10.2 Drug delivery using colloidal carriers
11 min read•august 20, 2024
Colloidal drug carriers are nanoscale systems that encapsulate and deliver therapeutic agents in the body. They offer advantages like enhanced solubility, improved bioavailability, and controlled release of drugs. Common types include , nanoparticles, , and .
These carriers can be prepared through methods like thin film hydration, solvent evaporation, and self-assembly. Characterization techniques assess their size, charge, drug loading, and morphology. Drug release mechanisms include diffusion, erosion, and stimuli-responsive triggers. Stability and safety are crucial considerations for clinical use.
Types of colloidal drug carriers
- Colloidal drug carriers are nanoscale systems designed to encapsulate, protect, and deliver therapeutic agents to target sites in the body
- They offer advantages over conventional drug formulations, such as enhanced solubility, improved bioavailability, and controlled release kinetics
- Common types of colloidal drug carriers include liposomes, nanoparticles, micelles, and dendrimers, each with unique properties and applications
Liposomes for drug delivery
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- Liposomes are spherical vesicles composed of phospholipid bilayers that enclose an aqueous core
- They can encapsulate both hydrophilic drugs in the aqueous core and hydrophobic drugs within the lipid bilayer
- Liposomes are biocompatible, biodegradable, and can be surface-modified for targeted delivery (PEGylation, antibody conjugation)
- Examples: Doxil (liposomal doxorubicin) for cancer treatment, AmBisome (liposomal amphotericin B) for fungal infections
Nanoparticles as drug carriers
- Nanoparticles are solid colloidal particles with sizes ranging from 1-100 nm
- They can be composed of various materials, such as polymers (PLGA, chitosan), lipids (), or inorganic compounds (gold, silica)
- Nanoparticles offer high drug , controlled release, and the ability to target specific tissues or cells
- Examples: Abraxane (albumin-bound paclitaxel nanoparticles) for cancer therapy, Feraheme (iron oxide nanoparticles) for iron deficiency anemia
Micelles in drug delivery systems
- Micelles are self-assembled nanostructures formed by amphiphilic molecules (surfactants, block copolymers) in aqueous media
- They have a hydrophobic core that can solubilize poorly water-soluble drugs and a hydrophilic shell that provides stability and stealth properties
- Micelles can enhance drug solubility, prolong circulation time, and facilitate to tumor sites via the enhanced permeability and retention (EPR) effect
- Examples: Genexol-PM ( of paclitaxel) for cancer treatment, Estrasorb (estradiol micellar formulation) for menopausal therapy
Dendrimers for targeted drug release
- Dendrimers are highly branched, globular polymeric nanostructures with a well-defined architecture and multiple functional groups on the surface
- They can encapsulate drugs within their interior cavities or conjugate them to the surface groups
- Dendrimers offer precise control over size, shape, and surface functionality, enabling targeted drug delivery and controlled release
- Examples: VivaGel (polyanionic lysine dendrimer) for HIV prevention and treatment, DEP (dendrimer-enhanced photodynamic therapy) for cancer treatment
Advantages of colloidal drug delivery
- Colloidal drug delivery systems offer several advantages over conventional drug formulations, addressing challenges such as poor solubility, low bioavailability, and non-specific distribution
- They can enhance the therapeutic efficacy and safety profile of drugs by improving their pharmacokinetic and pharmacodynamic properties
- Colloidal carriers can be designed to target specific tissues, cells, or even intracellular compartments, minimizing off-target effects and reducing systemic toxicity
Enhanced drug solubility
- Many newly discovered drug compounds exhibit poor water solubility, limiting their oral absorption and bioavailability
- Colloidal carriers, such as micelles and lipid-based nanoparticles, can solubilize hydrophobic drugs within their core, improving their apparent solubility and dissolution rate
- Increased drug solubility leads to enhanced absorption and higher plasma concentrations, potentially reducing the required dose and dosing frequency
Improved drug bioavailability
- Colloidal carriers can protect drugs from premature degradation in the gastrointestinal tract and bypass first-pass metabolism in the liver
- They can prolong the circulation time of drugs by reducing renal clearance and avoiding immune system recognition (stealth properties)
- Enhanced bioavailability results in higher drug exposure at the target site, improving therapeutic efficacy and reducing variability in patient response
Controlled drug release kinetics
- Colloidal carriers can be designed to release drugs in a controlled and sustained manner, maintaining therapeutic concentrations over an extended period
- Controlled release can be achieved through diffusion, erosion, or stimuli-responsive mechanisms, depending on the carrier composition and structure
- Sustained drug release reduces the peak-to-trough fluctuations in plasma levels, minimizing side effects and improving patient compliance
Targeted drug delivery to specific sites
- Colloidal carriers can be functionalized with targeting ligands (antibodies, peptides, aptamers) that bind to specific receptors or antigens overexpressed on diseased cells or tissues
- Targeted delivery increases drug accumulation at the desired site of action while minimizing exposure to healthy tissues
- Examples of targeted drug delivery include folate receptor-targeted liposomes for cancer therapy and transferrin receptor-targeted nanoparticles for brain drug delivery
Preparation methods for colloidal carriers
- Various preparation methods have been developed to synthesize colloidal drug carriers with desired properties, such as size, shape, composition, and drug loading
- The choice of preparation method depends on the type of colloidal carrier, the physicochemical properties of the drug, and the intended route of administration
- Optimization of the preparation process is crucial to obtain reproducible and stable colloidal formulations with high and minimal batch-to-batch variability
Thin film hydration for liposome formation
- Thin film hydration is a widely used method for preparing liposomes, involving the formation of a lipid film and its hydration with an aqueous phase
- Lipids are dissolved in an organic solvent, which is then evaporated to form a thin lipid film on the walls of a round-bottom flask
- The lipid film is hydrated with an aqueous solution containing the drug, followed by agitation or sonication to form liposomes
- The resulting liposomes can be further processed by extrusion or homogenization to obtain a uniform size distribution
Solvent evaporation in nanoparticle synthesis
- Solvent evaporation is a common technique for preparing polymeric nanoparticles, such as PLGA or PCL nanoparticles
- The polymer and drug are dissolved in a volatile organic solvent, which is then emulsified with an aqueous phase containing a stabilizer (surfactant or polymer)
- The organic solvent is evaporated under reduced pressure or at elevated temperature, leading to the precipitation of the polymer and the formation of nanoparticles
- The nanoparticle suspension is then purified by centrifugation or dialysis to remove excess stabilizer and free drug
Self-assembly of amphiphilic molecules into micelles
- Micelles are formed by the spontaneous self-assembly of amphiphilic molecules (surfactants or block copolymers) in aqueous media above their critical micelle concentration (CMC)
- The hydrophobic portions of the amphiphilic molecules aggregate to form the micellar core, while the hydrophilic portions form the outer shell
- Drugs can be incorporated into micelles by direct dissolution in the micellar solution or by co-solvent evaporation methods
- The size and morphology of micelles can be controlled by varying the composition and concentration of the amphiphilic molecules
Divergent vs convergent synthesis of dendrimers
- Dendrimers can be synthesized by two main approaches: divergent and convergent synthesis
- In divergent synthesis, the dendrimer grows outwards from a multifunctional core by successive addition of branching units and activation steps
- Convergent synthesis involves the separate preparation of dendron fragments, which are then coupled to a central core to form the complete dendrimer
- Divergent synthesis is more suitable for large-scale production, while convergent synthesis offers better control over the final structure and purity of the dendrimer
Characterization of colloidal drug carriers
- Comprehensive characterization of colloidal drug carriers is essential to ensure their quality, safety, and efficacy
- Various analytical techniques are employed to assess the physicochemical properties, drug loading, and stability of colloidal formulations
- Characterization data provide valuable insights into the structure-activity relationships and guide the optimization of colloidal carriers for specific applications
Size and size distribution analysis
- The size and size distribution of colloidal carriers significantly influence their biodistribution, cellular uptake, and drug release kinetics
- (DLS) is a common technique for measuring the hydrodynamic diameter and polydispersity index (PDI) of colloidal particles in suspension
- Nanoparticle tracking analysis (NTA) and electron microscopy (TEM, SEM) provide complementary information on the size, size distribution, and morphology of colloidal carriers
- Size measurements are crucial for quality control and batch-to-batch consistency of colloidal formulations
Surface charge and zeta potential
- The of colloidal carriers, expressed as , determines their colloidal stability, interactions with biological membranes, and cellular uptake
- Zeta potential is measured by laser Doppler electrophoresis, which assesses the electrophoretic mobility of particles in an applied electric field
- Highly charged colloidal carriers (zeta potential > ±30 mV) are generally more stable due to electrostatic repulsion, while neutral carriers may require steric stabilization
- Surface charge can be modulated by the choice of materials, surfactants, or surface modification strategies to optimize the performance of colloidal carriers
Drug encapsulation efficiency and loading capacity
- Drug encapsulation efficiency (EE) and loading capacity (LC) are critical parameters that quantify the amount of drug incorporated into the colloidal carrier
- EE is defined as the percentage of drug successfully encapsulated relative to the initial amount of drug added, while LC represents the mass of drug per unit mass of the carrier
- High EE and LC are desirable to minimize the amount of carrier material and achieve therapeutic drug concentrations at the target site
- Drug loading can be determined by separating the free drug from the carrier (e.g., by centrifugation, dialysis, or filtration) and quantifying the drug content by spectroscopic or chromatographic methods
Morphology and structural characterization techniques
- The morphology and internal structure of colloidal carriers can be visualized by various microscopic techniques, providing insights into their shape, size, and drug distribution
- (TEM) and scanning electron microscopy (SEM) offer high-resolution images of the carrier surface and internal structure
- Atomic force microscopy (AFM) enables the three-dimensional imaging of colloidal carriers and provides information on their surface topography and mechanical properties
- Small-angle X-ray scattering (SAXS) and neutron scattering (SANS) techniques can probe the internal structure and organization of colloidal carriers in solution
Drug release mechanisms from colloidal carriers
- Understanding the drug release mechanisms from colloidal carriers is crucial for designing formulations with desired release profiles and therapeutic outcomes
- Drug release can be governed by various factors, such as carrier composition, drug-carrier interactions, environmental conditions, and external stimuli
- Mathematical modeling of drug release kinetics helps predict the in vivo performance of colloidal carriers and guide formulation optimization
Diffusion-controlled drug release
- Diffusion is the most common mechanism of drug release from colloidal carriers, driven by the concentration gradient between the carrier and the surrounding medium
- Drug molecules diffuse through the carrier matrix or across the carrier membrane, depending on the type of colloidal system
- The rate of diffusion-controlled release is influenced by factors such as drug solubility, carrier porosity, and drug-carrier interactions
- Examples of diffusion-controlled release include drug release from liposomes, polymeric nanoparticles, and hydrogels
Erosion-mediated drug release
- Erosion-mediated release occurs when the colloidal carrier gradually degrades or dissolves in the biological environment, releasing the encapsulated drug
- The rate of erosion depends on the chemical composition and degradability of the carrier material, as well as the environmental conditions (pH, enzymes)
- Erosion can be surface-controlled (heterogeneous) or bulk-controlled (homogeneous), leading to different release kinetics
- Examples of erosion-mediated release include drug release from biodegradable polymeric nanoparticles (PLGA, PLA) and lipid-based carriers (solid lipid nanoparticles)
Stimuli-responsive drug release triggers
- Stimuli-responsive colloidal carriers can release drugs in response to specific internal or external triggers, enabling on-demand and spatiotemporally controlled drug delivery
- Internal stimuli include changes in pH (e.g., acidic tumor microenvironment), redox potential (e.g., glutathione in cancer cells), or enzymatic activity (e.g., matrix metalloproteinases in inflammation)
- External stimuli include temperature, light, magnetic fields, or ultrasound, which can be applied to trigger drug release at the desired site and time
- Examples of stimuli-responsive carriers include pH-sensitive liposomes, thermoresponsive polymeric micelles, and magnetic nanoparticles for hyperthermia-triggered release
Modeling and kinetics of drug release profiles
- Mathematical modeling of drug release kinetics helps elucidate the underlying release mechanisms and predict the in vivo performance of colloidal carriers
- Various kinetic models, such as zero-order, first-order, Higuchi, and Korsmeyer-Peppas models, can be applied to describe the drug release profiles
- The choice of the appropriate model depends on the release mechanism, carrier geometry, and drug-carrier interactions
- Model parameters, such as release rate constants and diffusion coefficients, can be extracted from experimental data and used for formulation optimization and quality control
Stability and storage of colloidal drug formulations
- Ensuring the stability and shelf life of colloidal drug formulations is critical for their successful development, manufacturing, and clinical application
- Colloidal carriers may undergo various physical and chemical instability processes during storage, such as , fusion, drug leakage, or degradation
- Proper formulation design, stabilization strategies, and storage conditions are essential to maintain the integrity and performance of colloidal drug carriers
Factors affecting colloidal stability
- Colloidal stability is influenced by various factors, including particle size, surface charge, surface chemistry, and the composition of the dispersion medium
- Attractive forces between colloidal particles, such as van der Waals interactions, can lead to aggregation and , while repulsive forces (electrostatic or steric) promote stability
- Chemical instability can arise from hydrolysis, oxidation, or other degradation reactions of the carrier materials or the encapsulated drug
- Environmental factors, such as temperature, pH, ionic strength, and the presence of destabilizing agents (proteins, electrolytes), can also impact colloidal stability
Sterilization methods for colloidal drug carriers
- Sterilization is a crucial step in the production of colloidal drug formulations to ensure their microbiological safety and comply with regulatory requirements
- Common sterilization methods for colloidal carriers include filtration, autoclaving, gamma irradiation, and aseptic processing
- The choice of sterilization method depends on the thermal and chemical stability of the carrier materials and the encapsulated drug, as well as the compatibility with the formulation components
- Sterilization conditions should be optimized to maintain the physicochemical properties and drug loading of the colloidal carriers while achieving the required sterility assurance level
Shelf life and storage conditions
- The shelf life of colloidal drug formulations is determined by their stability under specified storage conditions over a defined period
- Accelerated stability studies can be conducted to predict the long-term stability of colloidal carriers under stressed conditions (elevated temperature, humidity)
- Real-time stability studies are performed at the recommended storage conditions to monitor the physicochemical properties, drug content, and microbiological quality of the formulation over time
- Appropriate packaging materials and storage conditions (temperature, light protection) should be selected to minimize degradation and ensure the stability of colloidal drug carriers throughout their shelf life
Lyophilization for long-term stability
- Lyophilization (freeze-drying) is a widely used technique to enhance the long-term stability of colloidal drug formulations
- The process involves freezing the colloidal dispersion, followed by sublimation of the ice under vacuum, resulting in a dry powder that can be reconstituted before use
- Lyophilization reduces the mobility of the colloidal particles and minimizes degradation reactions, extending the shelf life of the formulation
- Cryoprotectants (sugars, polyols) and lyoprotectants (proteins, polymers) are often added to the formulation to prevent particle aggregation and preserve the structure of the colloidal carriers during the freezing and drying steps
Biocompatibility and safety considerations
- Assessing the biocompatibility and safety of colloidal drug carriers is paramount for their successful translation into clinical practice
- Colloidal materials should be non-toxic, non-immunogenic, and biodegradable to minimize adverse effects and ensure their safe elimination from the body
- Rigorous in vitro and in vivo studies are required to evaluate the toxicity, immunogenicity, and biodistribution of colloidal carriers before proceeding to clinical trials
Toxicity assessment of colloidal materials
- In vitro cytotoxicity assays, such as MTT
Key Terms to Review (23)
Active Targeting: Active targeting refers to the strategic design of drug delivery systems that use specific ligands or targeting moieties to bind to particular cells or tissues. This approach enhances the precision of drug delivery by ensuring that therapeutic agents are delivered specifically to diseased or targeted cells, minimizing damage to healthy tissues and improving treatment efficacy.
Aggregation: Aggregation refers to the process where particles in a colloidal system clump together to form larger aggregates. This phenomenon can affect the stability, behavior, and functionality of colloids across various applications, impacting their effectiveness and performance in different environments.
Anticancer therapy: Anticancer therapy refers to the various treatments used to combat cancer, aiming to eliminate cancer cells or inhibit their growth and spread. This therapy can take multiple forms, including chemotherapy, radiation therapy, targeted therapy, and immunotherapy, each with distinct mechanisms of action. In recent years, the incorporation of colloidal carriers has emerged as a promising strategy to enhance drug delivery and efficacy in anticancer therapies.
Dendrimers: Dendrimers are highly branched, tree-like macromolecules with a central core, multiple branching units, and terminal functional groups. Their unique structure allows for precise control over size, shape, and surface functionality, making them ideal candidates for various applications, particularly in drug delivery systems using colloidal carriers.
Diffusion-controlled drug release: Diffusion-controlled drug release refers to a mechanism where the release of a drug from a delivery system occurs primarily through the process of diffusion. This means that the rate at which the drug is released depends on its concentration gradient, the properties of the carrier, and the surrounding environment. This method is crucial in drug delivery systems, particularly those utilizing colloidal carriers, as it influences how effectively and efficiently a drug reaches its target site in the body.
Drug Encapsulation Efficiency: Drug encapsulation efficiency refers to the percentage of a drug that is successfully incorporated into a colloidal carrier, compared to the total amount of drug initially used during the formulation process. This metric is crucial for evaluating the performance of colloidal drug delivery systems, as higher efficiency often correlates with improved therapeutic outcomes, reduced side effects, and enhanced stability of the drug within the carrier. Understanding this term helps in optimizing formulations and assessing their potential for effective drug delivery.
Dynamic Light Scattering: Dynamic light scattering (DLS) is a technique used to measure the size and distribution of particles in a colloidal suspension by analyzing the time-dependent fluctuations in scattered light caused by Brownian motion. This method is crucial for understanding the behavior of colloids, as it provides insights into particle sizes, stability, and interactions.
Erosion-mediated drug release: Erosion-mediated drug release is a process in which the active pharmaceutical ingredients are gradually released from a carrier matrix through the physical erosion of the matrix material. This mechanism is particularly important in drug delivery systems that use colloidal carriers, as it allows for controlled and sustained release of medications over time, enhancing therapeutic efficacy while minimizing side effects.
Good Manufacturing Practice (GMP): Good Manufacturing Practice (GMP) refers to the regulations and guidelines that ensure products are consistently produced and controlled according to quality standards. GMP is crucial in industries like pharmaceuticals and food, as it helps minimize risks involved in production that cannot be eliminated through testing the final product. In the context of drug delivery using colloidal carriers, adhering to GMP ensures that these advanced drug delivery systems are safe, effective, and of high quality, ultimately protecting patient health and safety.
Liposomes: Liposomes are spherical vesicles made from phospholipid bilayers that can encapsulate drugs and other substances, allowing for targeted delivery within biological systems. They are composed of a hydrophilic (water-attracting) core surrounded by a hydrophobic (water-repelling) membrane, making them versatile for various applications, particularly in drug delivery where they can enhance solubility and bioavailability of therapeutic agents.
Loading Capacity: Loading capacity refers to the maximum amount of therapeutic agents that can be effectively encapsulated or associated with colloidal carriers. This concept is crucial in drug delivery systems, as it determines how much medication can be delivered to a target site, which impacts efficacy and safety. A higher loading capacity generally allows for a more effective treatment by ensuring sufficient drug levels reach the desired location while minimizing side effects.
Micelles: Micelles are aggregate structures formed by surfactant molecules in a solution, where the hydrophobic (water-repelling) tails of the surfactants cluster inward while the hydrophilic (water-attracting) heads face outward. This unique arrangement allows micelles to effectively encapsulate non-polar substances in an aqueous environment, playing a significant role in processes like emulsification and drug delivery.
Nanospheres: Nanospheres are tiny spherical particles typically ranging from 1 to 1000 nanometers in diameter, often made from polymers, metals, or silica. They play a crucial role in drug delivery systems as colloidal carriers due to their ability to encapsulate drugs, enhance solubility, and provide controlled release profiles, making them highly effective for targeted therapy.
Passive targeting: Passive targeting refers to the method of directing drug delivery systems, such as colloidal carriers, to specific sites in the body based on natural biological processes, without the need for active manipulation. This approach relies on factors like blood circulation, tissue permeability, and the intrinsic properties of the drug carriers, which can enhance the accumulation of therapeutic agents at desired locations. It is a fundamental strategy used in drug delivery systems to improve therapeutic efficacy and reduce side effects.
Pharmaceutical regulations: Pharmaceutical regulations refer to the laws and guidelines that govern the development, approval, manufacturing, and marketing of drugs and medical products. These regulations are essential to ensure that pharmaceutical products are safe, effective, and of high quality before they reach consumers. By establishing standards for clinical trials, manufacturing practices, and post-market surveillance, pharmaceutical regulations play a crucial role in protecting public health and ensuring that innovative drug delivery systems, like colloidal carriers, meet safety and efficacy criteria.
Polymeric micelles: Polymeric micelles are nanoscale structures formed by the self-assembly of amphiphilic block copolymers in aqueous solutions, where hydrophobic segments form a core and hydrophilic segments create a shell. This unique architecture allows polymeric micelles to encapsulate poorly soluble drugs, enhancing their bioavailability and stability. Their behavior can be influenced by factors such as temperature, pH, and the presence of other molecules, making them versatile carriers in various applications.
Sedimentation: Sedimentation is the process by which particles settle out of a fluid, typically due to gravity, forming a denser layer at the bottom. This phenomenon is crucial for understanding how colloidal systems behave, especially in the context of stability, transport, and separation methods.
Solid Lipid Nanoparticles: Solid lipid nanoparticles (SLNs) are submicron-sized carriers made from solid lipids that are used to encapsulate and deliver drugs in a controlled manner. These nanoparticles combine the advantages of both solid lipid carriers and conventional drug delivery systems, offering enhanced stability, improved bioavailability, and targeted drug delivery. They are an important tool in the development of colloidal carriers for therapeutic applications.
Stimuli-responsive drug release triggers: Stimuli-responsive drug release triggers are mechanisms that enable the controlled release of therapeutic agents from drug delivery systems in response to specific external stimuli. These triggers can be physical, chemical, or biological in nature and play a crucial role in enhancing the efficacy and safety of drug delivery by ensuring that the drug is released at the right time and place within the body. By utilizing these triggers, researchers can optimize treatment regimens and minimize side effects.
Surface Charge: Surface charge refers to the electric charge that resides on the surface of a colloidal particle, influencing its stability, interaction with other particles, and overall behavior in a suspension. This charge can affect how particles attract or repel each other, which is crucial for processes like deposition and drug delivery, as it can dictate how well colloidal carriers function in different environments.
Transmission Electron Microscopy: Transmission electron microscopy (TEM) is a high-resolution imaging technique that uses a beam of electrons to pass through thin samples, providing detailed images of the internal structure at the atomic level. This method is essential for studying materials and biological specimens, allowing researchers to visualize nanoscale features and obtain information about composition and crystallography.
Vaccine delivery: Vaccine delivery refers to the methods and systems used to administer vaccines effectively to individuals, ensuring optimal immune response and protection against diseases. This process can be enhanced by utilizing colloidal carriers, which improve the stability, bioavailability, and targeted delivery of vaccines to specific cells or tissues in the body.
Zeta Potential: Zeta potential is a scientific term that describes the electric charge at the slipping plane of a colloidal particle, influencing its stability and interactions in a colloidal system. This potential is critical because it helps predict the behavior of colloids in various environments, indicating whether they will remain stable or aggregate. The zeta potential is influenced by factors like pH, ionic strength, and the nature of the dispersed particles, making it essential for understanding colloidal systems in multiple applications.