Thermoresponsive systems have been intensively studied in cancer therapy. Nanoparticles of iron oxide were coated with a thermosensitive polymer and conjugated with R11 peptides (i.e., prostate cancer-specific peptide) for targeting and imaging of prostate cancer. A magnetic field guides the iron oxide nanoparticles to the desired site. The nanoparticle conjugate showed higher accumulation in the site of the tumor as compared with the nonconjugated nanoparticles (Wadajkar et al., 2013). Doxorubicin hydrochloride was loaded in magnetite nanohydrogels composed of PEG, poly(N-isopropyl acrylamide-co-itaconic anhydride) (P[NIPAAm-co-IA]), and Fe₃O₄ nanoparticles. The resultant system showed negligible drug release at physiological conditions while it exhibited its highest drug release values at a higher temperature around 41ºC and a pH value of about 5.3. This system also exhibited a slow drug release profile and high drug loading capacity. The in vitro cytotoxicity studies of this smart drug delivery system and its cellular uptake results were higher, which makes it a promising drug delivery system (Poorgholy et al., 2018). Many other thermoresponsive systems have been investigated in cancer therapy; some of them are listed in Table 6.10 (Zardad et al., 2016).

Ultrasound-responsive systems for drug delivery have been investigated over the past decade and showed ultrasound triggered the release of the encapsulated therapeutic agents from liposomes, multilayer capsules, microemulsions, and polymeric micelles. Ultrasound can penetrate deeply into tissues noninvasively. Drug release can be triggered by various physical factors after the application of ultrasound such as local hyperthermia, pressure variations, cavitations, and acoustic fluid streaming. Drug delivery systems and stimuli-responsive polymers that respond to either one or more of these stimuli have been developed to enhance targeting of cancer cells (Sirsi and Borden, 2014; Taghizadeh et al., 2015). Polymers that showed an ultrasound-enhanced degradation include poly[bis(p-carboxyphenoxy)]alkane anhydrides, polylactide, and polyglycolide (Bhatnagar and Venuganti, 2015). Ultrasound-responsive nanobubbles loaded with paclitaxel and siRNA’s targeting antiapoptosis genes were developed to overcome the efflux pump-mediated mechanism of drug resistance in hepatocellular carcinoma. After app low-frequency ultrasound to the tumor site, it was observed that this system increased drug penetration into the tumor, which resulted in decreasing tumor volume in mice (Yin et al., 2014). The main advantage of stimuli-responsive drug delivery systems is the ability to control the drug release by endogenous or exogenous stimuli. Unfortunately, these systems can be easily affected by many external factors, which results in problems such as low drug release accuracy and unwanted side effects. To overcome these problems, delivery systems with multistimuli responsive ability have been developed to enhance the accuracy of drug release in the complex pathological environment (Karimi et al., 2016; Zhuang et al., 2013). Many multistimuli responsive systems have been developed for different cancer types; some of these systems are listed in Table 6.11 (Bhatnagar and Venuganti, 2015).