INTRODUCTION:

Dendrimers are unique and carefully manufactured macromolecules that have received a lot of interest in chemistry, materials science, and medicine. Greek terms "dendron," which means tree, and "meros," which means portion, are the source of the English phrase "dendrimer." These molecules' exceptional capabilities and uses are attributed to their massively branched, tree-like architectures. Dendrimer synthesis is a regulated, iterative procedure that usually begins with a central core molecule.

The asymmetric and perfectly organized molecule is created by adding consecutive layers or generations of branches through methodical and well-defined methods. Because of their regulated development, dendrimers may be tailored to have certain functional groups, sizes, and shapes, which makes them adaptable platforms for a range of uses¹. Thanks to Donald Tomalia's groundbreaking work in the early 1980s on the divergent synthesis process, dendrimers have become a reality. A new age in macromolecular chemistry was ushered in by this ground-breaking method that made it possible for dendritic structures to develop systematically, layer by layer. In the years that followed, there was an increase in research activities, with different research teams working toward the synthesis of dendrimers with different core molecules and branching units. When the Dow Chemical Company released Polyamidoamine (PAMAM), the first dendrimer to be sold commercially, in 1990, the dendrimer industry began to take off. This was a turning point that brought dendrimers into practical use and aroused curiosity among the scientific community. Researchers have been able to better understand dendrimers' flexibility as they investigate their possibilities in medication delivery, catalysis, nanotechnology, and beyond^2,3. Because of these nanoscale designs' special qualities, research on dendrimers has focused more on biomedical applications. Because of their highly defined architectures, adjustable characteristics, and capacity to encapsulate medicinal substances, dendrimers showed promise in drug delivery systems. Dendrimers were essential in the invention of tailored drug delivery systems, imaging agents, and diagnostic tools in the 2000s, which paved the way for a paradigm change in medical practice. Two important characteristics of dendrimers are their well-defined molecular architecture, which enables exact control over their properties, and their mono-dispersity, which indicates that every dendrimer in a generation is almost identical. Drugs can be specifically encapsulated within dendrimers to prevent degradation and allow for controlled release. This may have an impact on enhancing the precision and effectiveness of medication distribution in therapeutic interventions. Due to their distinct structure and characteristics, dendrimers can be used in fluorescence and magnetic resonance imaging (MRI) among other imaging modalities. Imaging agents can be functionalized into them to improve sensitivity and contrast. Dendrimers are used in gene delivery, antibacterial agents, and tissue engineering scaffolds in addition to medication delivery. They can interact with biological systems because of their surface functions and three-dimensional structure⁴.

History of dendrimer:

Dendrimers were first conceptualized and pioneered by Donald A. Tomalia and his research team at Dow Chemical Company in the late 1970s and early 1980s. Tomalia is considered the "father of dendrimers" for his groundbreaking work in this field. In 1979, Tomalia synthesized the first dendrimer molecules, which he called "starburst polymers." These initial dendrimers were based on an ammonia core and branched out using amidoamine repeating units. Around the same time, in the early 1980s, another research group led by George R. Newkome at Louisiana State University independently reported the synthesis of similar branched macromolecules, which they called "arborols." The term "dendrimer" was coined in 1985 by Tomalia, derived from the Greek words "dendron" (tree) and "meros" (part), reflecting their highly branched, tree-like structure. Throughout the 1980s and 1990s, Tomalia and his colleagues at Dow Chemical continued to develop and refine the synthesis of poly (amidoamine) (PAMAM) dendrimers, which became one of the most widely studied and commercially available dendrimer families. During this period, other research groups also contributed to the advancement of dendrimer science, including the work of Jean Fréchet (Fréchet-type dendrimers), Craig Hawker (hyperbranched polymers), and Donald Tomalia (PAMAM dendrimers). In the late 1990s and 2000s, dendrimers gained broader attention due to their unique properties and potential applications in various fields, such as drug delivery, catalysis, sensing, and materials science. Today, dendrimer research continues to be an active area of investigation, with ongoing efforts to develop new dendrimer architectures, explore their applications, and understand their properties and behavior at the molecular level.⁵

Structure of dendrimer:

Dendrimers have a highly branched, tree-like structure that consists of three major architectural components, core, generations and terminal group. The core is the central initiator molecule from which the dendrimer branches out. It can be a single atom or a small molecule with multiple reactive sites. Common core molecules include ammonia, ethylenediamine, and polyols. Dendrimers are constructed in a radial fashion through successive generations or layers of branching units. Each generation represents a new set of branched monomers attached to the reactive sites of the previous generation. The terminal groups define the surface properties and reactivity of the dendrimer and can be tailored for specific applications.⁶ The overall structure of a dendrimer can be described as a series of concentric shells or generations surrounding the core. Each generation is composed of branched monomers, often referred to as repeating units, which are attached to the reactive sites of the previous generation. As the generation number increases, the number of terminal groups and the overall size of the dendrimer grow exponentially. This exponential growth is a unique feature of dendrimers, leading to a highly branched and densely packed structure. The branching units can be composed of various chemical moieties, such as amines, amides, ethers, esters, or aromatic rings, depending on the dendrimer family and the desired properties.⁷

Figure (1): Structure of dendrimer from central to the periphery, G0-G4 generations, representing central core, branches, and terminal parts including Dendron.

Physicochemical and biological properties of dendrimer:

Dendrimers exhibit a range of physicochemical and biological properties that make them unique and valuable in various applications.

Physicochemical Properties:

Size and Molecular Weight: Dendrimers are monodispersed because of their specified molecular weights. Dendrimer sizes can be manipulated by altering the quantity and production of branching layers. Different branching units, surface modifications, and core materials have been used to construct a variety of dendrimer classes. The three-dimensional form of a dendrimer is also dependent on its size; higher-generation dendrimers can incorporate drug molecules into their spherical conformation, whereas lower-generation dendrimers usually have open, amorphous structures⁸.

Branching Architecture: With layers of branches and a central core, dendrimers resemble trees in their highly branching structure. Precise control over the shape and surface functionality of the dendrimer is made possible by the controlled architecture.

Surface Functional Groups: Functional groups that can be customized for particular uses adorn the surface of dendrimers. The interactions, reactivity, and solubility of these functional groups with other molecules can be affected. The ability of dendrimers to enclose guest molecules is attributed to their internal empty spaces. Dendrimers' ability to encapsulate and release medications in a controlled way makes them useful in drug delivery applications.

Biocompatibility: A large number of dendrimers can be used in biological and medicinal applications because they are biocompatible. Dendrimers have been dubbed "smart" carriers despite their potential for toxicity because of their ability to target specific structures, cross biological barriers, circulate throughout the body for the amount of time needed for a therapeutic effect, and deliver drugs intracellularly. The main source of toxicity in dendrimers is the end group that is found on their periphery. Compared to a mine-ended PAMAM and PPI dendrimers, which usually show concentration-dependent toxicity and hemolysis, neutral or anionic group terminated dendrimers have shown a little less toxicity and hemolysis^9,10.

Biological Properties:

Drug Delivery: Because degraders can encapsulate pharmaceuticals, keep them from degrading, and release them in a controlled way, Dendrimers are utilized as drug delivery vehicles.

Imaging Agents: To facilitate the visibility of tissues or cells in medical imaging procedures, dendrimers can be functionalized with imaging agents for diagnostic reasons.

Gene transport: Dendrimers are useful in gene therapyapplications because they can bind to nucleic acids and promote the transport of genes.

Antibacterial Properties: Due to their antibacterial characteristics, several dendrimers may be used in the creation of novel antimicrobial agents.

Biological Interactions: Because of the functional groups on their surface, Dendrimers can interact with biological molecules like proteins. Therapeutic applications such as tailored drug delivery can be facilitated by utilizing these interactions.

Blood Circulation and Clearance: Dendrimers' size and surface properties can affect how long it takes for them to circulate through the bloodstream and how quickly they leave the body¹⁰.

Types:

Dendrimers can be classified based on their chemical structure, core composition, and the nature of branching units. Here are some common types of dendrimers along with brief explanations:

PAMAM dendrimers:

A type of dendrimer called polyamidoamine (PAMAM) dendrimers has been widely used in numerous scientific and technological applications. PAMAM dendrimers are helpful in fields including medication administration, imaging, catalysis, and materials research because of their clearly defined, highly branching structure. Ethylenediamine is frequently utilized to create the amine groups that make up the core of PAMAM dendrimers. The branching structure's primary starting point is the core. PAMAM dendrimers have a repeating branching unit radiating from the center and a dendritic, tree-like structure. Amino groups and amide bonds make up these branching components. PAMAM dendrimers as drug delivery vehicles have been thoroughly investigated. Their usefulness in targeted medication delivery applications stems from their capacity to encapsulate pharmaceuticals within their inner spaces and release them in a regulated manner¹¹. Kevin C Garala et al., studied that when aceclofenac a poorly soluble drug is given with G3 PAMAM dendrimer it increases the solubility of the drug¹².

Polypropylenimine dendrimers:

One family of dendrimers with a clearly defined and heavily branching structure is called polypropylene imine (PPI) dendrimers. A diaminobutane (DAB) core, which forms the foundation of the branching structure, is commonly seen in PPI dendrimers. PPI dendrimers have a dendritic structure made up of repetitive branching units that extend outward from the core. These units have a positively charged surface because they contain amine groups. The dendrimer structure is stabilized by the amide (peptide) bonds that join the branching units. Terminal amine groups make comprise the outermost layer, or perimeter, of PPI dendrimers. These amine groups can be functionalized for particular uses and add to the dendrimer's total positive charge. Their positively charged surface makes it easier for negatively charged nucleic acids (DNA or RNA) to bind with it, which encourages intracellular transport and cellular uptake. They are appropriate for catalytic applications due to their large surface area and distinct structure¹³.

Poly-l-lysine dendrimers:

Derived from the amino acid lysine, poly-L-lysine dendrimers are members of the dendrimer family. Positively charged amino acid lysine forms a highly branching, symmetrical architecture when it polymerizes into a dendrimer structure. The central core of poly-L-lysine dendrimers is usually made up of a moiety generated from lysine. There are several branching units extending from the core of the dendritic structure. Because lysine residues are present in every branching unit, the surface is positively charged. The dendrimer structure is stabilized by the amide (peptide) bonds that join the branching units. Terminal amine groups make up the outermost layer, or perimeter, of Poly-L-lysine dendrimers. The benefits of poly-L-lysine dendrimers include monodispersity, scalability control, and surface modification for diverse uses. Their amino group-derived positive charge is especially helpful when interacting with biological substances that have a negative charge¹⁴.

Dendrimer’s synthesis:The divergent synthesis method is frequently used. This approach begins with a multifunctional core molecule, which is typically a dendron or a tiny organic molecule. The next phase involves carrying out sequential reactions, adding branching layers and functional groups at each stage. The dendrimer grows outward during iterative rounds of this procedure, forming a controlled molecular weight structure that resembles a tree. Conversely, the convergent synthesis approach entails the autonomous synthesis of dendritic segments, which are then coupled to a central core. With this method, distinct branches can be created independently and then combined to create larger, more complicated dendrimers¹⁷. Because of their well-defined structure and customizable capabilities, these customized dendrimers find applications in a wide range of domains, such as medication delivery, imaging, catalysis, and materials research¹⁸.

Divergent approach: A popular method for creating dendrimers is the divergent approach, which entails developing the structure of the dendrimer from the inside out using a series of successive reactions. The divergent approach for dendrimer synthesis starts from a multifunctional core molecule and builds outward in a radial fashion through a series of iterative reaction steps. In each step, branched monomer units are attached to the reactive sites on the core or previous generation, followed by activation of the new terminal groups. This process is repeated to add successive generations of branched monomers, extending the highly branched architecture outward from the core. While conceptually straightforward, the divergent approach becomes more challenging at higher generations due to steric crowding effects and the exponentially increasing number of reactive sites, which can lead to incomplete reactions and structural defects. Nevertheless, it has been widely employed for synthesizing various dendrimer families like PAMAM, PPI, and polyaryl ether dendrimers by carefully controlling reaction conditions and purification methods.^19,20

Convergent approach: The convergent approach to dendrimer synthesis involves the preparation of dendritic wedges or dendrons that are subsequently coupled to a multifunctional core molecule. Each dendron is constructed in an inward direction by iteratively attaching branched monomers to an initiator molecule, creating a hyperbranched fragment with reactive end groups. The dendrons are grown in separate reaction vessels and purified at each generation to ensure structural perfection. In the final step, the purified dendrons are coupled to a suitable core molecule through their reactive end groups, yielding the desired dendrimer architecture. This inside-out strategy circumvents the steric problems associated with the divergent approach at higher generations. However, the convergent method requires careful design of the dendron synthesis and often suffers from low overall yields due to the inefficient final coupling step. Despite these challenges, the convergent approach has been employed for synthesizing various precise dendrimer structures, including Fréchet-type and poly(arylester) dendrimers.²¹

Characterizations of dendrimer:

Molecular Weight Determination: Size exclusion chromatography (SEC) and gel permeation chromatography (GPC) are two common methods used for this. Dendrimer molecular weight distribution can be ascertained by using these techniques, which divide molecules according to their size in solution.

Spectroscopy using Nuclear Magnetic Resonance (NMR): Atomic-level clarification of dendrimer structure is achieved through the application of NMR spectroscopy. It can verify the existence of functional groups or branches and provide details on the chemical environments of particular groups as well as the connectivity of atoms. Mass spectrometry, or MS, is a technique that helps identify any impurities and confirms the molecular formula of dendrimers by precisely measuring their mass. Mass spectrometry dendrimer analysis frequently uses two common techniques: electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). Dendrimer morphology, including size, shape, and surface topography, can be seen by imaging at nanoscale scales made possible by transmission electron microscopy (TEM) and atomic force microscopy (AFM).

Dynamic Light Scattering (DLS): DLS analyzes the Brownian motion of particles to determine the hydrodynamic size of dendrimers in solution. It offers details on the dendrimer size distribution and aggregation status. Using circular dichroism (CD) spectroscopy, one can examine the chirality of dendrimers. It provides information about the conformation and chirality of chiral compounds by measuring the differential absorption of left and right circularly polarized light by those molecules.

X-ray Crystallography: This method involves examining the diffraction pattern of X-rays dispersed by the crystal lattice to ascertain the three-dimensional atomic structure of dendrimers. It offers comprehensive details regarding the atomic arrangement in dendrimers.

Thermal Analysis: The thermal characteristics of dendrimers, such as their melting point, glass transition temperature, and thermal stability, are investigated using methods like differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)^22-27.

Pharmaceutical exertion of dendrimer drug delivery:

1. Dendrimer/drug complexes:

Drug delivery by dendrimer/drug complexes is a promising approach that utilizes dendrimers' special qualities to improve the solubility, stability, and targeted administration of different medicinal agents. These complexes, which have several advantages over traditional medication formulations, usually include the encapsulation or conjugation of medicines within dendrimer nanostructures. Dendrimers are nanoscale structures that can be efficiently delivered to target areas, such as tumors and inflammatory tissues. Their dimensions typically range from 1 to 10 nanometers. Dendrimer/drug complexes have been thoroughly studied to selectively accumulate drugs in tumor tissues by taking advantage of the increased permeability and retention (EPR) effect. This has allowed for the targeted delivery of chemotherapy drugs to solid tumors. When it comes to delivering vaccines, antimicrobial drugs, and nucleic acid-based medicines for the treatment of bacterial infections, malaria, and HIV, dendrimers have demonstrated potential. Dendrimers can generate stable nanoparticles for gene delivery and gene silencing applications by complexing with nucleic acids like plasmid DNA or siRNA. This could lead to the development of medicines for genetic diseases and cancer like AuNP –drug conjugate delivery forms a potent and efficient product which imparts stronger cytotoxic activity^28-30.

2. Dendrimer/drug conjugates:

Dendrimers, highly branched and symmetric nanostructures, have gained significant attention in drug delivery due to their unique properties. Dendrimer/drug conjugates represent a promising approach to enhance drug solubility, stability, targeted delivery, and controlled release. This article provides an overview of recent advances in the design, synthesis, and biomedical applications of dendrimer/drug conjugates. Dendrimer/drug conjugates can be synthesized through various methods, including encapsulation, surface functionalization, or covalent conjugation. The design of these conjugates involves careful consideration of dendrimer architecture, drug loading capacity, and targeting ligands. Surface modification techniques, such as click chemistry or amide bond formation, enable precise control over drug attachment and release kinetics. Additionally, dendrimers can be engineered to respond to external stimuli for triggered drug release. Targeting ligands, such as antibodies or peptides, further improves the selectivity of drug delivery. Dendrimer/drug conjugates have also been explored for the delivery of nucleic acid-based therapeutics, such as siRNA or gene editing tools, offering potential treatments for genetic disorders and viral infections. Furthermore, dendrimer-based scaffolds have been utilized for tissue engineering and drug-eluting implants, facilitating localized delivery of growth factors or antimicrobial agents^31-33.

3. Dendrimers in transdermal drug delivery:

Transdermal drug delivery offers a non-invasive route for delivering therapeutic agents across the skin barrier, bypassing the gastrointestinal tract and avoiding first-pass metabolism. However, the stratum corneum, the outermost layer of the skin, presents a formidable barrier to drug penetration. Dendrimers, with their unique structural properties and tunable surface functionalities, have emerged as promising nanocarriers for enhancing the permeation of drugs through the skin and improving transdermal drug delivery. Dendrimers can interact with the stratum corneum and disrupt its structure, thereby increasing the permeability of the skin barrier to drugs Their ability to overcome the limitations of conventional transdermal delivery systems, such as poor drug permeation and low bioavailability, makes them attractive candidates for developing novel transdermal formulations^34-36.

4. Oral drug delivery:

Oral drug delivery remains the preferred route for administering pharmaceuticals due to its convenience, patient compliance, and non-invasiveness. However, challenges such as low bioavailability, degradation in the gastrointestinal (GI) tract, and poor intestinal absorption limit the efficacy of orally administered drugs. Dendrimers can encapsulate hydrophobic drugs within their interior, enhancing their solubility in aqueous media and protecting them from enzymatic degradation in the GI tract. Surface modification of dendrimers with stabilizing agents further improves the stability of encapsulated drugs, ensuring their preservation during transit through the acidic environment of the stomach³⁷. A study done by researcher Kolhe et al., who synthesized a dendrimer-ibuprofen complex which results in better efficacy and pharmacological activity compared to pure ibuprofen³⁸.

5. Pulmonary drug delivery:

Dendrimers, with their unique structural properties and customizable surface functionalities, have emerged as versatile carriers for pulmonary drug delivery, offering advantages such as improved drug solubility, sustained release, and targeted delivery to specific lung regions. Dendrimers can interact with mucosal surfaces in the lungs and disrupt the mucus barrier, facilitating drug penetration into the underlying tissues. The small size and high surface-to-volume ratio of dendrimers enable efficient transport across the mucus layer, enhancing drug absorption and distribution within the lungs. Surface modification of dendrimers with targeting ligands allows for specific delivery of drugs to desired lung regions or cellular receptors. This enables localized drug delivery, minimizing systemic exposure and reducing off-target effects³⁹.

6. Intravenous (IV) drug delivery:

Dendrimers, with their unique nanostructural properties, offer a promising solution to enhance IV drug delivery by improving drug solubility, circulation time, and targeted delivery. Dendrimers can encapsulate drugs within their interior void spaces or on their surface, forming stable complexes that improve drug solubility and stability in the bloodstream. This encapsulation protects the drug from degradation and facilitates its transport to target tissues or cells. Surface modification of dendrimers with hydrophilic polymers, such as polyethylene glycol (PEG), reduces their recognition by the immune system and extends their circulation time in the bloodstream. This phenomenon, known as the "stealth effect," enhances the bioavailability of encapsulated drugs and allows for sustained drug release kinetics. Dendrimers have demonstrated significant potential in IV drug delivery across various therapeutic areas, including oncology, infectious diseases, and cardiovascular disorders⁴⁰.

7. Drug delivery to the Central Nervous System (CNS):

Dendrimers, with their unique properties, have shown promise in the field of drug delivery to the Central Nervous System (CNS). The blood-brain barrier (BBB) poses a significant challenge for delivering therapeutics to the CNS, as it restricts the passage of many drugs due to its tight junctions and efflux transporters. Dendrimers can be precisely engineered to have nanoscale dimensions, which allows them to penetrate the tight junctions of the BBB. Additionally, their surface can be functionalized with various ligands, such as peptides or antibodies, that can target specific receptors or transporters on the endothelial cells of the BBB, facilitating enhanced uptake into the brain.^41,42.

8. Gene delivery:

Dendrimers have emerged as promising vehicles for gene delivery due to their unique properties, including well-defined structure, multivalency, and surface functionalization capabilities. Gene delivery using dendrimers involves the encapsulation or complexation of nucleic acids (such as plasmid DNA, small interfering RNA, or mRNA) within dendrimer carriers, followed by their transport into target cells for therapeutic purposes. Dendrimers can condense negatively charged nucleic acids through electrostatic interactions, forming nano complexes or nanoparticles. The cationic nature of dendrimers allows them to interact with the phosphate backbone of nucleic acids, leading to the formation of stable complexes with reduced size and increased protection against enzymatic degradation. Small interfering RNA (siRNA) delivered by dendrimers can silence specific target genes, while plasmid DNA or mRNA can be used to express therapeutic proteins or correct genetic defects^43,44.

9. Vaccine development and delivery:

Dendrimers hold promise in vaccine development and delivery due to their unique properties, which can enhance antigen stability, promote immune responses, and enable targeted delivery. Encapsulation of antigens within dendrimers protects them from degradation and facilitates controlled release, prolonging their exposure to the immune system. Furthermore, dendrimers can be functionalized with targeting ligands to direct vaccine components to specific immune cells or tissues, enhancing vaccine efficacy and reducing off-target effects. Mucosal vaccination induces local immune responses at mucosal sites, which are crucial for protecting against mucosal pathogens and preventing their entry into the body^45,46.

10. Dendrimers in targeted-drug delivery:

Dendrimers, unique nanoscale macromolecules with well-defined structures and highly branched architectures, hold immense promise in the field of targeted drug delivery. Traditional drug delivery systems often suffer from limitations such as nonspecific distribution, poor solubility, and rapid clearance from the body, leading to suboptimal therapeutic outcomes and increased risk of side effects. Dendrimers, however, offer a versatile platform for precisely controlling drug delivery, enabling targeted accumulation at specific sites within the body while minimizing systemic exposure to healthy tissues. Dendrimers are synthesized with precise control over their size, shape, and surface functionality. This allows for the design of dendrimer-based drug delivery systems with tailored properties, including size-dependent biodistribution, controlled drug release kinetics, and specific targeting capabilities. Dendrimers possess a large number of functional groups on their surface and within their interior void spaces, enabling efficient encapsulation or conjugation of drug molecules. This high drug loading capacity allows dendrimers to carry a significant payload of therapeutic agents, maximizing the therapeutic effect while minimizing the required dose and potential side effects. Dendrimers can be functionalized with targeting ligands, such as antibodies, peptides, or small molecules, that recognize and bind to specific receptors or biomarkers expressed on target cells or tissues. This surface modification enables precise targeting of the drug-loaded dendrimers to disease sites, enhancing therapeutic efficacy and reducing off-target effects. Biodegradable dendrimers can degrade into non-toxic metabolites, minimizing long-term accumulation in the body and facilitating clearance after drug delivery^47-50.

11. Dendrimer in Cancer-Targeted Delivery:

Cancer-targeted delivery aims to deliver therapeutic agents specifically to tumor tissues while minimizing exposure to healthy cells, thereby enhancing treatment efficacy and reducing systemic toxicity. Dendrimers can be functionalized with targeting ligands, such as antibodies, peptides, or small molecules, that recognize and bind to overexpressed receptors or biomarkers on cancer cells. This surface modification enables specific targeting of the drug-loaded dendrimers to tumor tissues, enhancing drug accumulation and uptake while minimizing off-target effects. Dendrimers can exploit the EPR effect, which refers to the passive accumulation of nanoparticles in tumor tissues due to leaky vasculature and impaired lymphatic drainage. Drug-loaded dendrimers can preferentially accumulate in tumor tissues, allowing for targeted delivery of anticancer drugs while sparing healthy tissues. Dendrimers offer a versatile platform for co-delivery of multiple therapeutic agents, including chemotherapeutic drugs, nucleic acids, and imaging agents. Combination therapy using dendrimer-based nanocarriers can synergistically enhance anticancer efficacy, overcome drug resistance, and minimize adverse effects. Dendrimers can be functionalized with imaging agents, such as fluorescent dyes or contrast agents, for real-time visualization and monitoring of drug delivery and tumor response. This capability enables personalized treatment strategies and facilitates early detection of therapeutic response or disease progression^51,52.One effective application of this technique is the DEPTM conjugate, which is a PEGylated PLL-dendrimer-docetaxel combination. Starpharma is presently testing DEPTM in phase I clinical studies. In preclinical testing, this PEGylated dendrimer conjugate demonstrated a better anticancer impact over Taxotere® and boosted the tumor accumulation of docetaxel by a factor of 40. However, the ligand-mediated targeting strategy uses nanocarriers with surface-modified targeting ligands specific to tumor cells^53,54.FA-targeted dendrimers are embedded inside larger PEGylated NPs or carrier NPs using a newly developed technique^55-59.Due to their appropriate sizes, dendrimer-carrying NPs can remain in circulation for an extended period and concentrate at tumor sites through the EPR effect. The FA-targeted dendrimers can be released from the carrier NPs and actively bind to tumor cells by penetrating the tumor mass. The Hong group first demonstrated this concept by enclosing FA-targeted G4 PAMAM dendrimers (approximately 4 nm in diameter) in PEGylated poly (D, lactide) particles (about 100nm in diameter)^56,57.

Therapeutic role of Dendrimer:

A. Brain tumor imaging:

Dendrimers hold significant promise in the field of brain tumor imaging due to their unique properties and versatile functionality. Khan et al.,⁶⁰studied that when dendrimers are linked to nanoparticles, dendrimers can serve as highly efficient contrast agents for various imaging modalities, including magnetic resonance imaging (MRI), computed tomography (CT), and fluorescence imaging. Rodríguez-Galvan et al.,⁶¹ found that gadolinium (Gd)-chelated diagnostic agent was extensively useful in tumor imaging when used as a contrast agent. In brain tumor imaging, dendrimer-linked nanoparticles offer several advantages. Firstly, their small size and precise control over surface chemistry enable them to penetrate the blood-brain barrier (BBB), a critical challenge in brain tumor diagnostics and therapy. By crossing the BBB, these nanoparticles can accumulate selectively at the tumor site, enhancing the contrast between healthy brain tissue and the tumor⁶².

B. Anti-Inflammatory Therapy:

Dendrimers have emerged as promising candidates for anti-inflammatory therapy due to their unique properties, including their well-defined structure, multivalency, and ability to encapsulate or conjugate therapeutic agents. In the context of anti-inflammatory applications, dendrimers can be designed to target specific inflammatory pathways while minimizing off-target effects, offering potential advantages over traditional therapies. Most of the NSAIDs are poorly soluble and hydrophobic and also, they have a poor bioavailability⁶³. To improve the solubility of these drugs Yiyun C et al.,⁶⁴ performed a study in which they solubilized the NSAID in the presence of PAMAM dendrimer. By conjugating or encapsulating anti-inflammatory agents within dendrimers, their pharmacokinetics and biodistribution can be modulated, leading to improved drug solubility, stability, and bioavailability.

C. Antiviral Therapy:

Dendrimers can be designed to interact with viral surface proteins, such as glycoproteins or viral attachment proteins, thereby preventing the initial attachment and entry of the virus into host cells. Various studies have been performed to develop a product that is a conjugation of dendrimer and active substance so that the bioavailability, half-life, and target specificity of the product could be increased with lower side effects⁶⁵. Vacas-Cordoba E et al.,⁶⁶ performed a study and found that Polyanionic carbosilane dendrimers can interfere with the initial stages of the viral life cycle by binding to viral envelope glycoproteins (such as gp120) and blocking their interaction with CD4 receptors on host cells. This prevents viral attachment and entry into target cells, thereby inhibiting viral infection. These dendrimers can also disrupt the process of viral fusion, which is essential for the entry of HIV-1 into host cells. By binding to viral envelope proteins or interfering with membrane fusion events, polyanionic carbosilane dendrimers prevent the fusion of viral and cellular membranes, thereby blocking viral entry⁶⁷.

D. Antibacterial Therapy:

Antibacterial agents are substances that are specifically designed to inhibit the growth or kill bacteria, microorganisms that can cause infections and diseases. These agents can target bacteria through various mechanisms, either by interfering with essential bacterial processes or by damaging bacterial structures⁶⁸. Antibacterial agents play a crucial role in the prevention and treatment of bacterial infections, but the overuse and misuse of these agents can contribute to the development of antibiotic resistance, where bacteria become resistant to the effects of antibiotics and other antibacterial agents and also induce unwanted reactions (such as allergic reactions, hepatotoxicity, gastrointestinal effects, photosensitivity). Liu CY et al.,⁶⁹ studied that more than 60-70% of diseases causing bacteria are now resistant to the drugs given for the treatment of bacterial infection, like methicillin, it does not show an effect when given against nosocomial S. aureus. By encapsulating antibiotics or antimicrobial peptides within their nano-sized structure, dendrimers especially PAMAM can enhance drug stability and solubility while facilitating targeted delivery to bacterial cells. Their unique architecture allows for interactions with bacterial membranes, disrupting their integrity and leading to bacterial cell death. Furthermore, dendrimers can penetrate bacterial biofilms, which are notorious for their resistance to traditional antibiotics, and disrupt their structure, making them more susceptible to treatment⁷⁰.

Diagnostic application of dendrimer:

Imaging Agents:

Dendrimers can be functionalized with imaging probes such as fluorophores, radioisotopes, or magnetic nanoparticles. These dendrimer-based imaging agents enable the visualization of specific tissues, organs, or biological processes using techniques like fluorescence imaging, positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), or computed tomography (CT). By targeting specific biomarkers or disease-related molecules, dendrimer-based imaging agents provide valuable information for disease detection, staging, and monitoring⁷¹.

Contrast Agents:

In medical imaging, contrast agents are used to enhance the visibility of structures or tissues of interest. Dendrimers can serve as effective contrast agents due to their ability to encapsulate or conjugate high payloads of imaging agents. Furthermore, dendrimers can be engineered to target specific cells or tissues, improving contrast enhancement and diagnostic accuracy. For example, dendrimer-based MRI contrast agents can be designed to accumulate preferentially in tumor tissues, enhancing the detection of cancerous lesions⁷².

Biosensors:

Dendrimers are used in the development of biosensors, which are analytical devices capable of detecting and quantifying specific biomolecules or analytes. Dendrimers can serve as scaffolds for immobilizing sensing elements such as antibodies, enzymes, nucleic acids, or receptors. These sensing elements recognize target analytes through specific molecular interactions, leading to measurable signals such as fluorescence, electrochemical, or surface plasmon resonance (SPR) changes. Dendrimer-based biosensors offer high sensitivity, selectivity, and rapid detection capabilities, making them valuable tools for diagnosing diseases, monitoring therapeutic responses, or detecting environmental contaminants⁷³.

Molecular probe:

Dendrimers possess a large number of functional groups on their surface, providing ample opportunities for chemical modification. These functional groups can be selectively modified with various ligands, such as antibodies, peptides, aptamers, or small molecule targeting moieties. By conjugating specific ligands onto dendrimer surfaces, molecular probes can be tailored to recognize and bind to target molecules with high affinity and specificity. Dendrimers exhibit a high degree of multivalency, meaning they can display multiple copies of a ligand on their surface. This multivalent presentation enhances the binding affinity and avidity of molecular probes toward their target molecules, leading to improved sensitivity and selectivity. Multivalent interactions between dendrimer-based probes and target molecules result in enhanced signal amplification and discrimination, making them powerful tools for molecular recognition and detection^74,75.

Dendritic catalysts/enzymes:

Dendritic catalysts and enzymes refer to catalysts and enzymes that are immobilized or encapsulated within dendrimeric structures. These dendrimer-based catalysts and enzymes offer several advantages over their free counterparts, including enhanced stability, activity, selectivity, and recyclability. Dendrimers provide a versatile scaffold for the immobilization of catalysts or enzymes. Catalysts or enzymes can be covalently attached to the surface of dendrimers or encapsulated within their interior void spaces. This immobilization prevents the leaching or loss of catalysts or enzymes during reactions, enabling their efficient reuse and recycling⁷⁶.

Conclusion and future prospects:

To sum up, the ongoing studies on dendrimer-based drug delivery demonstrate the amazing potential of these nanocarriers to tackle important issues in therapeutic delivery. Researchers have made great progress in improving medication solubility, stability, and targeted distribution by utilizing their special features. This has improved therapeutic efficacy while reducing off-target effects. Furthermore, the creation of multifunctional dendrimer platforms has the potential to facilitate personalized treatment and theranostic applications. Even with these developments, problems like scalability, regulatory approval, and biocompatibility still need to be solved, which calls for more interdisciplinary cooperation and creativity. The potential for dendrimer-based drug delivery systems to transform healthcare by providing safer, more efficient, and customized therapeutic interventions for a variety of diseases presents itself as we continue to understand their complexities from the bench to the bedside. Top of FormDendrimer-based drug delivery has a vast future ahead of it and has the potential to completely transform several healthcare industries. Dendrimers provide a flexible framework for the targeted administration of therapeutic medicines with decreased side effects and increased efficacy, ranging from small compounds to biologics, thanks to their precisely programmable characteristics. Subsequent investigation into dendrimer structures and surface alterations will facilitate the creation of next-generation nanocarriers that can accomplish site-specific drug delivery and breach biological barriers like the blood-brain barrier. Furthermore, theranostic applications are made possible by the integration of multifunctional capabilities, such as imaging and diagnostic functionalities, which allow for the real-time monitoring of therapeutic responses. With further research, dendrimer-based drug delivery systems may prove useful for personalized medicine strategies that adjust therapies to the specific needs of each patient based on physiological, pathological, and genetic variables. All things considered, the future of dendrimer drug delivery includes developments in targeted therapy, precision medicine, and theranostics, providing ground-breaking approaches to enhance patient outcomes for a variety of illnesses.

Table 2. Different researchers and their findings on dendrimer.

S.N.	Researcher/year	Findings	Reference
1.	Xian S et al., /2024	Incorporating insulin into dendrimers or nanoscale complexes holds promise for improving the stability, bioavailability, and targeted delivery of insulin, particularly for the treatment of diabetes. Insulin was encapsulated within the interior void spaces of dendrimers. Dendrimers can provide a controlled release of insulin over time, prolonging its therapeutic effect and reducing the frequency of administration.	[77]
2	Zeynalzadeh S et al., /2023	Curcumin a natural compound derived from turmeric, is known for its anti-cancer properties, but its clinical efficacy is limited due to poor solubility and bioavailability so PAMAM dendrimer-curcumin complex was synthesized and evaluated by employment in cancer cell lines. The G4-FA revealed good efficiency in releasing the loaded curcumin and has a promising growth inhibitory effect on cancer cell lines.	[78]
3	Han H et al., /2023	For the treatment of Rheumatoid arthritis, a fluorinated polyamidoamie dendrimer was developed which delivers miR-23b which reduces inflammation by stimulating apoptosis along with that it inhibits the inflammatory response in macrophages.	[79]
4	Arora V et al., /2022	PAMAM, PLL & PPI dendrimers are used to conjugate the chemotherapy drugs that are used in the treatment of lung cancer so that their target specificity and efficiency increase	[80]
5	Zhang D et. Al., /2021	Ionizable amphiphilic Janus dendrimers offer an innovative platform for delivering mRNA. These dendrimers, characterized by their two distinct faces with differing chemical properties, provide a versatile system for mRNA encapsulation and delivery. The dendrimer's amphiphilic nature means it has both hydrophilic (water-attracting) and hydrophobic (water-repelling) regions. This structure enables the dendrimer to encapsulate mRNA within its hydrophobic core, protecting it from degradation in the extracellular environment and effevtively deliver mRNA to lungs. That is why it is proved to be effective in covid-19 vaccines development.	[81]
6	Wang G et al., /2020	Developed a dendrimer-camptothecin conjugate that can penetrate the PDA Tumors via transcytosis and has high anti-tumor activity in the pancreas. Camptothecin is poorly water-soluble and undergoes degradation in physiological conditions, limiting its efficacy. Conjugating camptothecin to a dendrimer improves its solubility and stability, enhancing its pharmaceutical properties and bioavailability.	[82]
7	Kesharwani, P. et al., /2019	The dendrimer-entrapped gold nanoparticle was formulated gold nanoparticles exhibit localized surface plasmon resonance (LSPR) effects, resulting in strong absorption and scattering of light in the visible and near-infrared (NIR) regions. Dendrimer-entrapped gold nanoparticles can be functionalized with imaging agents (e.g., fluorescent dyes, MRI contrast agents) for various imaging modalities, including fluorescence imaging, and magnetic resonance imaging (MRI).	[83]
8	Dong Y et al., /2018	Dendrimers used as nanocarriers for delivering small interfering RNA (siRNA) to targeted genes hold great promise for achieving potent gene silencing and anti-tumor activity. By delivering siRNA targeting specific genes involved in tumor growth or progression, dendrimer-based nanocarriers can effectively silence the expression of these genes, leading to anti-tumor effects.	[84]
9	Choudhary S et al., /2017	Proposed that when a hydrophobic drug is entrapped/encapsulated into a dendrimer then its permeability and solubility both increase accordingly and so drug efficiency also increases.	[85]
10	Chahal JS. et al., /2016	Dendrimer-encapsulated RNA vaccine holds significant promise for providing effective protection against highly dangerous microbes like the Ebola virus, H1N1 influenza virus, and Toxoplasma gondii. RNA molecules are encapsulated within the dendrimer structure, either through electrostatic interactions or physical entrapment, protecting the RNA from degradation and enhancing its stability.	[86]
11	Taratula O et al., /2015	A theranostic nanoplatform based on a single drug was developed for simultaneous NIR fluorescence and combinatorial phototherapy. e-imaging, utilizing both photothermal (PTT) and photodynamic (PDT) therapeutic processes. After being surface modified with polyethylene glycol (PEG), substituted silicon phthalocyanine (SiNc) was encapsulated within the hydrophobic interior of a generation 5 polypropylene imine dendrimer to create a biocompatible nano platform (SiNc-NP).	[87]
12	Xu L et al., /2014	Dendrimers can be precisely engineered to have a specific size and shape, which is advantageous for crossing the blood-brain barrier (BBB) and penetrating CNS tissues. This allows for targeted delivery of therapeutics to the brain. Dendrimers can encapsulate therapeutic molecules within their interior void spaces. This encapsulation protects the drug from degradation and allows for controlled release kinetics, prolonging its presence in the CNS.	[88]
13	Shcharbin, D et al., /2013	PAMAM dendrimers can encapsulate nucleic acids within their interior void spaces or bind them to their surface through electrostatic interactions. This encapsulation protects the nucleic acids from enzymatic degradation and immune recognition, enhancing their stability and bioavailability. Endosomal entrapment is a common barrier to efficient gene delivery. PAMAM dendrimers can promote endosomal escape through the proton sponge effect, wherein the influx of protons into endosomes triggers osmotic swelling, rupture, and release of dendriplexes into the cytoplasm.	[89]
14	Kanna S et al., /2012	At almost 90% term gestation the researchers administered Escherichia coli toxin into the rabbit mother's uterus. Upon birth, the kits were given either a saline solution, NAC (N-acetyl-l-cysteine) as a free medicine, or a dendrimer-NAC (D-NAC) conjugate. CP kits were administered D-NAC on the first day of life as part of a postnatal "rescue" that let them develop normally and learn to walk and hop. Neuron counts and inflammation levels in the successfully treated kits were comparable to those of the control group of healthy animals. In contrast, saline or NAC by itself had little impact.	[90]
15	Wang Y et al., /2011	The conjugation of doxorubicin with dendrimers has emerged as a promising strategy for enhancing the therapeutic efficacy of this potent anti-cancer drug while minimizing its associated side effects. This method involves modifying generation 5 (G5) PAMAM dendrimers with folic acid (FA) and fluorescein isothiocyanate (FI) via covalent conjugation, and then acetylating the remaining terminal amines (G5. NHAc-FI-FA) to deliver DOX specifically to cancer cells that overexpress high-affinity folic acid receptors (FAR).	[91]

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Received on 21.04.2024 Modified on 12.06.2024

Asian J. Pharm. Res. 2024; 14(3):242-254.

DOI: 10.52711/2231-5691.2024.00038

Type of dendrimer	Structure	characterization
PAMAM Dendrimer	Highly branched, spherical	Well-defined architecture, high uniformity, versatility in functionalization, biocompatible, used in drug delivery, imaging, and gene transfection
PPI dendrimers	Highly branched, spherical	Versatile, easily functionalized, biocompatible, used in drug delivery, imaging, and gene transfection
PEEK dendrimers	Branched, spherical	High thermal stability, mechanical strength, chemical resistance; potential applications in nanocomposites and membranes
Polyester dendrimers	Branched, dendritic	Biodegradable, potential for drug delivery and tissue engineering applications
Phosphorus-containing dendrimers	Dendritic	Flame retardant properties, potential applications in materials science, electronics, and biomedical
Carbosilane dendrimers	Branched, spherical	Versatile, biocompatible, used in drug delivery, imaging, and gene transfection
Polyglycerol dendrimers	Branched, dendritic	Biocompatible, hydrophilic, potential applications in drug delivery, imaging, and biomedical engineering
Melamine dendrimers	Highly branched	High degree of symmetry, potential applications in catalysis, sensing, and materials science
Dendronized polymers	Branched	Combining dendritic and linear polymer structures, used in drug delivery, surface modification, and materials science.