*4.6. Ultrasound Based Delivery*

Ultrasound (US) is an e fficient stimulus to be used for controlled drug delivery, because of its advantage of being non-invasive, the absence of ionizing radiations in it and its capability to penetrate deep into living tissues by tuning the parameters, such as frequency, duty cycles and exposure times [171,196]. To exploit the US stimulus, the surface of the MSN has been decorated by employing US sensitive components in capping moiety to prevent the premature release of drugs in healthy tissues, e.g., 2-tetrahydropyranyl methacrylate. A hydrophobic monomer with a US-sensitive group can be transformed to hydrophilic methacrylic acid under US stimulus and this phase change can trigger the drug release from MSN pores [197,198]. Shi and co-workers have reported US responsive perfluorohexane encapsulated MSN to be exploited for drug delivery [199,200]. Moreover, Vallet-Regí and co-workers have decorated the MSN surface by using ultrasound-responsive copolymer (poly (2-(2methoxy-ethoxy) ethylmethacrylate-co-2-tetrahydropyranyl methacrylate) [201]. In fact, certain parts of the copolymer having chemical bonds that are cleavable under US radiation can change the hydrophobicity of the copolymer after their US-triggered cleavage, leading the conformational changes in polymer to open the pores of MSN and release the cargo at the target site [201].

## **5. E** ff**ective Combination of Active Targeting Therapy and Stimuli-Responsive Therapy Using MSN in Cancer Therapy**

We have already discussed the various advantages of using MSN for drug delivery. Taken together, MSN exhibit large surface area, porous interior and tunable pore size to act as an excellent reservoir for di fferent drug molecules and other materials of interest. Moreover, the various MSN syntheses approaches, mainly simple and adjustable, o ffer an ease optimization for sizes and shapes to maximize cellular uptake [202–204]. Importantly, one can easily decorate the surface of MSN by attaching small molecules, antibodies, aptamers, carrier proteins or peptide ligands for active targeting specifically to the cancer region, exploiting overexpressed receptors. Meanwhile, the controlled release of drugs to the disease site without any leakage to healthy tissues can be achieved by employing gatekeepers for the end-capping of MSN, triggered by various internal or external stimuli, such as pH, redox, enzyme activity, heat, light or magnetic field [205,206]. To achieve the precise chemotherapy of cancer, the most desired drug delivery system should possess high drug loading e fficiency, site-specificity and the capacity of controlled drug release [207]. Hence, in this part of the review, we will report about the recently tried e fforts for surface modification of MSN, exploiting both the active targeting and stimuli responsive behavior simultaneously (Figure 3), to obtain high e fficacy with low dosage and minimize the o ff-target side e ffects of chemotherapy. Table 1 summarizes these simultaneously employed active targeting and stimuli responsive strategies developed up to date for MSN.

**Figure 3.** Multimodal decoration of MSN to achieve active targeting and stimuli responsive controlled release simultaneously.


**Table 1.** Simultaneously employed active targeting and stimuli responsive strategies using MSN in various cancer types.
