**6.4 Colorectal cancer**

Colorectal Cancer (CRC) is among the most common malignancy in humans. Its prevalence is increasing despite several advances in therapeutic and diagnostic interventions. CRC is caused due to gradual transformation of epithelial cells found in the intestinal lumen to tumor cells. Cancer treatment aims to utilize an anticancer agent that can induce apoptosis. These days, nanoparticles (NPs) are considered novel anticancer agents. Nanosized titanium dioxide nanoparticles (TiO2 NPs) with about <100 nm diameter possessing whiteness and opacity are publicly accepted. The biological properties of TiO2 NPs depend on their size, physicochemical properties, and surface area since particles with a large surface area are more chemically reactive [138]. Wei et al. reported the green synthesis of TiO2 from the extract of *Calendula officinalis* and evaluated its effects on colorectal carcinoma cell lines WiDr, LS123, DLD-1, and SW1417 [SW-1417]. TiO2 reduced the viability of all colorectal carcinoma cells in a dose-dependent manner [139]. Vigneshwaran et al. synthesized TiO2 nanoparticles from Lactobacillus and evaluated its cytotoxic effects on the HT-29 cell line. They reported ROS generation in HT-29 cells by the treatment with TiO2 NPs and the induction of apoptosis by intrinsic pathway [140].

## **6.5 Cervical cancer**

Cervical cancer is the malignancy of the uterine cervix. It is ranked fourth in commonly occurring cancer in women globally and second in the low and medium Human Development Index (HDI) [141]. The key risk factors include late menopause, increasing age, obesity, elevated estrogen levels, breast cancer, no childbirth, diabetes mellitus, and tamoxifen use. Some gene mutations can also cause cervical cancer [142]. The treatment strategies for cervical cancer include radiotherapy, immunotherapy, and chemotherapy [143]. Due to the severe adverse effects of chemotherapeutic drugs, research interest has been transferred to metallic nanoparticles [144–146].

Titanium nanoparticles can be used with other nanoparticles, such as zinc and silver, to evaluate their anticancer effects on cervical cancer cell lines [147]. Ag/AgBr/ TiO2 nanoparticles effectively eliminated xenograft tumors due to their photocatalytic activity [148]. Thermodynamic therapeutic potential, bioimaging, and doxorubicin delivery to cervical cancer cells by hybridized TiO2 and zinc phthalocyanine nanoparticles were also studied [149]. Yurt et al. synthesized zinc phthalocyanine and hybridized it with TiO2 to evaluate their photodynamic therapeutic effect and nuclear imaging potential. Intracellular localization of ZnPc and ZnPc/TiO2 in cervical adenocarcinoma (HeLa) and breast cancer cells was observed. High uptake of ZnPc/ZnPc-TiO2 by the cervical and breast cancer cells suggested their use as cancer theranostic agents [150]. TiO2 has also been reported to enhance caspase-3 activity and prevent the growth of HeLa cells [151].

### **6.6 Brain cancer**

The brain is probably the most mature organ of the human body, so its protection is a crucial issue [152]. Despite several advancements in developing therapeutic and diagnostic procedures, brain cancer is a great challenge to treat, and a successful therapeutic strategy still cannot be established. The major hurdles to establishing a successful treatment strategy for brain tumors include tumor recurrence, acquired resistance to chemotherapeutic agents, and complex central nervous system structure [153]. Glioblastoma is the most common and dangerous tumor in adults. Despite the availability of various treatments, such as chemotherapy, radiotherapy, and surgical resection, the prognosis is still inferior. Following the diagnosis, the life expectancy of glioblastoma patients is just 12–15 months, and the five-year survival rate is approximately 5% [154].

*Nano Titania Applications in Cancer Theranostics DOI: http://dx.doi.org/10.5772/intechopen.111626*

The blood-brain barrier (BBB) is a highly selective interface responsible for maintaining homeostasis, protecting from harmful agents, and providing all necessary molecules to the brain [155]. Brain disorders and tumors require the drug to cross the BBB to exert its therapeutic effect. Several lipophilic therapeutic agents can pass through the BBB, but due to its selective permeability, several other medications fail to cross it [156, 157]. Various pharmacological agents are considered potentially harmful external agents by the BBB. Thus they are removed by the efflux system, degraded by the enzymes, or hindered from crossing the BBB [158]. Only molecules smaller than 400 Daltons or less than nine hydrogen bonds are BBB permeable. Therefore, several nanomedicine-based approaches have been suggested to facilitate drug delivery across the BBB in the recent past [159, 160].

Nanoparticles have gained much interest in this regard [161–163]. It has been reported that engineered nanomaterials can cause neurotoxicity [164]. TiO2-NPs can induce neurotoxicity due to their ability to cross BBB [165–167]. They are potential candidates for treating glioblastoma multiforme (GBM) and other tumor types. Gene and protein expression analysis revealed the reduction of antitumor drug resistance and metastasis by inhibiting angiogenesis. These characteristics would make TiO2 promising therapeutic agents against cancer, particularly if other chemotherapeutic agents can be combined. Fuster et al. evaluated the anticancer effects of TiO2 NPs and ZnO-NP on the T98G glioblastoma cell line and reported that TiO2 is a more effective anticancer agent than ZnO. They demonstrated that TiO2 exposure disrupted the BBB and induced neuroinflammation and suggested the necessity of risk assessment regarding the TiO2 toxicity in the central nervous system [168]. Using ultrasoundsensitive piezoelectric nanoparticles, Marino et al. delivered electric stimulations to distant glioblastoma cells. Barium titanate NPs were functionalized with antibodies against transferrin receptors to target BBB and glioblastoma cells. The distant ultrasound-mediated piezo-stimulation caused a significant reduction in the proliferation of glioblastoma cells in vitro and greatly enhanced the chemotherapeutic sensitivity when combined with temozolomide [169].

### **6.7 Prostate cancer**

Cancer is the major cause of global mortality after cardiopulmonary arrest [170]. Prostate cancer is the fifth most common cancer worldwide and ranked second in men among common cancer types [171]. The onset of cancer can be characterized by delayed progression, tumor markers, detectable preneoplastic abrasion, and high prevalence [172]. Surgery is a successful option in some cases. However, after a few years, tumor recurrence can shorten chemotherapy as a valuable therapeutic option for prostate cancer. However, associated side effects such as toxicity, fatigue, difficulty breathing, low white blood cell count, and blood clotting hamper their efficacy for tumor eradication [173]. Recently, targeted drug delivery and stimulus-responsive release have minimized toxicity and improved drug delivery and accumulation at the target site [174, 175].

Different inorganic nanoparticles such as TiO2, graphene oxide, iron oxide, and porous silica have been used for drug delivery and anticancer therapeutic agents [173]. TiO2 NPs are considered potent drug carriers and photosensitizers due to their low cost, toxicity, and non-photobleaching characteristics [176, 177]. ROS generation by ultrasound-activated TiO2 NPs has been reported by various studies [29, 178, 179]. However, in comparison to light, ultrasound scattering in the tissue is weaker, making it penetrate deeply without losing energy [33]. Previous studies revealed that

combining TiO2 with rare earth or noble metals can increase ROS quantum yield [29, 180]. Ayca et al. synthesized TiO2 and ZnO NPs. They showed the potent inhibition of the growth of prostate cancer cells (DU-145) by TiO2 and ZnO2 nanocomposites [173]. Ultrasound-activated multifunctional system based on TiO2:Gd@DOX/FA for MRI-guided therapy for prostate cancer was developed by Yuan et al. [181]. This system acts as a sonosensitizer for sonodynamic therapy and drug nanocarriers for pH-responsive drug release. Gd doping to TiO2 improved their sonodynamic ability and their performance in MRI. In vitro and in vivo anticancer treatment proved the efficacy of TiO2:Gd/DOX/FA in inhibiting cancer by ultrasound-responsive chemosonodynamic therapy without damaging other organs and as MRI agents. Aksel et al. showed the formation of apoptotic bodies in the PC3 prostate cancer cell line by TiO2 NPs-mediated photo-sonodynamic therapy [30].

### **6.8 Bladder cancer**

Urothelial bladder cancer is among the most widespread malignancies [182]. It is categorized into two subgroups, i.e., Muscle-Invasive Bladder Cancer (MIBC) and Non-Muscle-Invasive Bladder Cancer (NMIBC). Most bladder cancers are NMIBC at diagnosis. Frequent tumor relapse is found in about 50–70% of NMBIC [183], and 10–15% tend to progress into MIBC [3, 184]. Chemotherapy or Bacillus Calmette-Guérin (BCG) and post-transurethral resection are the therapeutic interventions used [185]. Other therapeutic options are under investigation, including photodynamic therapy, radiotherapy, immunotherapy, gene therapy, and nanodrug delivery system using nanoparticles [186]. Among many therapeutic options, a photodynamic theory is less invasive than any surgical intervention [187]. Under physiological conditions, TiO2 NPs possess promising photodynamic characteristics and are suitable materials for cancer treatment. Studies reported the development of Ti(OH)4 in which peroxide was coated on TiO2 nanoparticles [188, 189]. Ti(OH)4 could absorb visible light and showed equivalent photocatalytic activity upon exposure to UV radiations with 90% greater photocatalytic efficiency than TiO2 NPs. Moreover, Ti(OH)4 can generate hydroxyl radicals when it comes in contact with water, even after numerous photodegradation cycles [188]. In another study, a bladder cancer cell line, MB49, was treated with various concentrations of Ti(OH)4, and the results demonstrated that photo exposure of Ti(OH)4 stimulated ROS generation and induced dose-dependent necrosis in cancer cells [190]. Black TiO2 NPs were used as photosensitizers triggered by near-infrared light with maximum 808 nm absorbance by T24 cells (bladder cancer cells). The cells were incubated with TiO2 NPs and irradiated at 808 nm. The results showed concentration-dependent enhanced antitumor activity by the black TiO2 NPs. Hence, black TiO2 was proven a potent anticancer agent, promising photosensitizer, and maximally active at near-infrared and visible light [191].

### **6.9 Skin cancer**

Skin cancer is the most common human malignancy due to the uncontrolled growth of tumor cells associated with the dermis and epidermis. Patients need recurrent treatment due to the aggravated and repetitive growth of tumor cells and, therefore, suffer from treatment-associated side effects and toxicity. Though the topical chemotherapeutic option is associated with less severe side effects, it is impeded due to the rapid liquifying characteristic of the polymers used in the therapy and tormenting-sized microneedles [192, 193].

### *Nano Titania Applications in Cancer Theranostics DOI: http://dx.doi.org/10.5772/intechopen.111626*

Melanoma is a type of skin cancer that appears in melanocytes (skin cells) [194]. Melanocytes are the producers of melanin, which gives color to the skin [4, 195]. Ultraviolet radiations are the leading cause of melanoma, adversely affecting DNA repair, skin cell growth [196], immunosurveillance, and apoptosis. These adverse reactions allow the activation of oncogene or deactivation of tumor suppressor genes and subsequent tumor development [197]. Clinically, nanoparticles are shown to have the ability of tumor reduction and lessen the side effects [198–200]. Conventional anticancer therapies, including chemotherapy, radiotherapy, and surgery, are associated with the risk of harming adjacent healthy cells. This problem can be overcome using chemotherapeutic agents conjugated nanoparticles that can precisely target tumor cells [201, 202]. TiO2 NPs possess unique characteristics and have been applied in various fields [203]. They also have immunomodulatory effects [204].

Titanium dioxide nanotubes (TNT) offer a larger surface for carrying molecules and have distinct physicochemical properties. They are potent anticancer agents. They have been conjugated with quercetin to evaluate their effect against melanoma. Quercetin is a flavonoid found in fruits and leafy vegetables and possesses antioxidant, antiviral, and anticancer effects. The in vitro anticancer effect of quercetinconjugated TNT (TNT-Qu) was evaluated on melanoma cells (B16F10). The results showed inhibitory effects of TNT-Qu on the migration of B16F10 cells, enhanced DNA fragmentation, and cell cycle arrest in the cells. Moreover, TNT-Qu was more cytotoxic to the B16F10 cells than quercetin or TNT alone [205]. The anticancer effect of TNT-Qu was also evaluated on the B16F10 mouse melanoma model and two-stage chemical carcinogenesis in vivo model. The study's results demonstrated enhanced antitumor effects of TNT-Qu than either of the two alone by the topical application of TNT-Qu. TNT-Qu treatment inhibited tumor growth and increased the survival time of the two-stage chemical carcinogenesis mice models [206]. TiO2 exhibits full-size dependent immunomodulatory effects in the nanorod form [207]. TiO2 NPs were hydrothermally converted to nanorods that greatly enhanced the loading efficiency of resveratrol, which would be a great anticancer agent for skin cancer [208]. Polyvinyl Alcohol (PVA) is biocompatible, hydrophilic, and biodegradable [209]. PVA nanofibers are a dressing material for wound healing [210, 211]. Conjugating a polymeric form of PVA with a pharmaceutical agent improves EPR and facilitates the slow and sustained release of the incorporated drugs [212]. Ekambaram et al. reported the anticancer effect of the green synthesized TiO2 nanorods loaded with resveratrolincorporated nanofibers against skin cancer cells (A431). They found inhibition in cancer cell growth by activating caspase enzymes [213].
