Draft:Polymeric micelles

Polymeric micelles represent a versatile platform of nanoparticles utilized in targeted drug delivery systems, providing the ability to advance treatment options. Targeted drug delivery research uses many strategies one being these micelles; as they offer a versatile platform for encapsulating therapeutic agents. The strategy of micelles holds promise to enhance drug delivery efficiency, enable treatments of complex diseases, and allow for personalized medicine.

A polymeric micelle is a shell structure formed with amphiphilic block copolymers. The amphiphilic block copolymers are made up of chemically linked, incompatible varying polymer-sized blocks.

What is a Micelle
A micelle is a nanosized colloidal particle that has a hydrophobic core and a hydrophilic surface. Commonly used in drug delivery applications due to their capability of being loaded with therapeutic agents either through the embedment in the hydrophobic core or through covalent interactions on the micelles hydrophilic surface (Polymeric Micelles for Targeted Drug Delivery Systems). Micelles are made up of block copolymers in aqueous solutions. They are amphiphilic, meaning that they have the unique property of having a hydrophilic shell and a hydrophobic core. To alter the potential nanomedical applications and expand the ability to use current micelle-based delivery systems optimization is important.

Loading the therapeutic in the core of the micelle improves the therapeutics' pharmacokinetic profile (i.e. how the body interacts with the therapeutic throughout its exposure). A desirable trait of the micelles is their ability to provide a controlled release mechanism into the circulatory system. Additionally, the design of the micelle helps prevent drug loss and opsonization (an immune response which flags foreign pathogens)

There is a great potential for the improvement of current polymeric micelle drug delivery systems. Certain factors such as toxicity of the therapeutic, PK profile of therapeutic compounds, maximum systemic concentration, clearance, volume of distribution all have room for improvement. Micelles disassemble in response to changes in pH, temperatures, enzyme levels, etc.

Making Polymeric Micelles
Micelles are prepared by various methods: dilution, lyophilization, solvent evaporation, dialysis, and oil-in-water emulsion. Block copolymers, random block copolymers, and grafted polymers are self-assembled into micelles. The type of polymer can widely affect the development of polymeric micelles and can be used as a tool to customize the micelles for specific applications. The copolymers used to form amphiphilic micelles are typically either block copolymers (di, tri, or tetra) or graft copolymers. Graft copolymers consist of a polymer chain that acts as a backbone and polymer chains that branch off of the backbone. Block copolymers use multiple polymers. There are two common methods of preparation used to develop micelles: direct dissolution in a selective solvent for one of the blocks and use of a nonselective solvent for the production of molecularly dissolved chains of block copolymer.

Common Amphiphilic Copolymers for Micelle Synthesis
N-phthaloylcarboxymethylchitosan, Poly(2-ethylhexyl acrylate)-b-poly(acrylic acid), Poly(tert-butyl acrylate)-b-poly(2-vinylpyridine), Poly(ethylene oxide)-b-polycaprolactone, Poly(e-caprolactone)-b-poly(ethylene glycol)-b-poly(e-caprolactone), Poly(e-caprolactone)-b-poly(methacrylic acid), Poly(ethyleneglycol)-b-poly(e-caprolactone-co-trimethylenecarbonate), Poly(aspartic acid)-b-polylactide, Poly(ethylene glycol)-block-poly(aspartate-hydrazide), Poly(N-isopropyl acrylamide-co-methacryl acid)-g-poly(D,L-lactide), Stearic acid-grafted chitosan oligosaccharide

Conventional
Conventional micelles that are formed by the hydrophobic interaction of the core of the micelle and the stabilizing interface (i.e. corona-forming block). Corona separates the core from aqueous environment.

Polyion complex micelles
Polyion complex micelles are formed by electrostatic interactions created by two oppositely charged entities. Oppositely charged polymers are added in the solution and penetrate into the corona of the micelle, generating electrostatic forces. These forces control the size and structure of the micelle corona.

Noncovalently connected polymeric micelles
Noncovalently connected polymeric micelles is a method used to prepare polymeric micelles where hydrogen bonding is used to form the micelle via self assembly. The core and corona of the micelle are connected via H-bonding or metal-ligand interactions.

Types of Polymeric Micelles
Polymeric micelles have numerous opportunities for material adjustment and modification resulting in many different types of polymeric micelles that can be tailored and used.

Trigger Based Polymeric Micelles
Health issues, pathogens, and conditions can elicit changes in a cellular microenvironment; polymeric micelles that have triggered effects based on their response to their environment are divided into categories.

Hypoxia Responsive Polymeric Micelles
Hypoxic conditions indicate low levels of oxygen in a tissue, which is often experienced by tumor cells. When specific polymeric micelles have come in contact with hypoxic cells, certain reactions can occur that initiate the release of the intended drug into the target area. Consistent use of these hypoxia responsive polymeric micelles involves loading the cells with the desired therapeutic compound to then release into the solid tumor environment where the micelle may become misshapen or dissolve completely resulting in the release of the compound. The individual polymers vary depending on the desired application, but most consistently incorporate polyethylene glycol (PEG) for its hydrophilic shell  and a unique polymer for its hydrophobic core, which is used to respond to the hypoxic conditions.

pH Responsive Polymeric Micelles
Intracellular pH changes can occur for reasons not limited to tumor growth. Polymeric micelles can be designed based on the pH environment that the studied condition produces. When the polymeric micelle is in the presence of the identified pH profile, breakdown due to ionization can occur to release the active it holds. These polymeric micelles are typically developed with block polymers whose binding dictate the success of the drug delivery. The surface properties of the micelles is particularly important, as it majorly dictates the receptor responses and resulting reactions leading to destabilization and release. This methodology has proved rather successful when implementing DOX on resistant cells.

Enzyme Responsive Polymeric Micelles
Pathological conditions sometimes result in the body releasing a certain enzyme(s) that is specific to that condition. For these situations, polymeric micelles have been used in varying ways to both directly or indirectly combat pathogenic progress. . Due to the expression of enzymes varying based on the condition being studied, the process and pattern of developing polymeric micelles for the cause is not consistent. That said, most often researchers have seen success when using enzyme- responsive micelles as targeted drug delivery on conditions that cause overexpression of micelle cleaving enzymes, such as MMP-2. The micelle is loaded with the drug, often DOX, and upon introduction to the environment, it is cleaved and the drug is released

Glucose-Sensitive Polymeric Micelles
Glucose-sensitive polymeric micelles are largely developed to provide a way to deliver insulin to diabetic humans. Their use relies on phenylboronic acids due to them being a glucose-responsive polymeric material. More specifically, the study that most current work is based on indicates that to create a polymeric micelle for this cause phenylboronic acids must bind both glucose oxidase and a carbohydrate binding lectin protein. This in turn successfully produces micelles that regulate insulin administration. However there are still issues to fix; the synthesization of phenylboronic esters and the introduction of two monomers, PBDEMA and PPyBDEMA, are two areas that are being studied to improve glucose-sensitive micelles.

Reduction-Sensitive Polymeric Micelles
The development of reduction-sensitive polymeric micelles can be used to enhance current cancer treatment methods. This type of micelle relies on cancer cells often overexpressing antioxidants, which have the ability to combat the positive damage being done by reactive oxygen species. . This is done by targeting the antioxidant produced by the cancer cells, often glutathione, as the method of micelle cleaving by employing reactive oxygen species to create a reduction stimulation. The contact with the antibiotic cleaves the micelle and releases the anticancer agents contained in the micelle

Dual-Responsive and Multi-Responsive Polymeric Micelles
The design of the aforementioned polymeric micelles were isolated to one stimuli type; however, recent work has been conducted to design micelles that will respond to two or three of these stimuli. Successful dual responsiveness stimuli types have included, pH, reduction , glucose , and enzymes. Multi-responsive micelles have been developed that react to light, PH, and temperature, yet less advancement has been seen when looking for the tri-response compared to a dual response. While methods to reach degradation of the polymeric micelles differ in most every study, it is typically a multistep process to get a reaction from one of the stimuli followed by the next, rather than a simultaneous reaction.

Application-Based Polymeric Micelles
The subsequent sections provide an overview of the application of nucleic acids, phytoconstituents, surface engineering methods, ligand conjugation, proteins, and biosensors micelles.

Nucleic Acid-Based Polymeric Micelles
Nucleic acids can alter gene expression and activity to treat specific illnesses, but certain barriers in the body result in the NAs losing effectiveness. An application of the polymeric micelles is to Encapsulate these NA in order to circumvent the loss of effectiveness.

Phytoconstituent-Loaded Polymeric Micelles
Phytoconstituents are compounds in charge of the protection against infection and illnesses. To increase solubility these compounds are coated in pluronic/PCL micelles leading to better uptake of the phytoconstituents. Loading into the Polymeric Micelles has also shown an increase in the bioavailability of orally ingested drugs.

Small Micelles Poor Solubility
The small micelle have limited ability to solubilize hydrophobic drugs effectively. The reduced size results in smaller amounts of drugs getting encapsulated. Potentially leading to inadequate solubility enhancement.

Low Loading Capacity
The limited loading capacity of micelles when encapsulating drugs creates a challenge when the goal is to deliver larger doses that have lower water solubility. An effect of this limitation is higher concentrations or more frequent dosing would be needed in order to achieve therapeutic efficacy.

Poor Implanted Physical Stability
The structural integrity can be compromised due to enzymatic degradation, pH variations, and interactions with biological components. The instability this creates can result in premature drug release or disassembly of the micelle structure.

Insufficient Binding and Uptake by Blood
Micelles can struggle to interact with blood components, such as proteins. The inability to adequately bind to these blood components may lead to rapid clearance from circulation. They are then unable to to reach target tissues or cells.