***About stimuli-responsive polymers in general
Stimuli-responsive polymers, commonly referred to as smart polymers, are materials that undergo significant and abrupt changes to their physical and chemical properties in response to external stimuli. The defining factor in stimuli-responsive polymers is a characteristically non-linear response to external related stimuli, allowing highly specific functionality even with very small external stimuli.1 This is reliant on the polymeric nature of such molecules, as response is typically binary in these materials, meaning that each subunit will exist either its base structural configuration or stimuli-altered state. Response is uniformly reflected across all monomers, and the sum of the whole affects non-linear response, resulting in drastic changes to the material even when response is minimal for each individual subunit.2 Other key functionalities of these polymers can often lie in their reversible nature. They typically rely on some critical threshold in accordance to their respective properties, in which their response is promoted based on their characteristic properties, with reversible effects observed if conditions recede past the given threshold.2 These properties are well defined in stimuli-responsive materials, and can be fine-tuned towards their requisite environment for a variety of applications, and are of particular important in pharmaceutical and other related biomedical applications.
***About stimuli-responsive polymers in medicine (talk about challenges of drugs, the most prevalent use is in specific targeted drug delivery, end with pH and thermos responsive being the most well represented and important in this field)
Synthetic polymers with these properties are able to effectively mirror biological systems themselves, in which they are able to adapt and alter their properties to remain viable and retain desired functionality as their environment changes.1 The array of stimuli types that can affect a response from sensitive polymers is widely varied, including temperature, electric or magnetic field, mechanical input, pH, or presence and concentration of other chemical compounds. Responses are similarly varied, encompassing variation in physical conformation, solubility, ionization state, hydrophilic and hydrophobic effects, among other factors. 1,2 Given the breadth of properties these materials exhibit, they can play a significant role in overcoming a variety of challenges facing pharmaceutical therapeutics. Many compounds that would otherwise result in a desirable effect in biological systems are faced with issues such as physical and chemical instability, degradation and neutralization before reaching their target, low bioavailability, or toxicity. In consequence, stimuli-responsive polymers can provide an important link between these desirable pharmacological effects and overcoming challenges surrounding them.2 The properties of stimuli-responsive polymers can be applied as a means to specifically targeted drug delivery with controlled rate in stable and biologically active form. it is critical that stimuli-responsive polymers can perform their intended function based on variables inherently present in the respective biological systems. As such, polymeric compounds sensitive to pH and temperature are among the most important and widely studied stimuli-responsive compounds and have immense potential in pharmaceutical applications.1,2
***About thermo-responsive polymers
Thermo-responsive polymers undergo changes based on the external stimulus being temperature related. In almost all cases, these polymers function based on volume phase transitions dependent on a specific temperature, the critical solution temperature, that cause significant changes in the solvation state of the material.3 Polymers which increase solubility upon heating are said to have an upper critical solution temperature, while polymers that become insoluble upon heating have a so called lower critical solution temperature. These critical solution temperature phase transitions are integral to the functionality of thermo-responsive polymers, and phase diagrams, in which a maxima are upper critical solution temperature and a minima are lower critical solution temperatures, detailed in figure 1.1 It is also possible for materials to exhibit both upper and lower critical solution temperature behaviors, with the polymeric material remaining insoluble in a region between the two, but in applicable functions for the requisite biological systems, this is unlikely to occur.1
Figure 1. General phase diagrams for thermo-responsive polymer-solvent mixtures observing a lower critical solution temperature (a) and upper critical solution temperature (b).
While aqueous environment is not necessary for materials to exhibit these properties, it is typically present due to the intended biological system. In most cases, the solubility of a polymer in aqueous solution is dependent on various factors such as molecular weight, temperature, or addition of co-solvents, and variation in these properties can cause a shift or even complete disappearance of upper and lower critical temperature behavior..3 Intra- and intermolecular forces variations are responsible for this change in hydration state. In insoluble form, hydrogen bonding is favored within the polymer molecules, while upon reaching a critical transition temperature it becomes thermodynamically favorable for hydrogen bonding with solvent to occur. The combination of changing hydrogen bonding properties and hydrophobicity variations is often accompanied by a coil-globule transition. Thermo-responsive polymeric chains adopt extended conformations in solution, and often collapse to form compact globuli at the phase transition temperature, and aggregation of these globules and turbidity are observed.1,3 Carefully controlling these competing hydrogen bonding properties is essential in developing thermo-responsive polymers that are viable in biological systems.1
***Synthesis mechanism or other interesting stuff(probably already in by now). Also about thermo hydrogels that simply swell rather than fully dissolving or insoluble
***About pH-responsive polymers
Stimuli-responsive polymers exhibiting pH sensitivity rely on the presence of ionizable pendant groups attached to the hydrophobic polymer backbone, and variation in ionization state of these groups affects both intermolecular forces and solvent interaction. These ionic functional groups are typically weak acids such as carboxylic or sulfonic acids, or basic groups such as amines, imidazoles, or pyridines, and the relationship between pKa of these groups and pH of the system facilitates the donation and acceptance of protons.4 Polymers with these features are classified as either polyacids (polyanions) or polybases (polycations), and are able to function with significant control over system behavior based on these properties.1,4 Given the nature of the intended physiological systems, typically with pH ranges from 3-10, an essential pH-pKa relationship necessity can be established, with the pKa defined as the pH at which half of the ionizable groups are ionized. This relationship is used to design polymeric compounds that will ionize at the specific pH range of their targets, and is critical in successful pH sensitive systems.4
When environmental pH reaches a transition of critical pH, the ionizable groups of pH-responsive polymers will donate or accept H+ ions, resulting in a change is ionization stat. With an overall increase in net charge, the degree of electrostatic repulsion between pendant groups will increase, and will cause the polymeric molecules to shift from a collapsed to expanded state. The reverse must be true as well, and if these polymer chains go from a highly charged to neutral state, they can adapt to similarly compact conformations.4
***Synthesis mechanism or other interesting stuff
***ABOUT USING THESE FOR DRUG DELIVERY, EXAMPLES, ETC. Modern research and applications, controlled drug release, hydrogels, anticancer treatment, poplymer-protein conjugates,
***conclusion
References
1.Schmaljohann, D. Thermo- and pH-responsive polymers in drug delivery. Adv. Drug Deliv. Rev. 2006, 58, 1655-1670.
2. Honey, J.; Rijo, J.; Anju, A.; Anoop, K. Smart polymers for the controlled deliver of drugs – a concise overview. Acta Pharm. Sin. B, 2014, 4, 120-127.
3. Gandhi, A.; Paul, A.; Sen, S.; Sen, K. Studies on thermoresponsive polymers: Phase behavior, drug delivery and biomedical applications. Asian J. Pharm. Sci. 2015, 10, 99-107.
4. Bazban-Shotorbani, S.; Hasani-Sadrabadi, M.; Karkhaneh, A.; Serpooshan, V.; Jacob, K.; Moshaverinia, A.; Mahmoudi, M. Revisiting structure-property relationship of pH-responsive polymers for drug delivery applications. J. Control. Release. 2017, 253, 46-63.