Multifunctional Nanomaterials for Cancer Therapeutics

Cancer is a heterogeneous disease which affects the major population around the globe. The current treatments of cancer include chemotherapy, which is associated with side effects which in turn hinders the efficacy of the drugs in use. With the help of targeted drug delivery, the efficiency of cancer-curing drugs could be improved, along with minimizing their side effects. Delivering the drugs to specific areas could be achieved through stimuli-responsive drug delivery systems. The fabrication of stimuli-responsive carriers are based on the exceptional properties of cancer cells/tissues/microenvironments when compared to the normal cell (Watermann and Brieger, 2017). The ideal characteristics of stimuli-responsive nanoplatforms include: (i) extreme selectivity for tumor microenvironment, and (ii) precession in stimuli responsiveness (Baek et al., 2015). Researchers have developed drug delivery systems in response to stimuli such as PH, temperature, enzymatic activity, etc. In order to attain effectiveness to the fabricated delivery system, these systems are designed with new modifications and functionalization to achieve a multi-stimulus response for cancer applications (Bagheri et al., 2018). Herein, a detailed explanation is discussed for fabrication procedures, along with the diversity in functionalization of mesoporous silica-based nanoplatforms for cancer therapeutics.

pH-Responsive Mesoporous Silica Nanoparticles

Mesoporous silica nanoparticle-based drug delivery systems can be controlled and manipulated through specific stimuli to generate precise responses. The stimulus can be broadly classified into two types, namely endogenous stimulus and exogenous stimulus (Mura et al., 2013). Endogenous stimuli are based on the differences in the microenvironment of normal tissues, when compared to tissues with a pathological condition, such as cancer tissues. These differences include: increased/decreased activity of certain enzymes, change in intercellular/intracellular pH, temperature, higher redox potential (Lin Zhu and Torchilin, 2012). Conversely, exogenous stimuli are generated as a response to physical alterations, like temperature changes, change in electric fields, ultrasound, and magnetic fields. Considering a tumor condition, stimuli in response to change in the pH condition is immensely exploited by researchers, due to differences in the pH of the microenvironment of tumours (~6), when compared to the pH of a normal tissue (-7.4). The difference in the pH across a tumor tissue further broadens when intracellular organelles, such as endosomes (pH=5.5) and lysosomes (pH<5.5) are compared to the extracellular microenvironment of a tumor. This abnormal change in pH values around a tumor region, along with capabilities of mesoporous silica nanoparticles, as a potent drug carrier provides opportunities for fabricated pH- responsive mesoporous silica nanoparticles as drug delivery systems for theranostic applications in the field of oncology (Xing et al., 2012). Wen et al. (2016) studied the conversion of cerium oxide nanoparticles into cerium ions in the reduction environment, like tumor for the development of multifunctional cerium oxide coated mesoporous silica nanoparticles. Cerium oxide nanoparticles could provide a fluorescent off-on platform because of the efficient fluorescence-quenching property of loaded entities, and the effective fluorescence storage capacity during release. The design of triple responsive cerium oxide-coated mesoporous silica nanoparticles were created for the stimuli of an intracellular glutathione and tumor acidic environment that degraded cerium oxide coating and the loading of photosensitizer, hematoporphyrin for light responsiveness of the system, along with the anticancer drug doxorubicin, for therapeutic effect (Wen et al., 2016).

In another approach, mesoporous silica nanoparticles were synthesized using tetraethyl orthosilicate (TEOS) as a silica source, while using a cetyltrimethylammonium bromide (СТАВ) template, and were conjugated with hematoporphyrin-3-Aminopropyl triethoxysilane to fabricate hematoporphyrin-conjugated mesoporous silica nanoparticles. Here, N, N'-dicyclohexylcarbodiimide was used as a condensing agent to mediate the specific reaction between the carboxylic group of hematoporphyrin and the amino group of 3-aminopropyl triethoxysilane to synthesize hematopor- phyrin-3-aminopropyl triethoxysilane. Further, doxorubicin was loaded to hematoporphyrin mesoporous silica nanoparticles before coating with cerium oxide nanoparticles using cerium nitrate as a precursor. This nano-system presented a comparatively high release of doxorubicin in the acidic environment, along with the presence of glutathione and irradiation by 650nm laser. A general understanding of the multi-functionalization of mesoporous silica nanoparticles with a pH-sensitivity is represented in Figure 3.1.

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