Smart polymersMaryam Kazemi

Pharm .D . Ph.D Student of Pharmaceutics

Shiraz University of Medical Sciences

Introduction to smart polymers• Smart polymers or stimuli-responsive polymers undergo large reversible changes, either physical or chemical , in their properties as a consequence of small environmental variations.

Temperature-responsive polymers:

• The three main classes of temperature responsive polymers are:

1. shape-memory materials 2. liquid crystalline materials 3. responsive polymer solutions

LCST & UCST

• When the phase separation occurs at an elevated temperature, this is referred to as lower critical solution temperature (LCST) transition

• while the reversed phase behavior is known as upper critical solution temperature (UCST) transition.

Types:• TRP which shows UCST

One phase above certain tempPhase separation below it

• TRP which shows LCSTMonophasic below a specific tempBiphasic above this temp

Find applications again as biomaterials mostly

Key types of temperature-responsive polymers in aque-ous solution

• Poly(acrylamide)s and poly(vinyl amide)s:• The most commonly studied and first reported thermoresponsive polymer in aqueous solution is poly( N -isopropylacrylamide) (PNIPAM).

• both PNIPAM and PVCL have been reported to be similarly biocompatible• The first established LCST is 32oC for poly(N-isopropylacrylamide) (PNIPAAm) in water solution

• making them ideal candidates for biomedical applications.

• In regard to the very similar properties of both polymers, it is quite surprising that PNIPAM is considered to be the gold standard of thermoresponsive polymers, especially for biomedical applications, and that PVCL has never reached or even come close to such a status.

Poly(oligo ethylene glycol (meth)acrylate)s(POEG(M)A)s

• Similar to PNIPAM and PVCL, multiresponsive POEG(M)As can be obtained by the incorporation of comonomers that respond to other stimuli, such as pH or UV-irradiation.

• interpenetrating polymer networks (IPNs). The absence of chemical bonds between the polymer chains allows a combination of the properties of each polymer and, sometimes, a synergistic effect on the whole properties of IPN s is obvious

UCST polymers• Thermoresponsive polymers with UCST behavior in water are quite

rare.especially in comparison to the rather generally observed LCST behavior.

• The best known type of polymers with UCST behavior in water are the so-called poly(betaine)s, which are zwitterionic polymers comprising both positive and negative charges in every repeat unit

REGEL® DEPOT TECHNOLOGY

• ReGel® is one of MacroMed's proprietary drug delivery systems.

• copolymer of poly (lactide-coglycolide)-poly (ethylene glycol) – poly (lactide-coglycolide)(PLGA-PEG-PLGA) in phosphate buffer saline. (Negative thermoresponsive)this polymer is sutable for hydrophilic large molecule drug delivery and lypophilic molecules.

• Thermally reversible gelling materials, such as ReGel®, are a unique class of compounds be-ing developed for parenteral delivery .

• MacroMed's first product, OncoGel®, is supplied as afrozen formulation of paclitaxel in ReGel® and is entering Phase II trials.

• CytorynTM is MacroMed's immunomodulatory localized peri-tumoral/intra-tumoral delivery system based on a combination of lymphokine interleukin 2 (IL-2) in ReGel®.

 pH-responsive polymers:• pH-sensitive polymers can be defined as polyelectrolytes that include in their structure weak acidic or basic groups that either accept or release protons in response to a change in the environmental pH.

• The acidic or basic groups of these polyelectrolytes can be ionized just like acidic or basic groups of monoacids or monobases; however, complete ionization of these systems is

more difficult due to electrostatic effects exerted by other adjacent ionized groups.

• For example enteric polymers have been used as coatings of tablets for this purpose, ex-amples of which include cellulose acetate butyrate and cellulose acetate phthalat .

these polymers are insoluble at low pH environments, (e.g., the stomach), however they are soluble in the less acidic regions of the gastrointestinal tract.

• A polyelectrolyte is a macromolecule that can dissociate to give polymeric ions when dissolved in water or other ionizing solvents. • Because of the repulsion between charges on the polymer chain, the system expands when it is ionized in a suitable solvent. However, if the solvent prevents ionization of the polyelectrolyte, the dissolved chain remains in a compact, folded state.

• There is a highly promising role of pH-responsive polymer systems for drug and gene delivery in the future.

• Typical examples of pH-sensitive polymers with anionic groups are poly(carboxylic acids) as PAA or poly(methacrylic acid) (PMA) and polysul-fonamides

Poly acrylic acid (PAA), poly vinylacetate diethylaminoacetate , polyethylene glycol (PEG)

Gene carriers:

• Gene carriers: The positively charged polymer-DNA complexes enter the cytoplasm by binding to the negatively charged cell membrane and endocytosis.

• Due to their buffering capacity between pH 5.0 and 7.2, the endosome is ruptured by the increased osmotic pressure after acidification of the endosome, and the

internal contents are released.

• Therefore, cationic polymers can efficiently deliver DNA into the cytoplasm without the help of any colipids as a liposomal compartment.

Biosensors

• the most popular applications of pH-sensitive polymers is the fabrication of insulin delivery systems for the treatment of diabetic patients.

• When there is a rich glucose environment, such as the bloodstream after a meal, the oxidation of glucose to gluconic acid catalyzed by glucose oxidase (GluOx) can lower the pH to approximately 5.8. This enzyme is the most widely used in glucose sensing, and makes possible the use of different types of pH-sensitive HGs for modulated insulin delivery.

 Photo-responsive polymers:• Among all the available stimuli light has recently attracted much attention since the stimu-

lus can be localized in time and space and it can also be triggered from outside the system.• Moreover, most of the photochemical processes involved do not require additional

reagents, and by-products are limited in most of the cases.

• The irradiation parameters, such as light intensity and wavelength and irradiation time, can easily be modulated to adequately comply with the system Photo-responsive polymers undergo a change in their properties in response to a light stimulus.

• Different molecular properties can be light-regulated, including :• 1.conformation• 2 . polarity• 3 .amphiphilicity• 4 .charge • 5. optical chirality• 6 .conjugation

• The light-induced molecular change is reflected in a macroscopic change of material properties like shape (i.e., contraction or bending), wettability, solubility, optical properties, conductivity, adhesion and so on.

• photo-responsive polymers (PRPs), it is very important to know what type of photo-responsive moieties is introduced in the polymer and what is the response of these moieties to a light irradiation. The nature of the photochemical reaction is thus the key parameter for a rational design of photo-responsive materials.

• Several photosensitive moieties, such as onitrobenzyl esters, may undergo an irreversible transformation during the irradiation whereas others can react reversibly (e.g.azobenzenes)

• A second parameter that influences the targeted application is the location of the photo-responsive moiety in the copolymer

Applications of PRPs in Solution

• The main envisioned application of PRPs in solution is light controlled delivery with micelles since light can penetrate to a certain extent into the skin. This characteristics of light can be employed to deliver active molecules (drugs) in a precise area of the body.• With this idea in mind, the simplest design consists of a block copolymer

micelle containing the drug encapsulated into a photo-responsive hydrophobic micellar core.

• Encapsulated nanoparticles into the onitrobenzyl-containing core of aqueous block copolymer micelles loaded with model molecules The accordingly loaded micelles were exposed to NIR light at 980 nm and the photons emitted at λ=350 nm by the up-converting nanoparticles were used for the irreversible photocleavage of the o-nitrobenzylesters. This process thus led to the disruption of the micelles and the release of the initially encapsulated payloads.

• By introducing a light-sensitive chromophore (e.g., trisodium salt of copperchlorophyllin) to PNIPAM hydrogels, visible light-responsive hydrogelswere prepared When light is applied to the hydrogel, the chromophore absorbs the light which is dissipated locally as heat by radiationless transitions, increasing the ‘local’ temperature of the hydrogel. Interestingly, this temperature increase alters the hydrogel swelling behavior.

Magnetically responsive polymer gels and elastomers:

• .Molecular magnets are systems where permanent magnetization and magnetic hysteresis can be achieved as a purely one-molecule phenomenon. These molecular magnets belong to a field that is still at an early stage of development. Their magnetic properties appear at extremely low temperatures and the magnetic response is rather weak

• Superparamagnetic iron oxide nanoparticles (SPIONs) show a great promise for a wide specter of bioapplications, due to their characteristic magnetic properties exhibited only in the presence of magnetic field.

• Their advantages in the fields of magnetic drug targeting and imaging are well established and their safety is assumed, since iron oxide nanoparticles have already been approved for in vivo application, however, according to many literature re-ports the bare metal oxide nanoparticles may cause toxic effects on treated cells

 Enzyme-responsive polymers:

• Enzyme-responsive polymers are unique in their ability to interact with biological surroundings through mechanisms that enable dynamic responses by signal amplification under constant conditions.

• For biological applications, enzymatic stimuli have further advantages. As they are already present in the biological environment, they are able to operate under the required conditions and do not have to be added exter-nally,Currently, enzyme-responsive polymers can be placed in one of four classes:

Thanks for your attention