**6. Anticancer effects**

Cancer remains a critical global threat due to severe complications such as unbearable physical pain, severe cytotoxicity, side effects, and compromised therapeutic efficacy of conventional therapeutic strategies, including surgical interventions, chemo- and radiotherapy [61–73]. Various studies are aimed at investigating the new therapeutic approaches, including Photodynamic Therapy (PTD), Chemodynamic Therapy (CDT), Sonodynamic Therapy (SDT), Photothermal Therapy (PTT), Starvation Therapy (ST), and Immunotherapy (IMT) having lower side effects and high-level efficiency [26, 74–79]. New therapeutic approaches have been effectively applied as a substitute to conventional therapies and merged with imaging techniques for diagnosis, which is quite optimistic for the diagnosis and treatment of cancer [80, 81]. Cancer theranostics, a combination of diagnostics and treatment, has recently gained much interest [82]. Several therapeutic strategies can be integrated with various imaging techniques to synthesize multifunctional tumor-targeted nanoprobes, having a significant therapeutic effect and improving tumor identification [83].

In recent years, a newly established field of nanomedicine has been instigated to offer various solutions. Nanomedicine is the implementation of nanomaterials, possessing particle sizes ranging from 1 to 100 nm, to diagnose, observe, prevent, *Nano Titania Applications in Cancer Theranostics DOI: http://dx.doi.org/10.5772/intechopen.111626*

**Figure 3.**

*Different types of cancer that can be treated with nano titania (developed by using BioRender).*

and treat disease [84]. Nanoparticles (NPs) have been extensively used as anticancer therapeutic agents, particularly in cargo delivery, i.e., genes, chemotherapeutic drugs, or contrast agents [70, 85–87], or alone, using their inherent toxicity, e.g., associated with the release of reactive oxygen/nitrogen species [88, 89]. Additionally, nanoparticles can be coated with a chemical or biological material to facilitate their stealth characteristics and minimize their tendency to aggregate in biological fluids. Moreover, they can be coupled with selected ligands to enhance their targeted cell delivery [90]. NPs can impulsively accumulate in the tumors because of the Enhanced Permeability and Retention (EPR) effect. They can easily pass through the tumor vasculature due to large pores, and inadequate lymphatic drainage allows their retention, expediting their therapeutic efficacy without being associated with the targeted ligands [91]. Nano titania-based anticancer therapy is well-known (**Figure 3**). Below are various types of cancers treated with nano titania.

### **6.1 Breast cancer**

Breast cancer is the primary cause of mortality in women ranging from 35 to 55 years of age in industrialized countries. The prevalence of breast cancer is relatively high because the breast is among the most vulnerable organ to malignancy (after the liver, lungs, and stomach) [92, 93]. Conventional treatment modalities

include surgery, chemo-, radio- and hormonal therapy, or a combination of these therapeutic options [94–96]. The complete removal of the tumor is challenging due to limited access to the region for surgery, side effects associated with conventional therapy, and the development of drug resistance. Hence, the five-year survival rate is limited to 20% [97]. Recently, pembrolizumab and atezolizumab, immunotherapeutic drugs, have received FDA approval. However, only triple-negative breast cancer patients can use these therapeutic drugs [98]. Therefore, designing a targeted drug delivery technique for anticancer therapy with minimal cytotoxicity in normal tissues is persistently required [99]. In this context, nanoparticles seemed to be a promising approach possessing low cytotoxicity, target specificity, mature drug distribution in the tumor, and fast elimination of the drug from the body [99–102].

TiO2 nanoparticles are among the prominent nanoparticles with both in vitro and in vivo applications. TiO2 nanoparticles exhibit distinct morphology and surface chemistry, adequate biocompatibility, employ intrinsic biological activity, reduced side effects, and insignificant eco-toxicity [103]. Previously, it was reported that TiO2 induces ROS generation by interfering with the EGFR signaling cascade, leading to apoptosis induction in tumor cells compared to nearby physiological cells [104]. However, there is little information about the therapeutic role of TiO2 in breast cancer compared to conventional therapeutic drugs, i.e., doxorubicin is lacking. Doxorubicin is among the most effective therapeutic drugs in ovarian and breast cancer [105]. However, its clinical application is restricted due to adverse effects, of which cardiotoxicity is the most significant [106]. Iqbal et al. synthesized TiO2 NPs from leaf extract of Zanthoxylum armatum and evaluated their safety and anticancer activity. They demonstrated that TiO2 NPs and doxorubicin were equally effective against breast cancer in vivo and ex vivo. TiO2 NPs exhibited anticancer activity by inducing ROS-dependent cell death in 4 T1 breast cancer cells. In vivo analysis in 4 T1 breast cancer cells containing BALB/c mice revealed that TiO2 NPs exerted doxorubicin comparable to anticancer activity and without any cardiotoxicity and body weight alteration as compared to doxorubicin [107].

Kim et al. analyzed the possible cytotoxicity in breast cancer cells. They used two cell lines, Hs578T and MDA-MB-231, which overexpress Epidermal Growth Factor Receptor (EGFR). EGFR is a transmembrane protein activated by binding growth factors and transmitting cellular signals inducing cell survival and propagation. They tried to elucidate the effect of alterations in extracellular signaling receptors mediated by TiO2 nanoparticles rather than focusing on the toxicity induced by TiO2-mediated ROS generation. They showed that the cytotoxicity caused by TiO2 nanoparticles in breast tumor cells is due to the interference in the EGFR-regulated signaling pathway, which reduced cell adhesion, survival, and propagation, thus inducing apoptosis [104]. Mahendran et al. used *Gloriosa superba* rhizome extract to synthesize crystalline TiO2 nanocatalysts. These TiO2 nanocatalysts caused exorbitant mitochondrial depolarization and DNA damage when treated with MCF-7 cells, primarily due to the persistent release of TiO2 nanoparticles and the generation of free radicals [19].

### **6.2 Pancreatic cancer**

Pancreatic cancer is the third major contributor of deaths caused by cancers in the United States [108], with a five-year survival rate of about 10% only [109, 110]. Only about 15–20% of cancer patients can avail the surgical treatment due to delayed diagnosis [111], and even after tumor resection, the five-year survival rate remains about 20% only [112–114]. Immune Checkpoint Blockade (ICB) therapeutic approaches have been developed which are based on the applicability of monoclonal

antibodies against PD-L1 (programmed cell death ligand 1) and CTLA-4 (cytotoxic T-lymphocyte antigen 4), able to support tumor eradication and protection from recurrence and metastasis [115–118]. However, these approaches failed to exhibit significant results in patients diagnosed with pancreatic cancer [119–121]. Hence, the combination of ICB and therapeutic approaches, able to enhance T-cell infiltration and activation in the tumor, can be promising for treating and preventing tumor relapse and metastasis [122–124].

Ultrasound exposure represents a non-invasive, inexpensive, and well-portable therapeutic tool [125–127] and is well-studied in the perspective of cancer treatment, in addition to its general utilization in imaging systems [126, 128–130]. Ultrasoundactivated sonodynamic therapy (SDT) can cause tumor cell death by inducing high levels of ROS generation, causing apoptotic or necrotic immunogenic cell death [131, 132]. Titanium diselenide (TiSe2) is a 2D transition metal dichalcogenide extensively used in photodynamic therapy due to its good photoresponsivity [133]. Chen et al. synthesized TiSe2 nanosheets and evaluated the combination of TiSe2-mediated sonodynamic therapy with PD-1 blockage for pancreatic cancer treatment in vitro using Pac02 cells and in vivo model of pancreatic cancer. They reported the generation of ROS by TiSe2 nanosheets upon exposure to non-invasive US irradiation and induction of immunogenic death of malignant cells, thereby promoting the maturation of dendritic cells and infiltration of activated T cells within the tumor. Besides inhibiting primary pancreatic tumor growth, this combinatorial therapeutic approach also inhibited the growth of distant tumors and lung metastasis [134].
