## 4 Drug Delivery
### Light- and Dual-Responsive Drug Delivery  
Light is an advantageous non-invasive exogenous stimulus that can be directed to a target site, and it provides an intriguing platform for drug delivery. However, since UV light is often used to trigger such systems, safety risks, as well as low tissue penetration, are matters of concern. The two main categories of light-responsive polymers that have been explored in drug delivery are those that undergo photochemical cleavage or photoisomerization [143]. For such UV-light induced cleavage, moieties, such as pyrenylmethyl esters, coumarinly esters, and _o_-nitrobenzyls, have been incorporated into polymeric systems [143; 144]. For example, the _o_-nitrobenzyl group was introduced into an ABC (A = PEG, B = poly(2-nitrobenzyl methacrylate) (PNBM), C = PNIPAM) miktoarm star, which could change its micellar morphology, in response to both light and temperature, due to its sensitive PNBM and PNIPAM arms, respectively (Figure 10) [66]. It is well known that the LCST of PNIPAM is 32 \({}^{\circ}\)C, but it was found to be 42 \({}^{\circ}\)C in the miktoarm polymer [145], which was attributed to the low MW of the PNIPAM block, as well as its clustering with PEG in the micellar coronae. Heating an aqueous micelle solution past this temperature increased micelle diameters from 97 to 142 nm, as PNIPAM chains aggregated with PNBM in the core. UV light irradiation was able to cleave and convert the _o_-nitrobenzyl functionalities into _o_-nitrobenzaldehyde and the carboxylic acid, proceeding through a Norrish II type intramolecular rearrangement. This rearrangement does not require an aqueous solvation, and as a result, can occur in micellar cores [146; 66; 147]. In the case of PNBM, UV-induced cleavage of _o_-nitrobenzyl moieties in its side chains converted the polymer to the now hydrophilic PMAA. DLS studies showed that the nanoparticle diameters increased by about 15 nm and had much wider dispersities. Using Nile Red as model cargo, below the LCST and without UV stimulus, its release was found to be negligible, while raising the solution temperature past the LCST only increased the cumulative release of Nile Red to 4.6% after 30 min. In contrast, UV irradiation of the sample led to a 64% release, showing the much stronger effect of converting the constituent polymer of the hydrophobic core into a hydrophilic chain. Figure 6: Structure and \({}^{1}\)O\({}_{2}\)-response of PEG-PCL\({}_{2}\) miktoarm star polymers with \(\beta\)-aminoacrylate junctions to 660 nm light in the presence of Ce6. In the photoisomerization category, azobenzenes, which are known for their ability to transition from trans to cis isomers upon UV irradiation, with an accompanying local polarity increase, are by far the most commonly employed functionalities [143; 144]. This differentiates azobenzene-containing drug carriers from photoleavable systems as they can transition between their \"on\" and \"off\" states, which can allow more precise tuning of drug release at desired sites [46]. A series of azobenzene containing AB\({}_{3}\) miktoarm star polymers (A = PAzo, B = poly(\(N\),\(N\)-diethylacrylamide)) have been synthesized [46]. Using a trifunctional-azido ATRP initiator, the polymerization of an azobenzene-containing methacrylate yielded a PAzo-core structure. It was then coupled with three PDEAA arms using click chemistry to form a miktoarm polymer. The effect of temperature on the miktoarm polymer assemblies was first assessed with DSC, through which an LCST of 27 \({}^{\circ}\)C was determined. PDEAA became hydrophobic above this temperature and resulted in a collapse of the micelle. Temperature reversal led to a partial reassembly. Irradiation of the dual-responsive PAzo-PDEAA\({}_{3}\) micelles also resulted in reversible morphological distortion, as well as an 8 nm increase in their D\({}_{\text{h}}\). While one might assume that temperature-associated changes would lead to cargo release, Nile Red was found to be associated within the collapsed micellar structure.