done included hemolysis assay, lactate dehydrogenase assay and prothrombin time assay (Naeini et al., 2010). The biocompatible dendrimer exhibited high drug loading and prolonged drug release, indicating its potential application as a vehicle for cancer treatment (Adeli et al., 2013).

Polyether dendrimers are functional dendrimers that are spherical and highly branched with cationic ether groups on the outer surface. Polyether dendrimers were synthesized for the first time by Hawker and Frechet in 1990 via the convergent approach (Figure 3J) (Hawker and Frechet, 1990). This polyether group is composed of the core material “1,1,1-tris(4′-hydroxyphenyl) ethane and the branching material benzyl bromide and 3,5-dihydroxybenzyl alcohol”. Jayaraman et al. described the synthesis of dendrimers with a backbone that consists of aliphatic polyethers. Due to the presence of “2-hydroxymethyl-1,3-propanediol moieties”, the prepared dendrimers emerged as good prospects for drug delivery with improved solubility (Kumbhar et al., 2021).

In another study, Malik et al. performed in vitro tests on the biocompatibility of these convergently synthesized polyether dendrimers. The findings indicated that such dendrimers with carboxylate and malonate interfacial conjugates were more biocompatible and hemolytic than cationic dendrimers. However, they were not hemolytic up to 1 h but were as hemolytic as anionic dendrimers after 24 h. It seems that these biodegradable polymers may less hazardous than standard dendrimers and their usage for drug delivery could be extended (Duncan, 2014).

It seems that making changes to the surface is one of the most effective ways to make dendrimers less harmful (Figure 3K). In this approach, the exposure of cationic groups such as amino groups to the surface of the dendrimer is minimized by modification or decoration with natural or anionic molecules to prevent their electrostatic interaction with cell membrane molecules, thus avoiding cytotoxicity mediated by cationic groups. Apart from reduced toxicity, surface-engineered dendrimers also can improve drug loading, biodistribution, pharmacokinetic profile, solubility, site-specific targeting stability, antimicrobial activity and gene delivery efficiency (Satija et al., 2007). There are several surface engineering approaches to modify surface groups on dendrimers such as PEGylation through the addition of PEG, which increases drug loading and decreases hemolytic toxicity, as seen in PAMAM dendrimers (Santos et al., 2019), saccharide addition via maltose, which decreases hemolytic toxicity, as seen in PPI dendrimers (Bhadra et al., 2003), acetylation by adding an acetyl group lessening toxicity effects and increase absorptivity of PAMAM dendrimers (Klajnert et al., 2008), bisection by adding carboxylic acid to minimize cytotoxicity (Kolhatkar et al., 2007) and peptide conjugation by tripeptide (arginine-glycerol aspartate) to minimize toxicity of cationic dendrimers (Jevprasesphant et al., 2003).

The use of polymeric delivery systems takes advantage of a drug’s pharmacokinetic properties, such as its solubility, half-life, and prolongation of plasma circulation time, to achieve optimal passive targeting. This ensures that the drug matrix is passively transported to the solid tumour (Ekladious et al., 2019). Furthermore, passive targeting certainly depends strongly on two parameters: The tumour endothelial permeability to macromolecules and the presence of reduced lymphatic outflow. These two factors determine how well passive targeting works. When these factors are improved, the likelihood of passive targeting would increase. The enhanced effect of permeation and retention, often called as the EPR effect, is a phenomenon unique to tumours. It was first discovered and stated by Matsumura and Maeda in 1986. Because tumours have defective blood vessels, they form vascular permeability factors. These factors ensure that the tumour tissue receives adequate nutrients and oxygen, allowing the tumour to develop rapidly. Aliphatic polyester dendrimers containing dimethylolpropionic acid have been identified as a promising possibility for the preparation of therapeutic anticancer conjugates. The results of in vitro and in vivo evaluation showed that the water-soluble polyester dendrimers were biocompatible. The delayed aggregation of dendrimers in important organs results in a prolonged period of dendrimer-mediated drug administration, which appears to be beneficial for the EPR effect of passively targeting tumours (Kheraldine et al., 2021). In addition, tumour cells would stimulate dilatation of blood channels through excessive release of permeability mediators (Greish et al., 2003; Gillies and Fréchet, 2005).

Polymeric drug conjugates and drug loaded polymeric micelles, dendrimers, polymeric nanoparticles and carbon nanotubes would selectively accumulate inside solid tumor owing to the EPR effect (Puri et al., 2009; Shcharbina et al., 2013). Constructions with hydrophilic surfaces and molecular weighing over 25 kDa–30 kDa would provide enhanced chances of targeting tumors by virtue of EPR, which is accompanied by a longer retention time during circulation (Kesharwani et al., 2015). Etrych et al. (2008) developed a biodegradable PAMAM dendrimer with a semi-telechelic Hydroxypropyl Methyl Cellulose (HPMA) polymer embedded with doxorubicin as the core for passive tumor targeting. The findings revealed that the dendronized nanoparticles with diameters ranging from 10 to several hundred nanometers were able to achieve passive targeting through the EPR effect (Etrych et al., 2011). The size range of nanocarriers will determine whether or not they can be retained and localised in target areas. There is general agreement that dendrimers up to 10 nm–20 nm in diameter are most appropriate for passive tumour targeting (She et al., 2013).

Massive membrane proteins and other macromolecules which are coupled with dendrimers would decrease their plasma clearance, resulting in increased half-life in the bloodstream. As a result, these conjugation systems provide a prolonged and precise delivery to tumor targets. Furthermore, a cisplatin-loaded 3.5 G PAMAM dendrimer demonstrated a 50-times rise in cisplatin accumulation at the tumor position when compared to free drugs (Kaminskas et al., 2011).

Chemotherapy is an essential procedure for cancer treatment in modern times but there is a lack of antineoplastic drugs that can act against the tumor mass. To find solutions to these problems, researchers and scientists have focused their efforts on developing novel anticancer drugs and drug delivery systems. Some examples of these innovations include tailored drug delivery methods that have high therapeutic efficacy and low toxicity. Active targeting is a strategy that can decrease the absorption of a drug in normal tissue and increase its concentration in malignant tissue (Janaszewska et al., 2019). It was found that the most efficient method for drug accumulation in solid tumours is known as EPR, which is achieved by passive tumour targeting. Although the majority of the pharmaceuticals are notoriously non-diffusible, intracellular targeting of cancer cells via passive diffusion of these substances is notoriously hard. In addition, administration of a low dose of drugs to certain cancer cells can lead to ineffectiveness of chemotherapy or other negative outcomes, such as the growth of cancers resistant to multiple drugs (also known as MDR malignancies) (Basile et al., 2012). Passive targeting and the EPR are therefore only able to deliver drugs to solid tumours that are porous and permeable. On the other hand, the EPR effect does not occur in a number of malignant tumours that are resistant to radiation because these cancers are impermeable (Gottesman et al., 2002). Active targeting overcomes some of these limitations by attaching precisely targeted ligands to the outside of nanostructures that exert an attractive force on specific receptors on cancer cells (Gottesman et al., 2002).

Dendrimers have several polar functional groups which might attached to a diversity of ligands on their surface to target tumors in active targeting. In one study, polymethacrylate (PMA)-crosslinked PAMAM dendrimers were prepared so that medications could more easily targeted the acidic microenvironment of the tumour. Folate-PEGylated PMA-PAMAM had a significant effect on drug accumulation and tumor regression at the tumor site (Shen et al., 2012).

The adhesion molecule integrin αvβ3 is commonly expressed in prostate, breast, ovarian, glioblastoma and melanoma cells. Peptides that include the amino acid sequence Arg-Gly-Asp (RGD) show a better affinity for the integrin αvβ3 protein (Li and Xu, 2005). PEGylated PAMAM dendrimers coated with RGD embedded with Doxorubicin (DOX) prolonged plasma circulation time, drug accumulation and bioavailability in brain tumors compared to DOX solution alone (Zhang et al., 2011).

According to the findings of Gupta and colleagues, a dendrimer loaded with DOX and folate-conjugated PPI was the improved option for targeting cancer. The novel dosage showed improved drug stability, release profile and toxicity, as well as better drug uptake in the cancer cell MCF -7 (Gupta et al., 2010). There are several ligands for targeting purposes in the brain and other body tissues such as thiamine, glucose, choline, serum albumin, folate, lactoferrin, L-glutamate, L-aspartate, folic acid, nucleoside, biotin, oligopeptide and aptamers. Nanoparticles that can be formed on the surface of dendrimers efficiently controlled the tumor progression (Lockman et al., 2003; Huang et al., 2008; Ulbrich et al., 2011).

Across the brain many transporters such as glucose transporter 1 (GLUT1), vitamin C transporter 2 (SVCT2), Na + -dependent vitamin transporter (SMVT), L-amino acid transporter 1 (LAT1), mono-carboxylic acid transporter 1 (MCT1) etc., works as carrier mediated transporters to transport nutrient through the BBB. Modification of surface characteristics of Dendrimers with the substrates or their analoues can promotes drug into brain via mentioned transporters ((Zhao et al., 2015; Jiang et al., 2021; Zhao et al., 2021).

Another most widely used way to internalized large drug moieties and growth factors in brain through brain tumor targeted delivery systems is receptor mediated transport. Most commonly expressed receptor on brain are low density lipoprotein receptor (LDL-R), apolipoprotein E (ApoE) receptor, EGFR, transferrin receptor (TfR), insulin receptor (IR) and integrin receptor (αvβ3) and can be employed efficiently to promote drugs and diagnostic agents into the brain for brain tumor treatment and imaging respectively (Yeini et al., 2021).

The BBB functions as a filter to control molecules that have entered the brain from the blood (Li et al., 2020). A series of specialized cells and transporters have been developed to manage the chemical environment of the CNS. It consists of endothelial cells that form specialized capillaries and extravascular components such as astrocytes, pericytes, and interneurons that make up the BBB (Xu et al., 2014). CNS nutrients and waste are regulated by these components which constitute as a physical barrier. The extracellular nucleases and peptidases, intracellular monoamine oxidase and cytochrome P450 enzymes are some of the proteins and enzymes that prevent toxicity of the central nervous system (Pisoschi et al., 2021).

The potent anticancer drug methotrexate is an antimetabolite of folate that has been shown to be effective in the treatment of various cancers. PAMAM dendrimers do possess capability of good drug carriers owing to precise description of their structures and a variety of different types of groups (De et al., 2022). Wu and colleagues utilized methotrexate to develop a drug carrier that targeted the epidermal growth factor receptor (EGFR) as well as their mutant isoform EG-FRvIII. This was done by binding an average of 12.6 methotrexate molecules to every fifth PAMAM dendrimer molecule, which was then conjugated to cetuximab. According to the researchers, particular molecular targeting is just one of several properties that an antibody-drug bioconjugate must meet to be therapeutically useful. However, no therapeutic benefit was observed when tumor mice were administered the bio-conjugate via CED instead of free methotrexate or cetuximab (Wu et al., 2006).

Table 2 presents an overview of the numerous PAMAM dendrimer types that have been utilized.

PAMAM dendrimers could be used to carry peptides and drugs to specific sites in a way that is effective and efficient (Abedi-Gaballu, et al., 2018). This is because they can enhance the biocompatibility of active compounds and decrease the number of times they need to be taken. The fact that PAMAM dendrimers produced natural podophyllotoxine and estramustine more bioavailable showed that they could be used as carriers. Along with stopping and killing more cells, PAMAM dendrimers also modified the manner in which these antimitotic agents were released. It also made these antimitotic agents work better at stopping tubulin polymerization, which is important for glioma cell survival (Tarach P & Janaszewska, 2021; Dixit & Sen, 2013).

In one work, PEGylated dendrimers, wheat germ agglutinin, and transferring ligands were used to encapsulate doxorubicin in G4 PAMAM dendrimers. The ability of the dendrimers to cross the BBB was enhanced by targeting wheat germ agglutinin (WGA) and transferrin (Tf). In addition, microscopic study showed that the nanoparticles had a size of about 20 nm. Compared with free drugs and dendrimers without Tf and WGA, the dendrimers containing Tf and WGA delivered a higher payload of doxorubicin to brain tumour sites. In another study, Swami and colleagues utilized PAMAM dendrimers to combine docetaxel (DTX) with p-hydroxylbenzoic acid (pHBA). The findings suggested that pHBA has a strong affinity for beta receptors which are found primarily in the CNS. Compared to free Docetaxel (DTX), dendrimers containing G4-pHBA-DTX delivered more drugs to the brain (Swami et al., 2015; Florendo et al., 2018; Igartúa et al., 2018; Vasconcelos-Ferreira et al., 2022).

When it comes to how they interact with nucleic acids, small molecule drugs are the complete opposite of dendrimers. Nucleic acids (DNA or RNA) can be delivered using dendrimers with surface amines. During physiological conditions, dendrimers are formed when amines interact with nucleic acids to produce dendrimer complexes. In terms of their physicochemical properties, hydroxyl and carboxyl groups are considered neutral under physiological conditions, whereas nucleic acids are considered to be anionic. Therefore, dendrimers containing these surface functional molecules cannot bind nucleic acids. The dendrimers and nucleic acids that form on amine-terminated dendrimers can exhibit considerable variation in size and structure due to the multiple charges in both (Dey et al., 2022). In addition to individual characterizing dendrimers (generations), the sizes are affected by the nucleic acid, the N/P ratio (also known as the charge ratio) between dendrimers and nucleic acids and the solvent properties (Sahu et al., 2023). As the dendrimers are being generated, their DNA binding affinity would increase. At charge ratios close to 1, the complexes would typically aggregate and fail. Therefore, dendrimer complexes with a higher density tend to have a smaller size distribution and better transfection efficiency. Apart from that, complexes with an increased dendrimer generation ratio have an increased charge ratio as well (two times more amines than phosphates in a dendrimer complex). Generally, nanometer-sized dendriplexes are formed when the generations and the N/P ratio are higher (Demeule et al., 2008; Huang et al., 2008). The efficiency of transfection varies greatly between dendrimer-nucleic acid complexes. In addition to depending on the structure of the complex, it also varies based on the type of cell and the density of the cell population. Dendriplexes have shown promising results in the field of biology. Therefore, it is an excellent opportunity for researchers to apply a range of analytical techniques to accurately describe the complexes formed by dendriplex formation.

According to a study done by Huang and his team, transferrin that is attached to dendrimer DNA dendriplexes of PAMAM increased the number of genes that were expressed in the brain twice. The same study also revealed “that conjugating lactoferrin to PAMAM dendrimers” using PEG spacers boosted dendrimer brain absorption by “4.6-fold compared to non-conjugated PAMAM dendrimers and by 2.2-fold compared to dendrimers conjugated to transferrin” in BALB/c mice (Huang et al., 2008). Low density lipoprotein (LRP) receptors are extensively produced in mammalian neural cells. Angiopep has demonstrated selectivity in targeting LRP receptors. “Angiopep-PEG-PAMAM loaded with DNA” caused higher gene expression “in the cortex, caudate putamen, hippocampus and substantia nigra of BALB/c mice than unconjugated PAMAM loaded with DNA (Ke et al., 2009).

Researchers have addressed the possibility that dendrimers may treat or ward off neurological and degenerative diseases of the brain. Because of the BBB, treating and/or preventing diseases that affect the central nervous system can be extremely difficult. One of the factors contributing to the ineffectiveness of this barrier is inadequate drug penetration. This particular limitation, however, can be overcome through the usage of dendrimers as nanocarriers (Rabiee et al., 2020).

A previous study by Serrama et al. (2015) used carbosilane dendrimers with targeted siRNA to prevent gene expression of a specific protein production in primary astrocytes and cytotoxicity. This study sheds light on the potential of carbosilane dendrimers for drug targeting in the brain.

Poly-l-lysine (PLL) dendrimers are an alternative option to PAMAM dendrimers. Their natural antiangiogenic properties and lower vascularization make them less likely to cause side effects. PLL inhibits tumor development by destroying necrosis and stimulating apoptosis. This contributes to the non-toxic effect PLL dendrimers have on healthy cells, bringing their therapeutic potential to the level of marketed anti-angiogenic drugs (Ryan et al., 2013; Singh et al., 2022). A DOX-loaded PLL dendrimer coupled mainly with folate was synthesised by Jain and colleagues. This dendrimer responded to pH and exhibited antiangiogenic and anticancer activities developed by the researchers (Gauro et al., 2021). There is also the possibility that PLL dendrimers could serve as vehicles for the delivery of anticancer drugs (Gao et al., 2016). Scientists have developed PLL dendrimers that can deliver anticancer drugs to specific tumor sites by binding DOX to the acid-labile bond HSBA (4-hydrazinosulfonylbenzoic acid). Due to the acid-labile binding, only 10% of the drug could be released at a pH of 7.4, while the entire amount of drug could be released at a pH of 5. The results also showed that a decrease in metabolic lability led to an increase in cellular absorption in vivo, suggesting that mechanistic targeting of PLL dendrimers may be possible (Kaminskas et al., 2011). Niidome and colleagues developed a G6 PLL dendrimer with PEG-linked penta-alanine or pentaphenylalanine, which made it possible to administer DOX in a targeted manner. The DOX was encased in either a penta-alanine or penta-phenylalanine core, both of which are hydrophobic. Penta-phenylalanine was found to have higher encapsulation efficiency than penta-alanine. DOX was released from the hydrophobic cavity over time as a function of pH. The created dendrimer accumulated more in cancer cells and significantly suppressed tumor development without causing weight loss, suggesting that PLL dendrimers can be targeted in the brain (Malik et al., 2018). Table 2 (Gao et al., 2016; Sharma et al., 2017; Malik et al., 2018; Nh et al., 2016) lists several types of PLL dendrimers.

A new synthesis approach is utilized to develop PPI dendrimers which are hyperbranched macromolecules (Kwan and Leung, 2020). The presence of amino terminal functional groups allows them to be conjugated with ligands such as folate and antibodies to deliver anticancer drugs to specific sites. Dendrimers are deemed as dangerous due to their cationic nature. Wang et al. (2012) utilized a method to circumvent this problem by preparing acetylated PPI dendrimers with 14.2% acylation and 95.3% Doxorubicin/methotrexate (DOX/MTX) loading. Dendrimers with more than 80% acylation were found to be protective against A549 and MCF -7 cells when injected and released over an extended period of time. Another study found that preparation of a folate-free diaminobutane G4 PPI dendrimer ligand would result in lower cytotoxicity. The results underscored that an ETP-loaded dendrimer had long-lasting activity and enhanced site-specific drug delivery (Sideratou et al., 2001). Gajbhiye and Jain conducted research to determine the effectiveness of a polysorbate 80 (P80)-anchored PPI dendrimer (P80-PPI) in transporting DTX (Docetaxel) to the cells in the brain. The study found that DTX-P80-PPI was more cytotoxic than the combination DTX-PPI and the free drug in a human glioma cell line U87MG. Within one week, DTX-P80-PPI demonstrated a possibility of declination in the size of brain tumors (by 50%) in which the significant permeation of P80 through the BBB was linked to this particular finding (Gajbhiye and Jain, 2011). Patel et al. developed a thiamine PPI dendrimer combination that was loaded with Paclitaxel (PTX) so that it could be transported to the brain. In this way, paclitaxel (PTX) could be transported into the brain (PTX-TM-PPI). According to the results of the study, the molecule could prolong the duration of action of drugs while reducing their harmful effects on the body. The PTX-loaded dendrimers and free drug were compared with PTX-TM-PPI, which significantly suppressed tumor formation in a human IMR-32 neuroblastoma cell line. In a separate research study, Patel et al. (2012) examined how effectively PPI dendrimers combined with other ligands, such as concanavalin A (Con A), sialic acid and glucosamine, transported PTX in the brain. According to the cytotoxicity data, the IC50 value of the ligand-anchored PPI dendrimer was three to six times lower than that of the free drug. As the biodistribution was studied, it was found that the ligand-anchored PPI dendrimers showed a higher concentration of the medication in the brain when compared to the free PTX. Not only that, the sialic acid also had better target efficacy than Con A and glucosamine. Table 2 has listed a few examples of PPI dendrimers.