4.3.1 pH Sensitive

The pH of tumor environment is acidic (6.5–7.2) compared with normal tissues (7.4). These differences in pH have been exploited to cleave the pH-sensitive ligands to release drugs from the micelles carriers. In a nutshell, under physiological condition (pH 7.4) drug molecules are entrapped inside nanomicelles. Therapeutic agents can be released selectively under acidic conditions such as tumor cell, endosomes, or lysosomes. Several pH-sensitive nanomicelles have been developed. The construct generated low toxicity and higher selectivity [68–72]. Anionic groups (poly acrylic acid, poly methacrylic acid, poly glutamic acid) and cationic groups (dimethylamino ethyl methacrylate, poly histidine) are common pH-sensitive components. For example, Bae et al. have prepared pH-sensitive poly(ethylene glycol)-poly(aspartate hydrazone adriamycin)–loaded nanomicelles, which release selectively in the low pH environment due to acid-sensitive hydrazine linker [73].

4.3.2 Temperature Sensitive

Temperature difference of the environment may have an effect on the CMC. The most common polymer is poly(N-isopropylacrylamide), which transforms to a hydrophobic insoluble polymer from hydrophilic polymer around 32°C. Soga et al. have developed another thermosensitive polymeric micelles [74–77].

4.3.3 Light Sensitive

A few studies indicate that hydrophobicity and hydrophilicity of nanomicelles can be shifted under light exposure. Briefly, nanomicelles can be disrupted or reversed by light. This property can be utilized to trigger drug release and delivery [78,79]. Andrew et al. have reported that the micellar system is very sensitive to infrared light causing release of fluorescence probe such as Nile red [80].

Ethylene Diamine Tetraacetate Acid Tetrasodium Salt (EDTA-4Na)

4.3.4 Ultrasound Responsive

Ultrasound can generate a frequency around 20 kHz or more, which can be utilized to enhance tumor drug uptake. Ultrasound has enhanced drug delivery by inducing (1) deeper tissue penetration, (2) perturbation of normal and tumor cell membrane, and (3) drug release from nanomicelle [81–85]. Marin et al. have studied the release and intracellular uptake of doxorubicin (Dox) from pluronic micelles, the most common ultrasound-sensitive nanomicelles. Higher Dox release from pluronic micelles was observed under high-frequency ultrasound [86].

4.3.5 Others

Other stimuli-responsive nanomicelle systems have been studied including enzyme- and redox-responsive systems. Enzymes are known to overexpresses in tumor cells. The oxidative and reductive enzyme expressions vary between intracellular and extracellular environments. Those differences are utilized in developing nanomicelle carrier to deliver drugs to the target.