Polymeric Micelles (PMs) are nano-sized drug delivery devices with a core-shell structure formed by self-assembly of amphiphilic block copolymers in aqueous solution as shown in Figure 1. In diluted aqueous solutions, amphiphilic molecules exist independently and function as surfactants to reduce surface tension at the air-water interface (Owenet al., 2012; Pepićet al., 2013).

Figure 1:
Formation and drug loading of polymeric micelles by self-assemble of amphiphilic block copolymers in aqueous solution.

The self-assembly above Critical Micelle Concentration (CMC) is an entropically favored phenomenon. During the process, the hydrophobic compartment of the copolymer forms the core of polymeric micelles, whereas the hydrophilic compartment forms the shell (Weiet al., 2009).

Polymeric micelles possess several characteristics that make them well-suited for therapeutic drug delivery purposes. The hydrophobic core of polymeric micelles can serve as a storage site for non-polar pharmaceutical compounds. By incorporating these medications into polymeric micelles, the need for formulation vehicles and the consequent toxicity are avoided (Oerlemanset al., 2010; Hanafyet al., 2018).

At or above their Critical Micelle Concentration (CMC), amphiphilic block copolymers adopt nano-sized, self-assembling polymeric micelles with core-shell architectures in aqueous fluids. The hydrophilic shells of these drug carrier systems provide a stable suspension of micelles in the circulatory system. However, the hydrophobic core improves the solubility of the medication by confining the poorly soluble portion within, hence enhancing its bioavailability (Luet al., 2020; Kahramanet al., 2015). A hydrophobic core can bind to weakly water-soluble medicines by either physical trapping or chemical adhesion, while a hydrophilic shell maintains colloidal stability (Wanget al., 2022).

As opposed to the usual free drug diffusion, polymeric micelles are delivered into cells by receptor-mediated endocytosis, therefore bypassing the P-glycoprotein (P-gp) efflux. P-gp is a potent drug efflux protein that obstructs the delivery of many medications to the brain, gut, and Multidrug-Resistant (MDR) tumors (Razzaqet al., 2021). Nevertheless, these systems have the disadvantages of generating large-sized aggregates that are beyond the desired size range for drug delivery systems utilizing nanoscale particles, as well as their instability in aqueous dispersion resulting in phase separated states (Luet al., 2013; Nouret al., 2016).

Unlike micellar structures made of traditional surfactant molecules, which are tiny molar mass molecules, polymeric micelles are generated at lower Critical Micelle Concentration (CMC) values. They are more persistent in vitro and in vivo because they dissociate at a slower rate and accumulate drugs more effectively at the target surface (Zhouet al., 2016). A critical and major aspect in determining the body arrangement of micelles when an Enhanced Permeation Retention effect (EPR) is involved is their restricted size range, which is comparable to that of viruses and lipoproteins (Boseet al., 2021). Significantly, polymeric micelles often exhibit a consistent particle size, exceptional thermal stability, compatibility with biological systems, and the capacity to encapsulate both hydrophilic and hydrophobic medications (Sohailet al., 2022).

Therefore, polymeric micelles are extensively employed in research as nanocarrier systems to transport drugs and other therapeutic agents, including anticancer drugs, proteins, nucleic acids, contrast/imaging agents, and antibiotics, to overcome antibiotic resistance and improve therapeutic effectiveness (Sinaniet al., 2023). Furthermore, these systems can exhibit intelligence and responsiveness to many environmental stimuli, including pH, electric and magnetic fields, and ultraviolet electromagnetic radiation (Mohammadiet al., 2023). Over a hundred polymeric micelle-based drug delivery formulations have progressed to different phases of clinical and preclinical studies in several countries (Caiet al., 2023). Mixed Polymeric Micelles (MPMs) are achieved by combining two or more distinct amphiphilic copolymers to enhance their characteristics and address the drawbacks of simple PMs, such as disaggregation/dissociation upon dissolution (Chenet al., 2016). In general, MPMs consistently demonstrate superior stability and encapsulation efficiency compared to basic PMs (Ferreiraet al., 2023; Senthilkumaret al., 2022).

Several parameters influence the size of polymeric micelles, including the molecular weight of the amphiphilic block copolymer, the number of amphiphiles that aggregate, the relative proportion of hydrophilic and hydrophobic chains, and the method of synthesis (Nealet al., 2021).

Amphiphilic block copolymers consist of two or more polymer blocks of varying sizes, which are preferably incompatible, chemically connected in a linear or branching arrangement. The units may consist of a neutral polymer (either hydrophilic or hydrophobic) or a polyelectrolyte (anionic, cationic, or zwitterionic) (Kuperkaret al., 2022; Wanget al., 2023). These copolymers, especially diblock and occasionally triblock copolymers have been intensively studied. The hydrophilic blocking component in these copolymers consists of nonionic surfactants of the Polyethyleneoxide (PEO) or Polyethylene Glycol (PEG) condensate type. Some of these surfactants may not be polymeric because of the low molecular weight PEO. These surfactants are commercially available and highly beneficial, such as Tweens®, Tritons®, Soluplus®, Cremophor EL®, Solutol HS15®, TPGS®, and others (Chaudhariet al., 2020). Poly (N-isopropylacrylamide) (PNIPAM), Polyvinyl Caprolactam (PVCL), Polyvinyl Pyrrolidone (PVP), Polyvinyl Alcohol (PVA), as well as some polyacids and poly bases, are well recognized hydrophilic blocking compounds (Atanaseet al., 2022). Polypropylene Oxide (PPO), Polylactic Acid (PAA), Polycaprolactone (PCL), Polybutylene Oxide (PBO), Polystyrene Oxide (PSO), Polybutadiene (PB), Polystyrene (PS), and Polymethylacrylate (PMA) are examples of hydrophobic blocks (Haladjovaet al., 2024). L-amino acid polymers, polyesters, and pluronic can also be used. These acids are extensively utilized as poly (L-aspartate) and poly (L-glutamate) and undergo derivatization based on their functional structures (Mehanet al., 2022).

Multiple studies have documented the importance of certain block polymers authorized by the Food and Drug Administration (FDA), including Poly (E-caprolactone) (PCL), Polylactic Acid (PLA), Polyglycolic Acid (PGA), and Polylactic acid-co-Glycolic Acid (PLGA), because of their biocompatibility, affordability, and biodegradability (Bartnikowskiet al., 2019). PEG is the most commonly used hydrophilic block due to its exceptional solubility in aqueous solutions and various organic solvents, so enabling versatile preparation methods. Additionally, PEG is non-toxic and has low immunogenicity. Lastly, PEG typically does not interact with biological components, hence facilitating its biodistribution after administration (Miyataet al., 2011). Although many co-polymers have a lower solubilization capability, they can simultaneously improve permeability more effectively than traditional solubilizers. D-α-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) is a hydrophilic compound classified as a fat-soluble form of vitamin E (Yanget al., 2018).

TPGS has lipophilic alkyl tail and hydrophilic polar head with Hydrophilic/Lipophilic Balance (HLB) value of 13.2 and Critical Micelle Concentration (CMC) of 0.02% w/w. It has been commonly utilized in solubilization, emulsification and wetting process (Guoet al., 2013). The solubility, absorption, and bioavailability of drugs can be improved with the help of TPGS, which also inhibits intestinal P-gp drug efflux and increases P-gp expression (Eedaraet al., 2014). The graft copolymer Soluplus® consists of a Polyethylene Glycol (PEG 6000) backbone with one or two side chains comprising of vinyl acetate unsystematically copolymerized with vinyl caprolactam (57% polyvinyl caprolactam, 30% polyvinyl acetate and 13% polyethylene glycol).

As it is hydrophilic and nonionic, its solubility does not change along with the gastrointestinal tract. It is slightly surface active, a property which could be useful to maintain supersaturation of poorly soluble drugs in the gastrointestinal tract (Raniet al., 2020). It can produce 80 nm-sized polymeric micelles in liquid media and improves passive diffusion across many routes of administration and has shown to be a flexible excipient for passive targeting (Pignatelloet al., 2022).

Another popular micellar carrier for the delivery of medicinal medicines with low solubility is poloxamer-188 block copolymer (Islamet al., 2021).

One type of amphiphilic copolymer is the graft copolymer, which consists of two polymer chains-one serving as the backbone and the other as the side grafted portion. In most cases, the copolymers exhibit characteristics shared by the grafts and the polymeric backbones (Kultheet al., 2012).

One way to categorize polymeric micelles is according to the intermolecular forces that separate the core segment from the water around it. They are categorized into three distinct sets (Nagaichet al., 2013).

Core and shell interact hydrophobically in water, generating micelles. Hydrophobic interactions can generate amphiphilic block co-polymers, such as poly (ethylene oxide). The compound is a blend of ethylene oxide and propylene oxide (Shuklaet al., 2021; Maboudiet al., 2024).

Micelles of this nature form when two or more ionic polymers with opposing charges, such as polyelectrolytes, bind electrostatically. The addition of these polymers to the solution enables them to permeate the micelle’s shell and generate specific PMs. The configuration and dimensions of the charged micelle coronas were governed by the Van-der Waals interaction forces and the electrostatic force (Luoet al., 2009).

These micelles readily form themselves in an aqueous solution, maintain their structural integrity, and possess a remarkably high capacity to transport drugs. The central region of the PICMs is utilized for encapsulating several therapeutic agents, including hydrophobic drug molecules, charged macromolecules, and metal complexation via hydrogen bonding, as well as hydrophobic and electrostatic interactions (Reddyet al., 2015). Methoxy polyethylene glycol-grafted chitosan is an example of a copolymer used to prepare polyion complex micelle (Jeonget al., 2009).

An innovative method that does not need block copolymers can also be employed to synthesize polymeric micelles. Polymeric micelles are formed by the self-assembly of homopolymer, random copolymer, graft copolymer, or oligomer particles, driven by interpolymer hydrogen bonding complexation. Non-covalently integrated micelles are formed when the core and shell of a homopolymer chain are joined at their end by certain intermolecular interactions, such as H-bonding or metal-ligand interactions (Mouryaet al., 2011).

Physicochemical properties of the block copolymers chosen for PMs synthesis determine the technique of preparation. The selected approach exerts a substantial influence on the physicochemical characteristics and the efficiency of drug encapsulation (Gaucheret al., 2005). The size, polydispersity index, and stability of copolymers are influenced by the sequence of addition, the ratio of aqueous to organic phases, and the concentration of the copolymers. Hence, it is beneficial to optimize these factors in order to determine a standard formula for producing PMs with favorable physicochemical and functional properties (Simõeset al., 2015).

Primarily, copolymers with excellent water solubility are employed in the direct dissolving technique for the production of PMs. This technique is quite straightforward and entails the combination of copolymers and pharmaceuticals in water-based solvents, along by mechanical processes such as agitation, sonication, and heating, to enclose the medications (Sotoudeganet al., 2016). Formation of PMs occurs as a result of the dehydration of the core-forming blocks. The copolymers and medicines are individually dissolved in aqueous solvents and then combined to produce Polymer Materials (PMs) (Cholkaret al., 2012).

Polymeric micelles are formed by the self-assembly of block copolymers with opposing charges in an aqueous solution. After undergoing multivalent electrostatic complexation, charged macromolecules like nucleic acids, proteins, and oligonucleotides are enclosed inside the core compartment. The PEG chains that surround the core constitute the protective shell compartment (Florinaset al., 2016).

Polyion Complex (PIC) micelles comprising positively charged PEG-b-poly (L-lysine) and negatively charged PEG-b-poly (aspartic acid) are composed of polymeric micelles formed by electrostatic interactions. Nevertheless, PIC micelles generated using this approach can be delicate under physiological circumstances and may detach and separate due to neutralization by salts and interactions with naturally existing polyelectrolytes or charged proteins. Therefore, it is necessary to stabilize PIC micelles in order to enhance their usefulness in biological settings (Nakamuraet al., 2020).

The solvent evaporation technique entails the disintegration of copolymers and pharmaceuticals in a shared solvent or chemically compatible solvents. When both polymers are dissolved in the solvent and are soluble in water, this is the preferred technique for producing polymeric micelles. A drug-copolymer thin film is produced via solvent evaporation. The introduction of water or buffers results in the spontaneous generation of polymeric micelles charged with drugs. In addition, the micelles are uniformly distributed in size whether processed using a sonicator or high-pressure extruder (Makhmalzadeet al., 2018; Rajablouet al., 2023; Zhaiet al., 2013).

The dialysis technique is employed when the chosen amphiphilic copolymers exhibit limited solubility in water. After dissolving the copolymer and drug in a shared solvent, an aqueous solvent is added to induce the production of micelles. The solution is subjected to prolonged dialyzation against water in order to eliminate the organic solvents. Choosing the appropriate solvent is crucial for this technique, as it directly impacts the physical properties of the micelles and the effectiveness of drug encapsulation (Vinchurkaret al., 2021).

Achieving an optimal ratio of aqueous and organic solvent is crucial. Typical solvents employed in this technique include N,N-dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, tetrahydrofuran, and others (Pignatelloet al., 2022; Islamet al., 2021; Kultheet al., 2012; Nagaichet al., 2013; Shuklaet al., 2021; Maboudiet al., 2024; Luoet al., 2009; Reddyet al., 2015; Jeonget al., 2009; Mouryaet al., 2011; Gaucheret al., 2005; Simõeset al., 2015; Sotoudeganet al., 2016; Cholkaret al., 2012; Florinaset al., 2016; Nakamuraet al., 2020; Makhmalzadeet al., 2018; Rajablouet al., 2023; Zhaiet al.,2013; Vinchurkaret al., 2021; Fesenmeieret al., 2024).

A novel co-axial turbulent jet with co-flow continuous technology has been recently developed for the synthesis of polymeric micelles. Previous studies have shown the use of this technology for the synthesis of liposomes, enabling continuous processing. The approach was demonstrated using a block copolymer of mPEG (5 kD)-PCL as the polymer for drug loading curcumin (Guptaet al., 2020).

Micelles exhibiting low polydispersity indices and high drug loading were generated using the technique. Another benefit of this procedure over the traditional preparation method is the control it provides over the processing settings (Baueret al., 2023).

An in situ charge-neutralization-controlled particle coagulation method has recently been developed for the creation of monodisperse polymeric particles. The anionic surfactant molecules adsorbed on the surface of particles are protected from cationic radicals produced during the breakdown of the initiator, which aid in particle coagulation. Through the use of in situ charge neutralization, both the particle number and the rate of micelle capture for initiator radicals are improved. By streamlining the emulsion polymerization process, the nucleation time of the particles is reduced, and monodisperse particles ranging in size from 200 to 300 nm are produced (Liuet al., 2016).

Another relatively new method for producing polymeric micelles that are sensitive to changes in light intensity and temperature is spiropyran-initiated atom transfer polymerization. With its reversibility, high sensitivity to light, and excellent photo fatigue resistance, spiropyran is among the most useful photochromic chemicals. This approach successfully synthesized various types of multi-responsive polymeric micelles. These micelles include spirogyra chain end groups, PNIPAM blocks, and PMMA (Faganet al., 2021; Chenet al., 2016).

Polymeric micelles are primarily developed to enhance three key aspects of drug performance: (1) the solubilization of hydrophobic or water-insoluble pharmaceuticals, (2) the modulated or prolonged release of a drug, and (3) the selective targeting of a certain cell type or organ (Movassaghianet al., 2015) which will be further elaborated upon below:

The incorporation of the drug into the hydrophobic core of polymeric micelles is the method by which inadequately water-soluble pharmaceuticals are solubilized (González-Iñiguezet al., 2024). The increased permeability and retention (EPR) effect of polymeric micelles can enable the improvement of aqueous formulations of hydrophobic medications, extension of their circulation time in vivo, enhancement of cellular absorption, and passive targeting at tumor sites (Yanget al., 2015).

Numerous studies have previously established that polymeric micelles may greatly improve the water solubility of medicines with low water solubility (Zlotnikovet al., 2023).

Polymeric Micelles (PMs) are of certain interest due to the protection of the hydrophobic drug contained in the micellar hydrophobic core by the outer hydrophilic corona. This corona helps to prevent the elimination of micelles by the mononuclear phagocytic system (MPS) in physical circulation, hence extending the in vivo circulation time owing to its brush-like nanostructure (Sanget al., 2019; Feng et al., 2021).

Micelles as medication carriers can provide several distinct advantages. They have the capacity to enhance the bioavailability of medications with limited solubility and prolong their presence in the bloodstream, therefore facilitating a gradual buildup in the specific area where effects are required. Micelles’ size enables them to gather in regions of the body with bleeding blood vessels and they may be selectively targeted by attaching a particular ligand to their outer surface (Feiet al., 2021).

In the aqueous medium, the micelles are structured in a manner where their outer surface consists of components that exhibit minimal reactivity towards tissue components or blood. This structural characteristic enables micelles to persist in the bloodstream for an extended period without being detected by phagocytic cells or dedicated proteins. A crucial characteristic of micelles as drug carriers is their long-lasting nature (Khan et al., 2024; Serras et al., 2020).

Overall, there are three primary approaches for incorporating medicines into polymer micelle cores; these will be further upon in the subsequent sections:

Through a well-engineered pH or enzyme sensitive linker, a drug is chemically linked to the core, forming a block of co-polymer that may be cleaved to release the drug in its active form inside a cell (Zhou et al., 2017). The conjugate functions as a polymer prodrug that spontaneously structures itself into a core-shell configuration, the structure of the polymer-drug bond and its stability are entirely determined by the pace at which the medication is released. The rate of drug release and the efficacy of the prodrug can be influenced by controlling the type of the polymer-drug linkage and the stability of the drug conjugate linkage (Zhang et al., 2020).

For hydrophobic drug compounds, the physical incorporation or dissolution of pharmaceuticals within block copolymer micelles is often more desirable than micelle-forming polymer-drug conjugates (Iurciuc-Tincu et al., 2021). Indeed, many polymers and drug molecules do not container active functional groups for chemical conjugation, and therefore, specific block copolymers must be designed for a given type of drug. Drugs can be physically incorporated into the fundamental structure of micelles using one of two approaches: (i) by the interaction with the hydrophobic core-forming section of the polymer, or (ii) by conjugating them to the polymer backbone utilizing labile bonds that may be broken under certain conditions to retrieve the active medicament (Ghosh et al., 2022; Perumal et al., 2018).

Micelles may enclose charged macromolecules like nucleic acids and proteins by means of electrostatic interactions, also known as charge neutralization, with block ionomers that have opposing charges. The generation of persistent PIC micelles, which can withstand physiological salt concentrations even in diluted circumstances, is facilitated by the multivalent complexation of charged groups on the core-forming segment of the block copolymer with numerous charged moieties on the payloads (Cabral et al., 2024).

The modulation of gastrointestinal transit time is a problem that can be addressed by extending the duration of medication presence within the gastrointestinal system. Polymeric nanocarriers have become important oral delivery vehicles due to their remarkable bioavailability, excellent drug trapping, controlled release, and low toxicity (El-Helalyet al., 2024; Alsafar et al., 2023).

Drug-loaded micelles in the systemic circulation exhibit extended retention duration and very efficient tissue permeability, enabling them to accumulate in sick tissue for passive targeting. In addition, polymeric micelles with stable, biocompatible, and solubilizing characteristics have attracted significant interest for oral delivery. Moreover, the encapsulated medication can be shielded not only from interaction with the gastrointestinal contents that are likely to cause breakdown and metabolism but also endowed with the properties of sustained-release and direct cellular absorption (Dianet al., 2014).

Drug administration via the intranasal route is the administration of drug formulations through the nose to produce a specific pharmacological effect. The intranasal route offers a non-invasive means of delivering pharmacological substances for target effects on the local, systemic, and Central Nervous System (CNS) (Lampteyet al., 2022). Intranasal administration should improve the drug’s brain bioavailability by overcoming first-pass metabolism, achieving the desired concentration at the target location, reducing undesirable side effects, and bypassing the blood-brain barrier through the olfactory area of the nasal orifice (Bothirajaet al., 2022).

Polymeric micelles are highly favored nanocarriers for brain delivery due to their optimal particle size, which allows them to easily penetrate the blood brain barrier and enhance the Encapsulation Efficiency (EE%) (Elezabyet al., 2017).

Using a nose-to-brain delivery system utilizing PEG-PCL-Tat micelles containing anti-cancer medicines and siRNA to rats with a brain tumor model, we successfully shown the remarkable suppression of brain tumor development and a significant extension of lifespan. Post-entry into the brain, the drug-loaded polymeric micelle should ideally exhibit selectivity towards tumor cells (Kanazawaet al., 2020).

To enhance drug targeting and minimize the side effects of traditional cancer chemotherapy, polymeric micelles have been extensively researched for the treatment of lung cancer. The objective is to investigate the enhanced targeting of micelles by modifying their surface to interact with tumor microenvironment conditions, such as pH or peptide targeting (Ibarra-Sánchezet al., 2022). The effectiveness of these micelles has been tested in a model of pulmonary melanoma metastasis. We investigated the loading of micelles with various drugs, such as antifungal agents for treating lung fungal infections with minimal side effects, and loading peptide-modified micelles with fasudil for pulmonary arterial hypertension to enhance the retention time of micelles in affected arterial cells (Rezazadehet al., 2018).

Ocular medication administration via the formation of multiblock polymers that enhance the solubility, stability, and bioavailability of drugs. Micelles have evolved as highly promising drug delivery systems for the treatment of diverse ocular disorders that impact distinct parts of the eye (Assiriet al., 2024).

Characterized by their amphiphilic properties, these polymers can create micelles in water, therefore facilitating the dissolution of pharmaceuticals that are not easily soluble in water. Micelle production enables the encapsulation of medicinal compounds within the hydrophobic core of the micelle, therefore safeguarding them from degradation and improving their transportation to the intended location within the eye (Safwatet al., 2020).

Polymeric micelles have become important pharmaceutical carriers due to their practical preparation methods, adaptable drug-loading protocols, and ability to host poorly soluble drugs in a dynamic manner. Specifically, adjusting the assembly/disassembly equilibrium of block copolymers controls drug loading/release.

The versatility of PMs formulations offers significant potential and opportunities for further investigation into their utility in medication delivery. The assumption is that PMs have the potential to make substantial contributions to forthcoming oral drug-delivery systems. Currently, research on PMs mostly concentrates on anti-cancer applications. Nevertheless, the effective extension of the uses of PMs in the treatment of various disorders is possible. Significant progress in the delivery of nucleic acids and proteins can also be accomplished via (PMs). Therefore, PMs are now being thoroughly researched and have the potential to be valuable instruments in addressing several outstanding challenges in pharmacological medication delivery.