# PolySorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy
## 4 PS-Conjugated Drugs or Drug Carriers  
Substituents conjugated to functional groups of polymeric drug carriers can alter their physicochemical properties and drug loading capacity, consequently affecting their drug delivery efficiency [101; 102; 103; 104; 105]. For example, polyglycerols (PGs) possessing multiple hydroxyl groups, which can be functionalized with other polymers and drugs, have been utilized as versatile drug carriers [103]. Drug-conjugated polymers have been developedto enhance drug stability in systemic circulation and increase drug encapsulation [103]. Conjugation of drugs to polymers via stimuli-responsive linkers has also achieved controlled drug release [104; 105]. For example, hyperbranched PG-polycaprolactone block copolymer (PG-_co_-PCL)-based NPs were developed for controlled delivery of gemcitabine (GEM) [104]. GEM was conjugated to the PG-_co_-PCL through polycarbonate blocks modified with pH-sensitive tertiary amine. The GEM-conjugated NPs were stable at pH 7.4 and released the GEM in pH-dependent manner. Amine-functionalized dendritic PG was also prepared and conjugated to paclitaxel (PTX) via biresponsive ester linkages [105]. PTX was rapidly released under hydrolytic or esterase-rich conditions. The examples mentioned above regarding the functionalization of polymeric drug carriers suggest the strategies for chemical modifications of PSs [103; 104; 105]. PSs bear three hydroxyl groups at the end of the ethylene oxide chains. These hydroxyl groups can be easily functionalized or transformed into various functional groups, including esters, ethers, carbonates, and carbamates. The possible chemical modifications of the PSs are summarized in Figure 4. These functional groups can be used to incorporate chemical drugs and proteins to increase the therapeutic effects and pharmacokinetics of PS-based formulations. Some bioesponsible linkers have also been utilized to achieve controlled drug release. Herein, we summarize recent progress regarding PS-conjugated drugs or drug carriers for biomedical applications. Photo-responsive microgels composed of polymeric \(\beta\)-cyclodextrintrin (P\(\beta\)-CD) and PS 20-coumarin conjugates (TCCs) have been developed [106]. TCC was prepared via covalent conjugation of coumarin to the hydroxyl groups of PS 20. In contrast, P\(\beta\)-CD was prepared by reacting epichlorohydrins with the hydroxyl groups of \(\beta\)-CDs. The addition of TCC to aqueous solutions of P\(\beta\)-CD led to the formation of microgels. The coumarin residue of TCC underwent dimerization and de-dimerization processes upon irradiation, which caused size variation in the particles. The size of the microgels was controlled by UV irradiation at different wavelengths. Irradiation with \(\lambda\) = 365 nm decreased the microgel size, whereas the size of the microgels was increased in response to UV irradiation at 254 nm. This photo-responsive microgel can be used as a drug carrier, and the drug release could be controlled using UV irradiation [107]. Cinnamic acid (CA) was identified as a UV protecting molecule because it absorbs a broad range of UV light. CA was covalently attached to a nonionic PS to obtain a UV absorbing emulsifier [108]. After covalent conjugation with a PS, the nature of molar extinction coefficient of CA residue did not change. This result indicates that CA could absorb  
Figure 4: Possible chemical modifications of PSs. Hydroxyl groups of PS can be functionalized (e.g., esters, carbonates, ethers, carboxylic acids, carbamate, and amines). the UV light after conjugation to the PS. In vitro cytotoxicity of various surfactant-CA conjugates were evaluated, and the cell viability was higher than 80% at the concentration of 0.2% for all the conjugates tested [108; 109]. Amphotericin B (AmB), a polyene antibiotic for the treatment of fungal and leishmaniasis infections, is insoluble in water and exhibits severe toxicity.